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Open AccessArticle Regressions of Breast Carcinoma Syngraft Following Treatment with Piperine in Combination with Thymoquinone

by Wamidh H. Talib

Sci. Pharm. 2017, 85(3), 27; doi:10.3390/scipharm85030027

Received: 12 May 2017 / Revised: 26 June 2017 / Accepted: 27 June 2017 / Published: 3 July 2017

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Abstract

Thymoquinone (TQ) and piperine, the active ingredients in cumin (Nigella sativa) and black pepper (Piper longum), respectively, exhibit various bioactivities including anticancer effects. The aim of the present study is to investigate the antineoplastic activity of a combination of

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Thymoquinone (TQ) and piperine, the active ingredients in cumin (Nigella sativa) and black pepper (Piper longum), respectively, exhibit various bioactivities including anticancer effects. The aim of the present study is to investigate the antineoplastic activity of a combination of TQ and piperine against breast cancer implanted in mice. The antiproliferative effects of TQ, piperine, and a combination of both agents were tested against mouse epithelial breast cancer cell line (EMT6/P) using MTT assay. The isobolographic method was used to calculate the combination index (CI). Degree of angiogenesis inhibition was detected by measuring vascular endothelial growth factor (VEGF) levels in tissue culture for all treatments. EMT6/P cells were inoculated in Balb/C mice and the antitumor effect of TQ, piperine, and their combination was assessed. Changes in tumor size were calculated for all treatments. Tumor histology was examined using the hematoxylin/eosin staining protocol. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) colorimetric assay and caspase-3 activity assays were used to detect apoptosis. Serum levels of interferon (INF)-γ, interleukin (IL)-4, IL-2, and IL-10 were measured using ELISA and treatment toxicity was evaluated by measuring serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and creatinine. A clear synergistic antiproliferative interaction between TQ and piperine was observed with CI value of 0.788. The combination therapy resulted in significant reduction in tumor size with percentage cure of 60% and percentage death of 0%. High degrees of apoptosis and geographical necrosis were induced in tumors treated with the combination therapy. Combination therapy caused significant decrease in VEGF expression and increased serum INF-γ levels. Normal serum levels of AST, ALT, and creatinine were observed in tumor-bearing mice treated with the combination therapy. The combination of TQ and piperine acts synergistically to target breast cancer in vitro and in vivo. This novel combination exerts its effect by angiogenesis inhibition, apoptosis induction, and shifting the immune response toward T helper1 response. This combination therapy deserves further investigation (including measurement of hypoxia-inducible factor (HIF)1α to be used in clinical studies. Full article

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Open AccessArticle Development of RP-HPLC, Stability Indicating Method for Degradation Products of Linagliptin in Presence of Metformin HCl by Applying 2 Level Factorial Design; and Identification of Impurity-VII, VIII and IX and Synthesis of Impurity-VII

by Sushant B. Jadhav, P. Sunil Reddy, Kalyanaraman L. Narayanan and Popatrao N. Bhosale

Sci. Pharm. 2017, 85(3), 25; doi:10.3390/scipharm85030025

Received: 21 May 2017 / Revised: 6 June 2017 / Accepted: 7 June 2017 / Published: 27 June 2017

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Abstract

The novel reverse phase-high performance liquid chromatography (RP-HPLC), stability indicating method was developed for determination of linagliptin (LGP) and its related substances in linagliptin and metformin HCl (MET HCl) tablets by implementing design of experiment to understand the critical method parameters and their

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The novel reverse phase-high performance liquid chromatography (RP-HPLC), stability indicating method was developed for determination of linagliptin (LGP) and its related substances in linagliptin and metformin HCl (MET HCl) tablets by implementing design of experiment to understand the critical method parameters and their relation with critical method attributes; to ensure robustness of the method. The separation of nine specified impurities was achieved with a Zorbax SB-Aq 250 × 4.6 mm, 5 µm column, using gradient elution and a detector wavelength of 225 nm, and validated in accordance with International Conference on Harmonization (ICH) guidelines and found to be accurate, precise, reproducible, robust, and specific. The drug was found to be degrading extensively in heat, humidity, basic, and oxidation conditions and was forming degradation products during stability studies. After slight modification in the buffer and the column, the same method was used for liquid chromatography–mass spectrometry (LC-MS) and ultra-performance liquid chromatography -time-of-flight/mass spectrometry UPLC-TOF/MS analysis, to identify m/z and fragmentation of maximum unspecified degradation products i.e., Impurity-VII (7), Impurity-VIII (8), and Impurity-IX (9) formed during stability studies. Based on the results, a degradation pathway for the drug has been proposed and synthesis of Impurity-VII (7) is also discussed to ensure an in-depth understanding of LGP and its related degradation products and optimum performance during the lifetime of the product. Full article

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Open AccessArticle Assessment of Antimicrobial and Antioxidant Activities of Nepeta trachonitica: Analysis of Its Phenolic Compounds Using HPLC-MS/MS

by Ekrem Köksal, Hatice Tohma, Ömer Kılıç, Yusuf Alan, Abdülmelik Aras, İlhami Gülçin and Ercan Bursal

Sci. Pharm. 2017, 85(2), 24; doi:10.3390/scipharm85020024

Received: 5 February 2017 / Revised: 3 May 2017 / Accepted: 11 May 2017 / Published: 15 May 2017

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Abstract

Continuing our work on the sources of natural bioactive compounds, we evaluated the antimicrobial and antioxidant activities of Nepeta trachonitica as well as its major phenolic content using the high-performance liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) technique. For antioxidant activity, ferric reducing antioxidant power

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Continuing our work on the sources of natural bioactive compounds, we evaluated the antimicrobial and antioxidant activities of Nepeta trachonitica as well as its major phenolic content using the high-performance liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) technique. For antioxidant activity, ferric reducing antioxidant power (FRAP) and cupric ion reducing antioxidant capacity (CUPRAC) methods were performed to measure the reducing power and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay was employed to evaluate the radical scavenging activity of the sample. For antimicrobial activity, three Gram-positive and four Gram-negative microbial species as well as three fungi species were tested. N. trachonitica appeared to have reasonable antioxidant activity and decent antimicrobial activity as indicated by the inhibition of the organisms’ growth. The most susceptible species were Bacillus subtilis ATCC 6633 and Escherichia coli ATCC 11229 among the organisms tested. Ethanol extract of the plant has the highest effect on Saccharomyces cerevisiae but no effect on Yarrowia lipolytica. The HPLC-MS/MS analysis showed that at least 11 major phenolic compounds of N. trachonitica exist, the major ones being rosmarinic acid, chlorogenic acid and quinic acid. The obtained results suggest that N. trachonitica could be a promising source for food and nutraceutical industries because of its antimicrobial and antioxidant properties and phenolic compounds. Full article

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Open AccessArticle The Effect of Education through Short Message Service (SMS) Messages on Diabetic Patients Adherence

by Wirawan Adikusuma and Nurul Qiyaam

Sci. Pharm. 2017, 85(2), 23; doi:10.3390/scipharm85020023

Received: 2 March 2017 / Revised: 27 April 2017 / Accepted: 3 May 2017 / Published: 12 May 2017

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Abstract

Poor adherence and a lack of understanding of medication instructions for oral antidiabetic use are key factors that inhibit the control of glycemic levels. The aforementioned situation needs intervention to improve medication adherence and the therapy. This study was conducted with a quasi-experimental

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Poor adherence and a lack of understanding of medication instructions for oral antidiabetic use are key factors that inhibit the control of glycemic levels. The aforementioned situation needs intervention to improve medication adherence and the therapy. This study was conducted with a quasi-experimental design with prospective data collection. The subjects of this study were 50 outpatients with type 2 diabetes melitus (T2DM) who had received oral antidiabetic medicine therapy at least six months prior to adherence measurement. The patients were classified into two groups—the control group and the intervention group. The intervention group received Short Message Service (SMS) messages of diabetes education, while the control group did not. Data collection was conducted by doing interviews and administering the Morisky Medication Adherence Scale (MMAS) questionnaire. The results showed the increase in adherence in the intervention group as 1.15 ± 1.04 and that in the control group as 0.72 ± 0.90. These results indicated that there were significant differences in MMAS score between the control and intervention groups (p < 0.05). The decrease in fasting blood glucose and glucose measured 2 h postprandially was greater in the intervention group than that in the control group. It was concluded that the provision of education through SMS had a positive effect on medication adherence and glycemic levels. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessArticle Evaluation of Rational Drug Use for Acute Pharyngitis Associated with the Incidence and Prevalence of the Disease at Two Community Health Centers in Indonesia

by Cindra T. Yuniar, Kusnandar Anggadiredja and Alfi N. Islamiyah

Sci. Pharm. 2017, 85(2), 22; doi:10.3390/scipharm85020022

Received: 29 December 2016 / Revised: 28 March 2017 / Accepted: 3 April 2017 / Published: 28 April 2017

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Abstract

According to Indonesia’s Result of Basic Health Research of 2013, prevalence of acute respiratory infection in 2007 and 2013 were not significantly different (25.5% and 25.0%, respectively). Identifying the cause of acute pharyngitis is a key point in determining the optimal treatment. The

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According to Indonesia’s Result of Basic Health Research of 2013, prevalence of acute respiratory infection in 2007 and 2013 were not significantly different (25.5% and 25.0%, respectively). Identifying the cause of acute pharyngitis is a key point in determining the optimal treatment. The main purpose is to evaluate the rational use of drugs and its irrational impact as well as the correlation of the drug use with the incidence and prevalence of acute pharyngitis. This study was a descriptive and observational study, carried out retrospectively and concurrently at two community health centers located in Bandung and Cimahi, Indonesia. There was overprescription of antibiotics in 80.01% of prescription cases, with a total of 8.98% being non-treatment option, and 62.43% being irrational use of corticosteroids. The incidence and prevalence of acute pharyngitis at one health center in Bandung were 2.45% and 2.31%, respectively, with an irrationality rate of 83.82%. Those recorded at one health center in Cimahi were 2.11% incidence and 2.00% prevalence with an irrational rate of 91.29%. It can be concluded that there is still an irrational use of medicines in the treatment of acute pharyngitis in community health centers. The higher incidence and prevalence might indicate the declining quality of health services. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessReview Neuroprotective and Cognitive Enhancement Potentials of Angelica gigas Nakai Root: A Review

by Kandhasamy Sowndhararajan and Songmun Kim

Sci. Pharm. 2017, 85(2), 21; doi:10.3390/scipharm85020021

Received: 21 February 2017 / Revised: 25 April 2017 / Accepted: 25 April 2017 / Published: 28 April 2017

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Abstract

Angelica gigas Nakai is an important medicinal plant with health promoting properties that is used to treat many disorders. In traditional herbal medicine, the root of this plant is used to promote blood flow, to treat anemia, and is used as sedative or

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Angelica gigas Nakai is an important medicinal plant with health promoting properties that is used to treat many disorders. In traditional herbal medicine, the root of this plant is used to promote blood flow, to treat anemia, and is used as sedative or tonic agent. The root contains various bioactive metabolites; in particular, decursin and decursinol (pyranocoumarin type components) have been reported to possess various pharmacological properties. Recently, several in vitro and in vivo studies have reported that the crude extracts and isolated components from the root of A. gigas exhibited neuroprotective and cognitive enhancement effects. Neuronal damage or death is the most important factor for many neurodegenerative diseases. In addition, recent studies have clearly demonstrated the possible mechanisms behind the neuroprotective action of extracts/compounds from the root of A. gigas. In the present review, we summarized the neuroprotective and cognitive enhancement effects of extracts and individual compounds from A. gigas root. Full article

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Open AccessArticle Pharmaceutical Equivalence of Clarithromycin Oral Dosage Forms Marketed in Nairobi County, Kenya

by Rebecca O. Manani, Kennedy O. Abuga and Hezekiah K. Chepkwony

Sci. Pharm. 2017, 85(2), 20; doi:10.3390/scipharm85020020

Received: 19 March 2017 / Revised: 19 April 2017 / Accepted: 19 April 2017 / Published: 26 April 2017

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Abstract

Clarithromycin is a broad-spectrum semi-synthetic macrolide indicated for treatment of pneumonias, Helicobacter pylori, and chlamydial and skin infections. The object of this study was to evaluate the pharmaceutical equivalence of 14 generic clarithromycin products marketed in Nairobi County, Kenya, to the innovator

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Clarithromycin is a broad-spectrum semi-synthetic macrolide indicated for treatment of pneumonias, Helicobacter pylori, and chlamydial and skin infections. The object of this study was to evaluate the pharmaceutical equivalence of 14 generic clarithromycin products marketed in Nairobi County, Kenya, to the innovator products, using in vitro dissolution profiles and similarity factors (f₂). Further, dissolution profiles of four innovator formulations manufactured in different sites were compared. Fourteen clarithromycin tablets/capsules and four suspensions were subjected to assay and comparative dissolution runs at pH 1.2, 4.5 and 6.8, for 60 and 90 min, respectively. All products complied with pharmacopoeial assay specifications. However, significant differences were observed in their dissolution profiles. The non-compliance rates for tablets/capsules were 50% at pH 1.2, 33% at pH 4.5 and 50% at pH 6.8, while none of the four suspensions were compliant. Overall, only four (25%) products complied with the specifications for similarity factor. The results obtained indicate that a significant percentage of generic clarithromycin products are pharmaceutically non-equivalent to the innovator products, and that assay and single-point dissolution tests are insufficient demonstration of equivalence between the generic and innovator products. Full article

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Open AccessArticle Antibacterial Activity of Ethanolic Extract of Cinnamon Bark, Honey, and Their Combination Effects against Acne-Causing Bacteria

by Elin Julianti, Kasturi K. Rajah and Irda Fidrianny

Sci. Pharm. 2017, 85(2), 19; doi:10.3390/scipharm85020019

Received: 22 December 2016 / Revised: 29 March 2017 / Accepted: 5 April 2017 / Published: 11 April 2017

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Abstract

Propionibacterium acnes and Staphylococcus epidermidis are the major skin bacteria that cause the formation of acne. The present study was conducted to investigate antibacterial activity of ethanolic extract of cinnamon bark, honey, and their combination against acne bacteria. The antibacterial activity of extract

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Propionibacterium acnes and Staphylococcus epidermidis are the major skin bacteria that cause the formation of acne. The present study was conducted to investigate antibacterial activity of ethanolic extract of cinnamon bark, honey, and their combination against acne bacteria. The antibacterial activity of extract of cinnamon bark and honey were investigated against P. acnes and S. epidermidis using disc diffusion. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were attained using Clinical and Laboratory Standard Institute (CLSI) methods. The interaction between cinnamon bark extract and honey was determined using a checkerboards method. The results showed that the MICs of cinnamon bark extract and honey against P. acne were 256 µg/mL and 50% v/v, respectively, while those against S. epidermidis were 1024 µg/mL and 50% v/v, respectively. The MBC of cinnamon bark extract against P. acnes and S. epidermidis were more than 2048 µg/mL, whereas the MBC for honey against P. acnes and S. epidermidis were 100%. The combination of cinnamon bark extract and honey against P. acnes and S. epidermidis showed additive activity with a fractional inhibitory concentration index (FICI) value of 0.625. Therefore, the combination of cinnamon bark extract and honey has potential activity against acne-causing bacteria. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessArticle The In Vitro–In Vivo Safety Confirmation of PEG-40 Hydrogenated Castor Oil as a Surfactant for Oral Nanoemulsion Formulation

by Heni Rachmawati, Miranti Anggraeni Novel, Sri Ayu, Guntur Berlian, Olivia Mayasari Tandrasasmita, Raymond Rubianto Tjandrawinata and Kusnandar Anggadiredja

Sci. Pharm. 2017, 85(2), 18; doi:10.3390/scipharm85020018

Received: 22 December 2016 / Revised: 13 March 2017 / Accepted: 27 March 2017 / Published: 31 March 2017

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Abstract

Evaluation on the safety use of high concentration of polyoxyl 40 (PEG-40) hydrogenated castor oil as a surfactant for oral nanoemulsion was performed in Webster mice. As previously reported, nearly 20% of PEG-40 hydrogenated castor oil was used to emulsify the glyceryl monooleate

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Evaluation on the safety use of high concentration of polyoxyl 40 (PEG-40) hydrogenated castor oil as a surfactant for oral nanoemulsion was performed in Webster mice. As previously reported, nearly 20% of PEG-40 hydrogenated castor oil was used to emulsify the glyceryl monooleate (GMO) as an oil to the aqueous phase. Thermodynamically stable and spontaneous nanoemulsion was formed by the presence of co-surfactant polyethylene glycol 400 (PEG-400). Standard parameters were analyzed for nanoemulsion including particle size and particle size distribution, the surface charge of nanoemulsion, and morphology. To ensure the safety of this nanoemulsion, several cell lines were used for cytotoxicity study. In addition, 5000 mg/kg body weight (BW) of the blank nanoemulsion was given orally to Webster mice once a day for 14 days. Several parameters such as gross anatomy, body weight, and main organs histopathology were observed. In particular, by considering the in vivo data, it is suggested that nanoemulsion composed with a high amount of PEG-40 hydrogenated castor oil is acceptable for oral delivery of active compounds. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessArticle A PCR-Based Molecular Detection of Strongyloides stercoralis in Human Stool Samples from Tabriz City, Iran

by Reza Ghasemikhah, Mohammad Amin Tabatabaiefar, Seyed Ali Shariatzadeh, Abbas Shahbazi and Teymour Hazratian

Sci. Pharm. 2017, 85(2), 17; doi:10.3390/scipharm85020017

Received: 28 November 2016 / Revised: 15 March 2017 / Accepted: 19 March 2017 / Published: 27 March 2017

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Abstract

Strongyloides stercoralis is a nematode causing serious infections in immunocompromised patients. In chronically infected patients, the low parasitic content as well as the resemblance of the larvae to several other species make diagnosis basedonmorphology difficult. In the present study, a PCR-based method targeting

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Strongyloides stercoralis is a nematode causing serious infections in immunocompromised patients. In chronically infected patients, the low parasitic content as well as the resemblance of the larvae to several other species make diagnosis basedonmorphology difficult. In the present study, a PCR-based method targeting the internal transcribed sequence 2 (ITS2) of the rDNA region was examined for the molecular detection of S. stercoralis infection from the stool samples. A total of 1800 patients were included. Three fresh stool samples were collected per patient, and S. stercoralis isolates were identified by the morphological method. A subset of isolates was later used in the PCR-based method as positive controls. Additionally, negative and no-template controls were included. Data analysis was accomplished using an x² test. Ap-value less than 0.05 was considered significant. In total, fivestool samples were found to be infected with S. stercoralis using the morphology method. PCR method detected S. stercoralis DNA target from all of the fiveDNA samples extracted from positive fecal samples. Conclusions: The PCR method used for amplifying a short fragment was successful for diagnosis of S. stercoralis in fecal samples and can be reliable for directly detecting the parasite bypassing morphological method. Full article

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Open AccessArticle Effect of Vernonia amygdalina Del. Leaf Ethanolic Extract on Intoxicated Male Wistar Rats Liver

by Maria Immaculata Iwo, Sergia Louisa Sjahlim and Siti Farah Rahmawati

Sci. Pharm. 2017, 85(2), 16; doi:10.3390/scipharm85020016

Received: 29 December 2016 / Revised: 16 March 2017 / Accepted: 16 March 2017 / Published: 23 March 2017

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Abstract

Vernonia amygdalina has been shown to have antioxidant activity, and is also expected to have hepatoprotective activity. This study was conducted to study the effect of V. amygdalina ethanol extracts on intoxicated rat livers. Fresh leaves were extracted in ethanol, and the hepatoprotective

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Vernonia amygdalina has been shown to have antioxidant activity, and is also expected to have hepatoprotective activity. This study was conducted to study the effect of V. amygdalina ethanol extracts on intoxicated rat livers. Fresh leaves were extracted in ethanol, and the hepatoprotective activity was tested on male Wistar rats induced with a combination of isoniazid (INH) and rifampicin. Parameters observed were the activity of the enzyme alanine transferase (ALT), serum albumin levels, liver index, and histopathological of the rat liver. The results showed that 50 and 100 mg/kg rat body weight of V. amygdalina ethanol extracts could prevent liver intoxication, starting on day 14. Based on serum albumin concentrations and ALT activity, the high dose extract (100 mg/kg) was more potent as a hepatoprotective agent compared to the extract at a low dose (50 mg/kg). The group of rats treated with a high dose extract showed normal liver index compared to the positive control. Through histology examination, the liver of rats treated with a high dose extract (100 mg/kg) showed minimal liver cell structure damage, and showed similar patterns to the normal rat. Based on these results, it can be concluded that V. amygdalina ethanol extracts can be used to protect the liver in a combination of INH and rifampicin as antituberculosis treatment. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessArticle Stability Study and a 14-Day Oral Dose Toxicity in Rats of Plantain Leaf Extract (Plantago lanceolata L.) Syrup

by Kenza Mansoor, Fadi Qadan, Mathias Schmidt, Eyad Mallah, Wael Abudayyih and Khalid Matalka

Sci. Pharm. 2017, 85(1), 15; doi:10.3390/scipharm85010015

Received: 18 February 2017 / Revised: 15 March 2017 / Accepted: 16 March 2017 / Published: 22 March 2017

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Abstract

Plants have been used since antiquity to treat and prevent diseases. Plantain (Plantago lanceolata L.) is traditionally used for the treatment of the common cold and associated symptoms such as cough. This study was designed to evaluate the oral toxicity of plantain

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Plants have been used since antiquity to treat and prevent diseases. Plantain (Plantago lanceolata L.) is traditionally used for the treatment of the common cold and associated symptoms such as cough. This study was designed to evaluate the oral toxicity of plantain leaf extract-containing syrup. In preparation of the toxicological examination and to ensure the quality of the herbal preparation, analytical methods were developed and validated, and stability testing was performed. Physicochemical and microbial quality, thin layer chromatography patterns and high performance liquid chromatography fingerprints complied with the specifications during the entire period of stability testing. The marker substance, acteoside, remained within the stability-defining limits of 90%–110% for quantitative determinations. No hint of toxicity emerged from 14-day repeat dose toxicity testing in rats. The animals were given doses of 3, 6, or 12 mL of syrup per kg body weight by gavage twice daily. All animals showed normal appearance and behavior. Body and organ weights at the end of the study were similar to those in the control group. Overall, P. lanceolata syrup was found to be stable and non-toxic under the test conditions. Full article

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Open AccessArticle Combination Effect of Antituberculosis Drugs and Ethanolic Extract of Selected Medicinal Plants against Multi-Drug Resistant Mycobacterium tuberculosis Isolates

by Prabasiwi Nur Fauziyah, Elin Yulinah Sukandar and Dhyan Kusuma Ayuningtyas

Sci. Pharm. 2017, 85(1), 14; doi:10.3390/scipharm85010014

Received: 22 December 2016 / Revised: 14 March 2017 / Accepted: 15 March 2017 / Published: 20 March 2017

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Abstract

Adverse drug reaction and resistance to antituberculosis drugs remain the causes of tuberculosis therapeutic failure. This research aimed to find the combination effect of standard antituberculosis drugs with Hibiscus sabdariffa L., Kaempferia galanga L., and Piper crocatum N.E. Br against multi-drug resistant (MDR)

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Adverse drug reaction and resistance to antituberculosis drugs remain the causes of tuberculosis therapeutic failure. This research aimed to find the combination effect of standard antituberculosis drugs with Hibiscus sabdariffa L., Kaempferia galanga L., and Piper crocatum N.E. Br against multi-drug resistant (MDR) Mycobacterium tuberculosis isolates. Two MDR strains (i.e., isoniazid/ethambutol resistant and rifampicin/streptomycin resistant) of M. tuberculosis were inoculated in Löwenstein–Jensen medium containing a combination of standard antituberculosis drugs and ethanolic extracts of H. sabdariffa calyces, K. galanga rhizomes, and P. crocatum leaves using various concentration combinations of drug and extract. The colony numbers were observed for 8 weeks. The effect of the combination was analyzed using the proportion method which was calculated by the mean percentage of inhibition reduction in a number of colonies on drug–extract containing medium compared to extract-free control medium. The results showed that all three plant extracts achieved good combination effects with rifampicin against the rifampicin/streptomycin resistant strain. Antagonistic effects were, however, observed with streptomycin, ethambutol and isoniazid, therefore calling for caution when using these plants in combination with antituberculosis treatment. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

Open AccessArticle Dehydroepiandrosterone (DHEA) Feeding Protects Liver Steatosis in Obese Breast Cancer Rat Model

by Reza Hakkak, Andrea Bell and Soheila Korourian

Sci. Pharm. 2017, 85(1), 13; doi:10.3390/scipharm85010013

Received: 14 February 2017 / Revised: 10 March 2017 / Accepted: 13 March 2017 / Published: 20 March 2017

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Abstract

Obesity is a major health problem in the US and globally. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, cancers, hyperlipidemia, and liver steatosis development. Dehydroepiandrosterone (DHEA) is a dietary supplement used as an anti-obesity supplement. Previously, we reported

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Obesity is a major health problem in the US and globally. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, cancers, hyperlipidemia, and liver steatosis development. Dehydroepiandrosterone (DHEA) is a dietary supplement used as an anti-obesity supplement. Previously, we reported that DHEA feeding protects 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The objectives of this study were to investigate the effects of obesity and DHEA feeding on liver steatosis, body weight gain, and serum DHEA, DHEA sulfate (DHEA-S), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) levels. Female Zucker rats were randomly assigned to either a control diet or a control diet with DHEA supplementation for 155 days. Livers were collected for histological examination. Serum was collected to measure DHEA, DHEA-S, IGF-1, and IGFBP-3. Our results show that DHEA-fed rats had significantly less liver steatosis (p < 0.001) than control-fed rats and gained less weight (p < 0.001). DHEA feeding caused significant decreases (p < 0.001) in the serum levels of IGF-1 and IGFBP-3 and significantly increased (p < 0.001) serum levels of DHEA and DHEA-S. Our results suggest that DHEA feeding can protect against liver steatosis by reducing body weight gain and modulating serum IGF-1 and IGFBP-3 levels in an obese breast cancer rat model. Full article

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Open AccessArticle Alginate-Based Composite Sponges as Gastroretentive Carriers for Curcumin-Loaded Self-Microemulsifying Drug Delivery Systems

by Arpa Petchsomrit, Namfa Sermkaew and Ruedeekorn Wiwattanapatapee

Sci. Pharm. 2017, 85(1), 11; doi:10.3390/scipharm85010011

Received: 19 December 2016 / Revised: 8 March 2017 / Accepted: 8 March 2017 / Published: 15 March 2017

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Abstract

Alginate-based composite sponges were developed as carriers to prolong the gastric retention time and controlled release of curcumin-loaded self-microemulsifying drug delivery systems (Cur-SMEDDS). Liquid Cur-SMEDDS was incorporated into a solution made up of a mixture of polymers and converted into a solid form

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Alginate-based composite sponges were developed as carriers to prolong the gastric retention time and controlled release of curcumin-loaded self-microemulsifying drug delivery systems (Cur-SMEDDS). Liquid Cur-SMEDDS was incorporated into a solution made up of a mixture of polymers and converted into a solid form by freeze-drying. The ratio of alginate as the main polymer, adsorbent (colloidal silicon dioxide), and additional polymers—sodium carboxymethyl cellulose (SCMC), hydroxypropyl methylcellulose (HPMC)—was varied systematically to adjust the drug loading and entrapment efficiency, sponge buoyancy, and the release profile of Cur-SMEDDS. The optimum composite sponge was fabricated from a 4% alginate and 2% HPMC mixed solution. It immediately floated on simulated gastric fluid (SGF, pH 1.2) and remained buoyant over an 8 h period. The formulation exhibited an emulsion droplet size of approximately 30 nm and provided sustained release of Cur-SMEDDS in SGF, reaching 71% within 8 h compared with only 10% release from curcumin powder. This study demonstrates the potential of alginate-based composite sponges combined with self-microemulsifying formulations for gastroretention applications involving poorly soluble compounds. Full article

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Open AccessArticle n-Hexane Insoluble Fraction of Plantago lanceolata Exerts Anti-Inflammatory Activity in Mice by Inhibiting Cyclooxygenase-2 and Reducing Chemokines Levels

by Nanang Fakhrudin, Eny Dwi Astuti, Rini Sulistyawati, Djoko Santosa, Ratna Susandarini, Arief Nurrochmad and Subagus Wahyuono

Sci. Pharm. 2017, 85(1), 12; doi:10.3390/scipharm85010012

Received: 7 February 2017 / Revised: 5 March 2017 / Accepted: 8 March 2017 / Published: 13 March 2017

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Abstract

Inflammation is involved in the progression of many disorders, such as tumors, arthritis, gastritis, and atherosclerosis. Thus, the development of new agents targeting inflammation is still challenging. Medicinal plants have been used traditionally to treat various diseases including inflammation. A previous study has

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Inflammation is involved in the progression of many disorders, such as tumors, arthritis, gastritis, and atherosclerosis. Thus, the development of new agents targeting inflammation is still challenging. Medicinal plants have been used traditionally to treat various diseases including inflammation. A previous study has indicated that dichloromethane extract of P. lanceolata leaves exerts anti-inflammatory activity in an in vitro model. Here, we examined the in vivo anti-inflammatory activities of a n-hexane insoluble fraction of P. lanceolata leaves dichloromethane extract (HIFPL). We first evaluated its potency to reduce paw edema induced by carrageenan, and the expression of the proinflammatory enzyme, cyclooxygenase (COX)-2, in mice. The efficacy of HIFPL to inhibit COX-2 was also evaluated in an in vitro enzymatic assay. We further studied the effect of HIFPL on leukocytes migration in mice induced by thioglycollate. The level of chemokines facilitating the migration of leukocytes was also measured. We found that HIFPL (40, 80, 160 mg/kg) demonstrated anti-inflammatory activities in mice. The HIFPL reduced the volume of paw edema and COX-2 expression. However, HIFPL acts as an unselective COX-2 inhibitor as it inhibited COX-1 with a slightly higher potency. Interestingly, HIFPL strongly inhibited leukocyte migration by reducing the level of chemokines, Interleukine-8 (IL-8) and Monocyte chemoattractant protein-1 (MCP-1). Full article

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Open AccessArticle Six-Month Chronic Toxicity Study of Tamarind Pulp (Tamarindus indica L.) Water Extract

by Irene Iskandar, Finna Setiawan, Lucy D N Sasongko and I Ketut Adnyana

Sci. Pharm. 2017, 85(1), 10; doi:10.3390/scipharm85010010

Received: 22 December 2016 / Revised: 27 February 2017 / Accepted: 27 February 2017 / Published: 8 March 2017

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Abstract

Tamarind water extract has been shown to demonstrate an anti-obesity effect. In this research, long-term use of tamarind pulp water extract safety was evaluated. Tamarind pulp was extracted by reflux method, followed by freeze-drying to obtain dry extract. Wistar rats were divided into

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Tamarind water extract has been shown to demonstrate an anti-obesity effect. In this research, long-term use of tamarind pulp water extract safety was evaluated. Tamarind pulp was extracted by reflux method, followed by freeze-drying to obtain dry extract. Wistar rats were divided into six groups, with 20 animals of each sex per group. The control group and satellite control group received carboxymethylcellulose sodium (CMC-Na) 0.5% 1 mL/100 g bw (body weight) per day. Treatment groups received tamarind pulp extract at doses of 75, 200, 1000, satellite 1000 mg/kg bw per day for six months. After six months, control groups and the treatment group were sacrificed. Satellite groups were sacrificed one month later. Relative organ weights, hematology and clinical biochemistry profiles were determined. After six months, there were no significant change in body weight, hematologic, and clinical biochemistry profiles of the tested group. Body weight of male rats in the satellite 1000 mg/kg bw group was significantly increased in week 30 compared to the satellite control group (p < 0.05). The relative spleen weight of female rats of the 200 mg/kg bw group was reduced (p < 0.05). The relative kidney weight of male rats in the 1000 mg/kg bw group was increased (p < 0.05). This study showed that tamarind pulp extract was generally safe and well tolerated at the tested dose. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessArticle Serum Cystatin C as a Biomarker in Diffuse Large B-Cell Lymphoma

by Nada E. Hammouda, Manal A. Salah El-Din, Mamdouh M. El-Shishtawy and Amal M. El-Gayar

Sci. Pharm. 2017, 85(1), 9; doi:10.3390/scipharm85010009

Received: 22 October 2016 / Revised: 28 February 2017 / Accepted: 28 February 2017 / Published: 8 March 2017

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Abstract

Elevated serum levels of cystatin C are found to be related to poor outcome and metastatic potential of some malignant disorders. To evaluate the clinical prominence of serum cystatin C in diffuse large B-cell lymphoma (DLBCL), blood samples were obtained from 58 patients

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Elevated serum levels of cystatin C are found to be related to poor outcome and metastatic potential of some malignant disorders. To evaluate the clinical prominence of serum cystatin C in diffuse large B-cell lymphoma (DLBCL), blood samples were obtained from 58 patients at the time of diagnosis and paired blood samples were obtained from 22 patients at the time of remission. Also, serum cystatin C level was measured in matched healthy controls. Serum cystatin C levels were significantly more elevated in DLBCL patients than in controls (p < 0.0001). Furthermore, paired-sample analysis revealed that pretreatment cystatin C levels were reduced significantly in patients who achieved remission after therapy (p = 0.016). High serum cystatin C levels were correlated with age over 60 years (p = 0.049), extra-nodal involvement (p = 0.005) and with high serum lactate dehydrogenase (LDH) (p < 0.013). Elevated serum cystatin C levels were associated with extra-nodal involvement and they were significantly reduced to normal range after the remission. However, Kaplan–Meier curves revealed no survival difference in the pretreatment serum cystatin C levels. Therefore, serum cystatin C may be a novel biomarker that reflects tumor burden in DLBCL but bears no prognostic significance regarding survival. Full article

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Open AccessArticle Anticancer Dose Adjustment for Patients with Renal and Hepatic Dysfunction: From Scientific Evidence to Clinical Application

by Tomi Hendrayana, André Wilmer, Verena Kurth, Ingo GH Schmidt-Wolf and Ulrich Jaehde

Sci. Pharm. 2017, 85(1), 8; doi:10.3390/scipharm85010008

Received: 22 December 2016 / Revised: 4 February 2017 / Accepted: 20 February 2017 / Published: 27 February 2017

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Abstract

Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study aimed at providing health professionals with a feasible and time-saving tool to adapt

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Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study aimed at providing health professionals with a feasible and time-saving tool to adapt the dose of anticancer agents for patients with renal or hepatic dysfunction. A guideline for anticancer agents was developed based on a literature search. An algorithm was generated to enhance the efficiency of the dose adaptation process. Finally, the dosing guideline was converted into an easy-to-use Excel^TM tool. The concept was applied to a total of 105 adult patients at the Centre for Integrated Oncology, Bonn, Germany. In total, 392 recommendations for dose adaptation were made and 320 (81.6%) recommendations were responded to by the oncologists. 98.4% of the recommendations were accepted. The algorithm simplifies the decision and screening process for high-risk patients. Moreover, it provides the possibility to quickly decide which laboratory tests are required and whether a dose adjustment for a particular anticancer drug is needed. The Excel^TM tool provides a recommended individual dose for patients with renal or hepatic dysfunction. The effectiveness of this strategy to reduce toxicity should be investigated in further studies before being adopted for routine use. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessArticle Antimutagenic Activity of Ethanol Extract of Rhaphidophora pinnata (L.f) Schott Leaves on Mice

by Masfria, Sumaiyah and Aminah Dalimunthe

Sci. Pharm. 2017, 85(1), 7; doi:10.3390/scipharm85010007

Received: 22 December 2016 / Revised: 7 February 2017 / Accepted: 2 February 2017 / Published: 17 February 2017

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Abstract

Rhaphidophora pinnata is suggested to prevent or treat cancer of genetic mutations. In this study, antimutagenic activity of an ethanol extract of Rhaphidophora pinnata leaves was evaluated by using a bone marrow micronucleus assay on mice. Male mice (20–30 g) were treated for

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Rhaphidophora pinnata is suggested to prevent or treat cancer of genetic mutations. In this study, antimutagenic activity of an ethanol extract of Rhaphidophora pinnata leaves was evaluated by using a bone marrow micronucleus assay on mice. Male mice (20–30 g) were treated for sevendays with an ethanol extract of Rhaphidophora pinnata leaves at a dose of 500, 750 and 1000 mg/kg/day/orally, prior to exposure to cyclophosphamide (i.p. 30 mg/kg), 24 h after the end of the treatment. Antimutagenic activity was determined by the decrease of micronuclei (MN). The results showed that a single administration of all variant doses of the extract had significantly decreased the micronucleus formation in bone marrow cell of mice as compared to the cyclophosphamide group. The ethanol extract of Rhaphidophora pinnata leaves had antimutagenic activity against cyclophosphamide-induced gene mutation. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

Open AccessArticle A Validated Stability-Indicating HPLC Method for Simultaneous Determination of Amoxicillin and Enrofloxacin Combination in an Injectable Suspension

by Nidal Batrawi, Shorouq Wahdan and Fuad Al-Rimawi

Sci. Pharm. 2017, 85(1), 6; doi:10.3390/scipharm85010006

Received: 12 November 2016 / Revised: 2 February 2017 / Accepted: 2 February 2017 / Published: 16 February 2017

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Abstract

The combination of amoxicillin and enrofloxacin is a well-known mixture of veterinary drugs; it is used for the treatment of Gram-positive and Gram-negative bacteria. In the scientific literature, there is no high-performance liquid chromatography (HPLC)-UV method for the simultaneous determination of this combination.

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The combination of amoxicillin and enrofloxacin is a well-known mixture of veterinary drugs; it is used for the treatment of Gram-positive and Gram-negative bacteria. In the scientific literature, there is no high-performance liquid chromatography (HPLC)-UV method for the simultaneous determination of this combination. The objective of this work is to develop and validate an HPLC method for the determination of this combination. In this regard, a new, simple and efficient reversed-phase HPLC method for simultaneous qualitative and quantitative determination of amoxicillin and enrofloxacin, in an injectable preparation with a mixture of inactive excipients, has been developed and validated. The HPLC separation method was performed using a reversed-phase (RP)-C18e (250 mm × 4.0 mm, 5 μm) column at room temperature, with a gradient mobile phase of acetonitrile and phosphate buffer containing methanol at pH 5.0, a flow rate of 0.8 mL/min and ultraviolet detection at 267 nm. This method was validated in accordance with the Food and Drug Administration (FDA) and the International Conference on Harmonisation (ICH) guidelines and showed excellent linearity, accuracy, precision, specificity, robustness, ruggedness, and system suitability results within the acceptance criteria. A stability-indicating study was also carried out and indicated that this method can also be used for purity and degradation evaluation of these formulations. Full article

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Open AccessArticle Transmission Electron Microscopy of XDR Mycobacterium tuberculosis Isolates Grown on High Dose of Oﬂoxacin

by Mohammad Arjomandzadegan, Maryam Sadrnia, Leonid Titov, Larissa Surkova, Hossein Sarmadian, Reza Ghasemikhah and Hossein Hosseiny

Sci. Pharm. 2017, 85(1), 3; doi:10.3390/scipharm85010003

Received: 23 September 2016 / Accepted: 3 January 2017 / Published: 2 February 2017

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Abstract

The aim of the study was to investigate behavior of resistant Mycobacterium tuberculosis (MTB) isolates under a high dose of oﬂoxacin and its morphological changes. 19 extensively drug resistant (XDR) clinical isolates of MTB were grown on Löwenstein–Jensen medium containing progressively increasing concentrations

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The aim of the study was to investigate behavior of resistant Mycobacterium tuberculosis (MTB) isolates under a high dose of oﬂoxacin and its morphological changes. 19 extensively drug resistant (XDR) clinical isolates of MTB were grown on Löwenstein–Jensen medium containing progressively increasing concentrations of oﬂoxacin (2, 4, 8, 16, 32 mg/L). Ultra-structure analyses of resistant isolates grown on oﬂoxacin were conducted by transmission electron microscopy (TEM). Fixation was carried out by 4% glutaraldehyde in 0.1 M sodium cacodylate buffer on 300 mesh carbon formvar copper grid. The samples were negatively stained with uranium acetate suspension. All19XDRMTBisolatesweregrownandformedcoloniessuccessfullyon2,4,8mg/L,sevenisolates on16mg/L,andfourisolateson32mg/Loﬂoxacin. Morphologicalchangesandunusualformswere detected in 8, 16 and 32 mg/L oﬂoxacin at 43%, 76.5% and 81% of cells, respectively. Swollen form (protoplast like), ghost-like cell, degraded forms, and in a few cases, detached cytoplasm from cell wall were clearly detected in high drug concentrations in comparison to control. Changes in morphology were increased with increasing oﬂoxacin concentrations (p < 0.05). Some XDR isolates could be successfully grown on high doses of oﬂoxacin (32 mg/L), but with changes in morphology. It was concluded that several magnitudes of the drug doses could not prevent growth of drug resistant forms. Full article

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Open AccessArticle Natural Products as New Treatment Options for Trichomoniasis: A Molecular Docking Investigation

by Mary Snow Setzer, Kendall G. Byler, Ifedayo Victor Ogungbe and William N. Setzer

Sci. Pharm. 2017, 85(1), 5; doi:10.3390/scipharm85010005

Received: 16 November 2016 / Accepted: 23 January 2017 / Published: 27 January 2017

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Abstract

Trichomoniasis, caused by the parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually-transmitted disease, and there can be severe complications from trichomoniasis. Antibiotic resistance in T. vaginalis is increasing, but there are currently no alternatives treatment options. There is a need

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Trichomoniasis, caused by the parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually-transmitted disease, and there can be severe complications from trichomoniasis. Antibiotic resistance in T. vaginalis is increasing, but there are currently no alternatives treatment options. There is a need to discover and develop new chemotherapeutic alternatives. Plant-derived natural products have long served as sources for new medicinal agents, as well as new leads for drug discovery and development. In this work, we have carried out an in silico screening of 952 antiprotozoal phytochemicals with specific protein drug targets of T. vaginalis. A total of 42 compounds showed remarkable docking properties to T. vaginalis methionine gamma-lyase (TvMGL) and to T. vaginalis purine nucleoside phosphorylase (TvPNP). The most promising ligands were polyphenolic compounds, and several of these showed docking properties superior to either co-crystallized ligands or synthetic enzyme inhibitors. Full article

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Open AccessArticle Chrysin Protects Rat Kidney from Paracetamol-Induced Oxidative Stress, Inflammation, Apoptosis, and Autophagy: A Multi-Biomarker Approach

by Fatih Mehmet Kandemir, Sefa Kucukler, Eyup Eldutar, Cuneyt Caglayan and İlhami Gülçin

Sci. Pharm. 2017, 85(1), 4; doi:10.3390/scipharm85010004

Received: 20 November 2016 / Revised: 6 January 2017 / Accepted: 16 January 2017 / Published: 26 January 2017

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Abstract

Paracetamol (PC) is a safe analgesic and antipyretic drug at therapeutic doses, and it is widely used in clinics. However, at high doses, it can induce hepatotoxicity and nephrotoxicity. Chrysin (CR) is a natural flavonoid that has biological activities that include being an

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Paracetamol (PC) is a safe analgesic and antipyretic drug at therapeutic doses, and it is widely used in clinics. However, at high doses, it can induce hepatotoxicity and nephrotoxicity. Chrysin (CR) is a natural flavonoid that has biological activities that include being an antioxidant, an anti-inflammatory, and an anti-cancer agent. The main objective of this study was to investigate the efficacy of CR against PC-induced nephrotoxicity in rats. CR was given orally via feeding needle to male Sprague Dawley rats as a single daily dose of 25 or 50 mg/kg for six days. PC was administered orally via feeding needle as a single dose on the sixth day. PC caused significant glutathione depletion, lipid peroxidation, increased serum toxicity markers (serum urea and creatinine), and reductions in activities of antioxidant enzymes (superoxide dismutase — SOD, catalase — CAT, and glutathione peroxidase — GPx). The renal protective effect of CR was associated with decreasing the regulation of serum renal toxicity markers and increasing the regulation of antioxidant enzyme activities. Additionally, PC led to significant increases in the levels of inflammatory markers including tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-33 (IL-33). Furthermore, PC induced apoptotic tissue damage by increasing cysteine aspartate-specific protease-3 (caspase-3) activity and autophagic tissue damage by increasing the expression of light chain 3B (LC3B). CR therapy significantly decreased these values in rats. This study demonstrated that CR has antioxidant, anti-apoptotic, anti-inflammatory and anti-autophagic effects on PC-induced kidney toxicity in rats. Full article

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Open AccessArticle New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ⁶,1-Benzothiazine-3-Carboxylates

by Liliana Azotla-Cruz, Irina V. Lijanova, Igor V. Ukrainets, Natalya V. Likhanova, Octavio Olivares-Xometl and Natalya L. Bereznyakova

Sci. Pharm. 2017, 85(1), 2; doi:10.3390/scipharm85010002

Received: 27 November 2016 / Revised: 3 January 2017 / Accepted: 4 January 2017 / Published: 12 January 2017

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Abstract

According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction

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According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N-alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K₂CO₃ system the reaction of methyl 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (¹Н and ¹³С) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models. Full article

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Open AccessArticle Interaction between DNA and Drugs Having Protonable Basic Groups: Characterization through Affinity Constants, Drug Release Kinetics, and Conformational Changes

by Liliana P. Alarcón, Yolima Baena and Rubén H. Manzo

Sci. Pharm. 2017, 85(1), 1; doi:10.3390/scipharm85010001

Received: 27 October 2016 / Revised: 16 December 2016 / Accepted: 22 December 2016 / Published: 4 January 2017

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Abstract

This paper reports the in vitro characterization of the interaction between the phosphate groups of DNA and the protonated species of drugs with basic groups through the determination of the affinity constants, the reversibility of the interaction, and the effect on the secondary

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This paper reports the in vitro characterization of the interaction between the phosphate groups of DNA and the protonated species of drugs with basic groups through the determination of the affinity constants, the reversibility of the interaction, and the effect on the secondary structure of the macromolecule. Affinity constants of the counterionic condensation DNA–drug were in the order of 10⁶. The negative electrokinetic potential of DNA decreased with the increase of the proportion of loading drugs. The drugs were slowly released from the DNA–drug complexes and had release kinetics consistent with the high degree of counterionic condensation. The circular dichroism profile of DNA was not modified by complexation with atenolol, lidocaine, or timolol, but was significantly altered by the more lipophilic drugs benzydamine and propranolol, revealing modifications in the secondary structure of the DNA. The in vitro characterization of such interactions provides a physicochemical basis that would contribute to identify the effects of this kind of drugs in cellular cultures, as well as side effects observed under their clinical use. Moreover, this methodology could also be projected to the fields of intracellular DNA transfection and the use of DNA as a carrier of active drugs. Full article

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Open AccessCorrection Correction: Budiarto, Bugi Ratno and Desriani. Detection of HER2 Gene Polymorphism in Breast Cancer: PCR Optimization Study. Sci. Pharm. 2016, 84, 103–111

by Bugi Ratno Budiarto and Desriani

Sci. Pharm. 2016, 84(4), 753; doi:10.3390/scipharm84040753

Received: 21 November 2016 / Revised: 1 December 2016 / Accepted: 21 November 2016 / Published: 2 December 2016

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Abstract The authors wish to make the following corrections to their paper [1]:[...] Full article

Open AccessAddendum Addendum: Šarić-Kundalić, B.; Fialová, S.; Dobeš, C.; Ölzant, S.; Tekeľová, D.; Grančai, D.; Reznicek, G.; Saukel, J. Multivariate Numerical Taxonomy of Mentha Species, Hybrids, Varieties and Cultivars. Sci. Pharm. 2009, 77, 851–876

by Broza Šarić-Kundalić, Silvia Fialová, Christoph Dobeš, Silvester Ölzant, Daniela Tekeľová, Daniel Grančai, Gottfried Reznicek and Johannes Saukel

Sci. Pharm. 2016, 84(4), 752; doi:10.3390/scipharm84040752

Received: 21 November 2016 / Revised: 2 December 2016 / Accepted: 21 November 2016 / Published: 2 December 2016

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Abstract In the published paper [1], the following plant species are listed: Mentha longifolia var. lavanduliodora, Mentha spicata and Mentha spicata var. crispa.[...] Full article

Open AccessReview Influence of Fragrances on Human Psychophysiological Activity: With Special Reference to Human Electroencephalographic Response

by Kandhasamy Sowndhararajan and Songmun Kim

Sci. Pharm. 2016, 84(4), 724-751; doi:10.3390/scipharm84040724

Received: 10 October 2016 / Revised: 14 November 2016 / Accepted: 21 November 2016 / Published: 29 November 2016

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Abstract

The influence of fragrances such as perfumes and room fresheners on the psychophysiological activities of humans has been known for a long time, and its significance is gradually increasing in the medicinal and cosmetic industries. A fragrance consists of volatile chemicals with a

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The influence of fragrances such as perfumes and room fresheners on the psychophysiological activities of humans has been known for a long time, and its significance is gradually increasing in the medicinal and cosmetic industries. A fragrance consists of volatile chemicals with a molecular weight of less than 300 Da that humans perceive through the olfactory system. In humans, about 300 active olfactory receptor genes are devoted to detecting thousands of different fragrance molecules through a large family of olfactory receptors of a diverse protein sequence. The sense of smell plays an important role in the physiological effects of mood, stress, and working capacity. Electrophysiological studies have revealed that various fragrances affected spontaneous brain activities and cognitive functions, which are measured by an electroencephalograph (EEG). The EEG is a good temporal measure of responses in the central nervous system and it provides information about the physiological state of the brain both in health and disease. The EEG power spectrum is classified into different frequency bands such as delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz) and gamma (30–50 Hz), and each band is correlated with different features of brain states. A quantitative EEG uses computer software to provide the topographic mapping of the brain activity in frontal, temporal, parietal and occipital brain regions. It is well known that decreases of alpha and beta activities and increases of delta and theta activities are associated with brain pathology and general cognitive decline. In the last few decades, many scientific studies were conducted to investigate the effect of inhalation of aroma on human brain functions. The studies have suggested a significant role for olfactory stimulation in the alteration of cognition, mood, and social behavior. This review aims to evaluate the available literature regarding the influence of fragrances on the psychophysiological activities of humans with special reference to EEG changes. Full article

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Open AccessArticle A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexole

by Ratih S. I. Putri, Effi Setiawati, Syifa A. Aziswan, Fenny Ong, Raymond R. Tjandrawinata and Liana W. Susanto

Sci. Pharm. 2016, 84(4), 715-723; doi:10.3390/scipharm84040715

Received: 5 September 2016 / Revised: 7 November 2016 / Accepted: 14 November 2016 / Published: 18 November 2016

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Abstract

The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of

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The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of pramipexole evaluated in the study was manufactured by PT Dexa Medica, Palembang, Indonesia, the other, used as the reference, by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. All eligible subjects were required to fast before each drug administration period, which was separated by a one-week washout period. Pramipexole concentrations in plasma were assayed using a validated ultra performance liquid chromatography with mass spectrometry (UPLC-MS/MS) detector. The evaluated pharmacokinetic parameters included the area under the plasma concentration curve from time zero to the last observed measurable concentration (AUC_0-t), the area under the plasma concentration curve extrapolated to infinite time (AUC_0-∞), the maximum plasma concentration (C_max), the time to reach C_max (t_max), and the plasma concentration half-life (t_1/2). To evaluate the bioequivalence of those two pramipexole formulations, 90% confidence intervals (CIs) for geometric mean ratios of both formulations were calculated for AUC and C_max parameters, while t_max and t_1/2 differences were analyzed on the non-transformed data using Wilcoxon matched-pairs and a Student’s paired t-test, respectively. The 90% CIs for the geometric mean ratios of the two pramipexole formulations were 95.89% (90.73%–101.34%), 95.53% (89.75%–101.68%), and 92.11% (84.35%–100.58%) for AUC_0-t, AUC_0-∞, and C_max, respectively. There were no statistically significant differences for t_max and t_1/2 between the two pramipexole formulations. It is concluded that two pramipexole formulations in this study were bioequivalent. Full article

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Open AccessArticle Synthesis, Spatial Structure and Analgesic Activity of Sodium 3-Benzylaminocarbonyl-1-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazin-4-olate Solvates

by Igor V. Ukrainets, Lidiya A. Petrushova, Svitlana V. Shishkina, Lina A. Grinevich and Galina Sim

Sci. Pharm. 2016, 84(4), 705-714; doi:10.3390/scipharm84040705

Received: 5 August 2016 / Accepted: 19 September 2016 / Published: 19 October 2016

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Abstract

In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the

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In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original N-benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses. Comparison of the results obtained while studying the peculiarities of the synthesized compounds spatial structure and biological properties revealed an important structure-action relationship. In particular, it was shown that the intensity of analgesic effect of different conformational isomers of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamide may change considerably: while low active conformers are comparable with piroxicam, highly active conformers are more than twice as effective as meloxicam. Full article

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Open AccessArticle Effect of Cyclodextrin Types and Co-Solvent on Solubility of a Poorly Water Soluble Drug

by Suporn Charumanee, Siriporn Okonogi, Jakkapan Sirithunyalug, Peter Wolschann and Helmut Viernstein

Sci. Pharm. 2016, 84(4), 694-704; doi:10.3390/scipharm84040694

Received: 15 June 2016 / Accepted: 1 September 2016 / Published: 18 October 2016

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Abstract

The aim of the study was to investigate the solubility of piroxicam (Prx) depending on the inclusion complexation with various cyclodextrins (CDs) and on ethanol as a co-solvent. The phase-solubility method was applied to determine drug solubility in binary and ternary systems. The

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The aim of the study was to investigate the solubility of piroxicam (Prx) depending on the inclusion complexation with various cyclodextrins (CDs) and on ethanol as a co-solvent. The phase-solubility method was applied to determine drug solubility in binary and ternary systems. The results showed that in systems consisting of the drug dissolved in ethanol–water mixtures, the drug solubility increased exponentially with a rising concentration of ethanol. The phase solubility measurements of the drug in aqueous solutions of CDs, β-CD and γ-CD exhibited diagrams of A_L-type, whereas 2,6-dimethyl-β-CD revealed A_P-type. The destabilizing effect of ethanol as a co-solvent was observed for all complexes regardless of the CD type, as a consequence of it the lowering of the complex formation constants. In systems with a higher concentration of ethanol, the drug solubility was increased in opposition to the decreasing complex formation constants. According to this study, the type of CDs played a more important role on the solubility of Prx, and the use of ethanol as a co-solvent exhibited no synergistic effect on the improvement of Prx solubility. The Prx solubility was increased again due to the better solubility in ethanol. Full article

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Open AccessArticle Destabilization Mechanism of Ionic Surfactant on Curcumin Nanocrystal against Electrolytes

by Heni Rachmawati, Annisa Rahma, Loaye Al Shaal, Rainer H. Müller and Cornelia M. Keck

Sci. Pharm. 2016, 84(4), 685-693; doi:10.3390/scipharm84040685

Received: 11 August 2016 / Accepted: 31 August 2016 / Published: 18 October 2016

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Abstract

We have successfully developed curcumin nanosuspension intended for oral delivery. The main purpose is to improve bioavailability through enhancing its solubility. The nanoparticles were stabilized using various stabilizers, including polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), sodium carboxymethylcellulose (Na-CMC), d-α-tocopheryl polyethylene glycol 1000

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We have successfully developed curcumin nanosuspension intended for oral delivery. The main purpose is to improve bioavailability through enhancing its solubility. The nanoparticles were stabilized using various stabilizers, including polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), sodium carboxymethylcellulose (Na-CMC), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and sodium dodecyl sulfate (SDS). The average diameter of particles, microscopic appearance, and sedimentation of each preparation was observed and compared. Each stabilizer demonstrated a different degree of inhibition of particle aggregation under electrolyte-containing simulated gastrointestinal (GIT) fluid. Non-ionic stabilizers (PVA, PVP, and TPGS) were shown to preserve the nanosuspension stability against electrolytes. In contrast, strong ionic surfactants such as SDS were found to be very sensitive to electrolytes. The results can provide useful information for the formulators to choose the most suitable stabilizers by considering the nature of stabilizers and physiological characteristics of the target site of the drug. Full article

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Open AccessArticle Analytical Enantio-Separation of Linagliptin in Linagliptin and Metformin HCl Dosage Forms by Applying Two-Level Factorial Design

by Sushant B. Jadhav, Rahul M. Mane, Kalyanraman L. Narayanan and Popatrao N. Bhosale

Sci. Pharm. 2016, 84(4), 671-684; doi:10.3390/scipharm84040671

Received: 28 June 2016 / Accepted: 3 August 2016 / Published: 17 October 2016

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Abstract

A novel, stability indicating, reverse phase high-performance liquid chromatography (RP-HPLC) method was developed to determine the S-isomer of linagliptin (LGP) in linagliptin and metformin hydrochloride (MET HCl) tablets (LGP–MET HCl) by implementing design of experiment (DoE), i.e., two-level, full factorial design (2

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A novel, stability indicating, reverse phase high-performance liquid chromatography (RP-HPLC) method was developed to determine the S-isomer of linagliptin (LGP) in linagliptin and metformin hydrochloride (MET HCl) tablets (LGP–MET HCl) by implementing design of experiment (DoE), i.e., two-level, full factorial design (2³ + 3 centre points = 11 experiments) to understand the critical method parameters (CMP) and its relation with the critical method attribute (CMA), and to ensure robustness of the method. The separation of the S-isomer, LGP and MET HCl in the presence of their impurities was achieved on Chiralpak^® IA-3 (Amylose tris (3, 5-dimethylphenylcarbamate), immobilized on 3 µm silica gel) stationary phase (250 × 4.6 mm, 3 µm) using isocratic elution and detector wavelength at 225 nm with a flow rate of 0.5 mL·min⁻¹, an injection volume of 10 µL with a sample cooler (5 °C) and column oven temperature of 25 °C. Ethanol:Methanol:Monoethanolamine (EtOH:MeOH:MEA) in the ratio of 60:40:0.2 v/v/v was used as a mobile phase. The developed method was validated in accordance with international council for harmonisation (ICH) guidelines and was applied for the estimation of the S-isomer of LGP in LGP–MET HCl tablets. The same method also can be extended for the estimation of the S-isomer in LGP dosage forms. Full article

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Open AccessArticle Development and Validation of Miglitol and Its Impurities by RP-HPLC and Characterization Using Mass Spectrometry Techniques

by Kesavan Balakumaran, Mosesbabu Janagili, Nagaraju Rajana, Sureshbabu Papureddy and Jayashree Anireddy

Sci. Pharm. 2016, 84(4), 654-670; doi:10.3390/scipharm84040654

Received: 23 April 2016 / Accepted: 11 August 2016 / Published: 14 October 2016

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Abstract

Alpha glucoside inhibitors used to treat type-2 diabetes mellitus (DM) are likely to be safe and effective. These agents are most effective for postprandial hyperglycemia. Miglitol is a type of drug used to treat type-2 DM. A simple, selective, linear, precise and accurate

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Alpha glucoside inhibitors used to treat type-2 diabetes mellitus (DM) are likely to be safe and effective. These agents are most effective for postprandial hyperglycemia. Miglitol is a type of drug used to treat type-2 DM. A simple, selective, linear, precise and accurate reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for a related substance of miglitol and its identification, and characterization was done by different mass spectrometry techniques. The gradient method at a flow rate of 1.0 mL/min was employed on a prevail carbohydrate ES column (250 × 4.6 mm, 5 μm particle size) at a temperature of 35 °C. Mobile phase A consisted of 10 mM dipotassium hydrogen orthophosphate adjusted to pH 8.0 using concentrated phosphoric acid and mobile phase B consisted of acetonitrile. The ultraviolet detection wavelength was 210 nm and 20 μL of the sample were injected. The retention time for miglitol was about 24.0 min. Forced degradation of the miglitol sample was conducted in accordance with the International Conference on Harmonisation (ICH) guidelines. Acidic, basic, neutral, and oxidative hydrolysis, thermal stress, and photolytic degradation were used to assess the stability-indicating the power of the method. Substantial degradation was observed during oxidative hydrolysis. No degradation was observed under the other stress conditions. The method was optimized using samples generated by forced degradation and sample solutions spiked with impurities and epimers. Good resolution of the analyte peak from peaks, corresponding to process-related impurities, epimers and degradation products, was achieved and the method was validated as per the ICH guidelines. The method can successfully be applied for routine analysis of miglitol. Full article

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Open AccessArticle Evaluation of Certain Pharmaceutical Quality Attributes of Lisinopril Split Tablets

by Khairi M. S. Fahelelbom, Moawia M. M. Al-Tabakha, Nermin A. M. Eissa and Jeevani Javadi

Sci. Pharm. 2016, 84(4), 646-653; doi:10.3390/scipharm84040646

Received: 10 March 2016 / Accepted: 28 July 2016 / Published: 11 October 2016

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Abstract

Tablet splitting is an accepted practice for the administration of drugs for a variety of reasons, including dose adjustment, ease of swallowing and cost savings. The purpose of this study was to evaluate the physical properties of lisinopril tablets as a result of

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Tablet splitting is an accepted practice for the administration of drugs for a variety of reasons, including dose adjustment, ease of swallowing and cost savings. The purpose of this study was to evaluate the physical properties of lisinopril tablets as a result of splitting the tablets either by hand or with a splitting device. The impact of the splitting technique of lisinopril (Zestril^® tablets, 20 mg) on certain physical parameters such as weight variation, friability, disintegration, dissolution and drug content were studied. Splitting the tablets either by hand or with a splitter resulted in a minute but statistically significant average weight loss of <0.25% of the tablet to the surrounding environment. The variability in the weight of the hand-split tablet halves was more pronounced (37 out of 40 tablet halves varied by more than 10% from the mean weight) than when using the tablet splitter (3 out of 40 tablet halves). The dissolution and drug content of the hand-split tablets were therefore affected because of weight differences. However, the pharmacopoeia requirements for friability and disintegration time were met. Hand splitting of tablets can result in an inaccurate dose and may present clinical safety issues, especially for drugs with a narrow therapeutic window in which large fluctuations in drug concentrations are undesirable. It is recommended to use tablets with the exact desired dose, but if this is not an option, then a tablet splitter could be used. Full article

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Open AccessArticle Cytotoxic Compounds from Brucea mollis

by Mai Hung Thanh TUNG, Ho Viet ĐUC, Tran Thu HUONG, Nguyen Thanh DUONG, Do Thi PHUONG, Do Thi THAO, Bui Huu TAI, Young Ho KIM, Tran The BACH and Nguyen Manh CUONG

Sci. Pharm. 2013, 81(3), 819-832; doi:10.3797/scipharm.1206-02

Received: 3 June 2012 / Accepted: 31 December 2012 / Published: 29 September 2016

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Abstract

Ten compounds, including soulameanone (1), isobruceine B (2), 9-methoxy-canthin-6-one (3), bruceolline F (4), niloticine (5), octatriacontan-1-ol (6), bombiprenone (7), α-tocopherol (8), inosine (9), and apigenin

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Ten compounds, including soulameanone (1), isobruceine B (2), 9-methoxy-canthin-6-one (3), bruceolline F (4), niloticine (5), octatriacontan-1-ol (6), bombiprenone (7), α-tocopherol (8), inosine (9), and apigenin 7-O-β-D-glucopyranoside (10), were isolated from the leaves, stems, and roots of Brucea mollis Wall. ex Kurz. Their structures were determined using one- and two-dimensional NMR spectroscopy and mass spectrometry. All compounds were evaluated for their cytotoxic activity against KB (human carcinoma of the mouth), LU-1 (human lung adenocarcinoma), LNCaP (human prostate adeno-carcinoma), and HL-60 (human promyelocytic leukemia) cancer cell lines. Compound 2 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC₅₀ values of 0.39, 0.40, 0.34, and 0.23 μg/mL, respectively. In addition, compounds 3 and 5 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC₅₀ values around 1–4 μg/mL. Compounds 9-methoxycanthin-6-one (3) and niloticine (5) have been discovered for the first time from the Brucea genus. Full article

Open AccessArticle Formulation, Characterisation, and in Vitro Skin Diffusion of Nanostructured Lipid Carriers for Deoxyarbutin Compared to a Nanoemulsion and Conventional Cream

by Rendra P. Tofani, Yeyet C. Sumirtapura and Sasanti T. Darijanto

Sci. Pharm. 2016, 84(4), 634-645; doi:10.3390/scipharm84040634

Received: 14 April 2016 / Accepted: 12 July 2016 / Published: 20 July 2016

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Abstract

The long-term use of topical hydroquinone as an anti-hyperpigmentation treatment has well-known, unwanted effects. Deoxyarbutin (4-[(tetrahydro-2H-pyran-2-yl)oxy]phenol) is a relatively new tyrosinase inhibitor, with stronger inhibitory potency than hydroquinone, that exhibited decreased cytotoxicity against melanocytes and other cells. This study developed novel nanostructured lipid

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The long-term use of topical hydroquinone as an anti-hyperpigmentation treatment has well-known, unwanted effects. Deoxyarbutin (4-[(tetrahydro-2H-pyran-2-yl)oxy]phenol) is a relatively new tyrosinase inhibitor, with stronger inhibitory potency than hydroquinone, that exhibited decreased cytotoxicity against melanocytes and other cells. This study developed novel nanostructured lipid carriers (NLCs) for improved topical delivery of deoxyarbutin (dArb), leading to improved depigmenting efficacy. dArb is a hydrophobic substance, but it easily degrades in aqueous medium and is thermolabile. Screening and optimisation of the solid lipid, liquid lipid, surfactant, co-surfactant and production methods were performed to choose the optimum particle size and stability for NLCs. One percent dArb NLCs were obtained from a combination of cetyl palmitate (CP) and caprylic/capric tryglicerides (Myr) in 12% total lipids using poloxamer 188 (P-188) and polyethylene glycol (PEG) 400 as a surfactant and co-surfactant, respectively, with a particle diameter of approximately 500 nm and a polydispersity index (PI) <0.4. These NLCs were produced using the simple method of high-shear homogenisation (10,000 rpm, 5 minutes) and ultrasonication (3.5 min). The compatibility between the substances in the formula was evaluated using Fourier Transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The morphology of the NLCs was observed using transmission electron microscopy (TEM). In vitro penetration of dArb NLCs was evaluated and compared to the nanoemulsion (NE) and conventional emulsion (CR) delivery methods across Spangler’s membrane (SS). Delivery improvement was clearly observed, and after 8 h of application, dArb gel-NLCs showed the highest dArb penetration, followed by liquid NLCs, NE, and CR. Full article

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Open AccessArticle Investigation of the Bioequivalence of Rosuvastatin 20 mg Tablets after a Single Oral Administration in Mediterranean Arabs Using a Validated LC-MS/MS Method

by Abdel Naser Zaid, Rowa Al Ramahi, Rita Cortesi, Ayman Mousa, Nidal Jaradat, Nadia Ghazal and Rana Bustami

Sci. Pharm. 2016, 84(3), 536-546; doi:10.3390/scipharm84030536

Received: 25 March 2016 / Accepted: 4 June 2016 / Published: 30 June 2016

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Abstract

There is a wide inter-individual response to statin therapy including rosuvastatin calcium (RC), and it has been hypothesized that genetic differences may contribute to these variations. In fact, several studies have shown that pharmacokinetic (PK) parameters for RC are affected by race. The

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There is a wide inter-individual response to statin therapy including rosuvastatin calcium (RC), and it has been hypothesized that genetic differences may contribute to these variations. In fact, several studies have shown that pharmacokinetic (PK) parameters for RC are affected by race. The aim of this study is to demonstrate the interchangeability between two generic RC 20 mg film-coated tablets under fasting conditions among Mediterranean Arabs and to compare the pharmacokinetic results with Asian and Caucasian subjects from other studies. A single oral RC 20 mg dose, randomized, open-label, two-way crossover design study was conducted in 30 healthy Mediterranean Arab volunteers. Blood samples were collected prior to dosing and over a 72-h period. Concentrations in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method. Twenty-six volunteers completed the study. Statistical comparison of the main PK parameters showed no significant difference between the generic and branded products. The point estimates (ratios of geometric mean %) were 107.73 (96.57–120.17), 103.61 (94.03–114.16), and 104.23 (94.84–114.54) for peak plasma concentration (C_max), Area Under the Curve (AUC)_0→last, and AUC_0→∞, respectively. The 90% confidence intervals were within the pre-defined limits of 80%–125% as specified by the Food and Drug Administration and European Medicines Agency for bioequivalence studies. Both formulations were well-tolerated and no serious adverse events were reported. The PK results (AUC_0→last and C_max) were close to those of the Caucasian subjects. This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 20 mg oral dose of RC under fasting conditions. Both formulations also showed comparable safety results. The PK results of the test and reference in the study subjects fall within the acceptable interval of 80%–125% and they were very close to the results among Caucasians. These PK results may be useful in order to determine the suitable RC dose among Arab Mediterranean patients. Full article

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Open AccessArticle Synthesis, Structure, and Analgesic Properties of Halogen-Substituted 4-Hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides

by Igor V. Ukrainets, Lidiya A. Petrushova, Svitlana V. Shishkina, Lyudmila V. Sidorenko, Galina Sim and Olga V. Kryvanych

Sci. Pharm. 2016, 84(3), 523-535; doi:10.3390/scipharm84030523

Received: 10 May 2016 / Accepted: 10 June 2016 / Published: 17 June 2016

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Abstract

As potential new analgesics, the corresponding 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides have been obtained by amidation of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with aniline and its halogenated analogsin boiling dry xylene. The peculiarities of the mass and nuclear magnetic resonance (¹

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As potential new analgesics, the corresponding 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides have been obtained by amidation of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with aniline and its halogenated analogsin boiling dry xylene. The peculiarities of the mass and nuclear magnetic resonance (¹Н and ¹³С) spectra of the synthesized compounds are discussed. Using X-ray diffraction analysis, the ability of the compounds to form stable solvates with N,N-dimethylformamide has been shown on the example of 4-bromo-substituted derivative. It should be further studied to be considered in their crystallization. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick (tail immersion test) among halogen-substituted 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides, substances which are considerably superior to meloxicam and piroxicam by their analgesic activity have been found. They are of interest for further profound studies. Full article

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Open AccessArticle Bioequivalence Study of Two Orodispersible Rizatriptan Formulations of 10 mg in Healthy Volunteers

by Mercè Cánovas, Francisco Polonio and Francesc Cabré

Sci. Pharm. 2016, 84(3), 514-522; doi:10.3390/scipharm84030514

Received: 27 November 2015 / Accepted: 24 January 2016 / Published: 13 June 2016

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Abstract

The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions

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The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions design. The test and reference formulations were administered in two treatment days, separated by a washout period of seven days. Plasma concentrations of rizatriptan were obtained by the LC/MS/MS (Liquid chromatography tandem-mass spectrometry) method. Log-transformed AUC_0-t (area under the plasma concentration-time curve from zero to the last measurable concentration) and C_max (maximum plasma concentration) values were tested for bioequivalence based on the ratios of the geometric means (test/reference). The t_max (time to reach maximum plasma concentration) was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC_0-t and C_max were within the bioequivalence acceptance range of 80%–125%. According to the European Guideline, it may therefore be concluded that the test formulation of rizatriptan 10 mg orodispersible tablet is bioequivalent to the reference formulation (Maxalt^® Max 10 mg oral lyophilisate). The safety profile of both formulations was consistent with the summary of the product characteristics. Full article

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Open AccessArticle Suitability of Root and Rhizome Anatomy for Taxonomic Classification and Reconstruction of Phylogenetic Relationships in the Tribes Cardueae and Cichorieae (Asteraceae)

by Elisabeth Ginko, Christoph Dobeš and Johannes Saukel

Sci. Pharm. 2016, 84(4), 585-602; doi:10.3390/scipharm84040585

Received: 18 August 2015 / Accepted: 27 May 2016 / Published: 27 May 2016

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Abstract

The value of root and rhizome anatomy for the taxonomic characterisation of 59 species classified into 34 genera and 12 subtribes from the Asteraceae tribes Cardueae and Cichorieae was assessed. In addition, the evolutionary history of anatomical characters was reconstructed using a nuclear

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The value of root and rhizome anatomy for the taxonomic characterisation of 59 species classified into 34 genera and 12 subtribes from the Asteraceae tribes Cardueae and Cichorieae was assessed. In addition, the evolutionary history of anatomical characters was reconstructed using a nuclear ribosomal DNA sequence-based phylogeny of the Cichorieae. Taxa were selected with a focus on pharmaceutically relevant species. A binary decision tree was constructed and discriminant function analyses were performed to extract taxonomically relevant anatomical characters and to infer the separability of infratribal taxa, respectively. The binary decision tree distinguished 33 species and two subspecies, but only five of the genera (sampled for at least two species) by a unique combination of hierarchically arranged characters. Accessions were discriminated—except for one sample worthy of discussion—according to their subtribal affiliation in the discriminant function analyses (DFA). However, constantly expressed subtribe-specific characters were almost missing and even in combination, did not discriminate the subtribes. Most anatomical characters showed at least some degree of homoplasious evolution limiting their suitability as phylogenetically informative characters. Full article

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Open AccessArticle Anomalous Separation of Small Y-Chromosomal DNA Fragments on Microchip Electrophoresis

by Mohammad Jabasini, Ashraf Ewis, Youichi Sato, Yutaka Nakahori and Yoshinobu Baba

Sci. Pharm. 2016, 84(3), 507-513; doi:10.3390/scipharm84030507

Received: 2 March 2016 / Accepted: 13 May 2016 / Published: 26 May 2016

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Abstract

We investigated an anomalous DNA separation where two DNA fragments from the human Y-chromosome sY638 (64 bp) and sY592 (65 bp), with only one base pair difference, were separated. This result is abnormal since in a previous study, we found that 5 bp

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We investigated an anomalous DNA separation where two DNA fragments from the human Y-chromosome sY638 (64 bp) and sY592 (65 bp), with only one base pair difference, were separated. This result is abnormal since in a previous study, we found that 5 bp was the minimum difference between two DNA fragments that the microchip electrophoresis system can separate. The formation of a mini-loop in the structure of the DNA fragment of sY638 (64 bp) was strongly expected to be the reason. To investigate this, we synthesized three modified DNA fragments for sY638 (64 bp), and the modifications were in two expected locations for possible mini-loop formation. Later, the separation between sY592 (65 bp) and the three modified fragments of sY638 (64 bp) was not possible. Thus, we conclude that the formation of a mini-loop in the structure of the DNA is the reason behind this anomalous separation. Full article

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Open AccessArticle Effect of Aromatic Substitution of Curcumin Nanoformulations on Their Stability

by Siriporn Okonogi, Ornchuma Naksuriya, Suporn Charumanee and Jakkapan Sirithunyalug

Sci. Pharm. 2016, 84(4), 625-633; doi:10.3390/scipharm84040625

Received: 22 February 2016 / Accepted: 31 March 2016 / Published: 19 April 2016

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Abstract

Curcumin, a poorly water-soluble bioactive compound, was successfully loaded into three different aromatic contents of hydroxypropylmethacrylamide (HPMA)-based polymeric micelles in order to develop water-soluble curcumin nanoformulations (Cur-Nano). The stability study of Cur-Nano was done by keeping the formulations at 4, 30, and 40

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Curcumin, a poorly water-soluble bioactive compound, was successfully loaded into three different aromatic contents of hydroxypropylmethacrylamide (HPMA)-based polymeric micelles in order to develop water-soluble curcumin nanoformulations (Cur-Nano). The stability study of Cur-Nano was done by keeping the formulations at 4, 30, and 40 °C for 90 days. The physical appearance, curcumin remaining, and particle size of Cur-Nano were examined by visual inspection, high-performance liquid chromatography, and dynamic light scattering, respectively. After the storage period, the Cur-Nano composed of 100% aromatic-substituted polymer exhibited the highest stability of curcumin (80% of curcumin remaining) with a similar particle size as measured on the first day (50–60 nm) in all storage conditions. Curcumin in Cur-Nano composed of 25% and 0% aromatic-substituted polymer was significantly less stable accordingly. The results suggested that aromatic substitution to HPMA-based polymeric micelles can significantly enhance the stability of the loaded curcumin, considerably due to the π-π stacking interactions between the aromatic groups of curcumin and the polymer. It is concluded that curcumin-loaded polymeric micelles with high substituted aromatic content can be promising candidates with good storage stability for further clinical evaluations. Full article

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Open AccessArticle Quality Control of Traditional Cannabis Tinctures: Pattern, Markers, and Stability

by Wieland Peschel

Sci. Pharm. 2016, 84(3), 567-584; doi:10.3390/scipharm84030567

Received: 9 March 2016 / Accepted: 29 March 2016 / Published: 18 April 2016

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Abstract

Traditional tinctures of Cannabis sativa L. became obsolete before elucidation of the main cannabinoids and routine quality testing for medicines. In view of increasing medicinal use of cannabinoids and associated safety concerns, tinctures from a Δ9-tetrahydrocannabinol (THC)-type chemovar were studied. High-performance liquid chromatography

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Traditional tinctures of Cannabis sativa L. became obsolete before elucidation of the main cannabinoids and routine quality testing for medicines. In view of increasing medicinal use of cannabinoids and associated safety concerns, tinctures from a Δ9-tetrahydrocannabinol (THC)-type chemovar were studied. High-performance liquid chromatography with diode-array detection (HPLC/DAD) was used to determine THC, Δ9-tetrahydrocannabinolic acid A (THCA), cannabinol (CBN), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannflavin A/B, and total phenolics. Derived group and ratio markers describe absolute and relative profiles when varying plant part (flos, folium), extraction solvent (EtOH percentage), storage conditions (‘shelf’ or ‘fridge’ up to 15 months), and pasteurization (2 h 70 °C, 20 min 80 °C). Tinctures from female flowering tops contained ten-fold more cannabinoids than tinctures from leaves; tinctures (80%–90% EtOH) contained ten-fold more cannabinoids than tinctures (40% EtOH). The analysis of CBGA + CBG, the main co-cannabinoids aside from THCA + THC, appears more relevant than CBDA + CBD. The decarboxylation of THCA to THC—the main change during storage of freshly prepared tinctures—is after 15 months in the ‘fridge’ comparable to 3 months on the ‘shelf’. Minimally increased CBN totals did not correlate to diminished totals of THCA and THC (up to 15% after 3 months ‘shelf’, 45% after 15 months ‘fridge’). Instead, total cannabinoids or acidic/neutral cannabinoid ratios are better stability markers. Moderate changes after pasteurization and partial losses below 10% for total cannabinoids after 9 months ‘fridge’ indicate possibilities for a reasonable shelf life. Yet storage and use of non-stabilized tinctures remain critical without authorized specification and stability data because a consistent cannabinoid content is not guaranteed. Full article

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Open AccessArticle The Study of Structure—Analgesic Activity Relationships in a Series of 4-Hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic Acid Toluidides and Xylidides

by Igor V. Ukrainets, Lidiya A. Petrushova, Lyudmila V. Sidorenko, Alexandra A. Davidenko and Marina A. Duchenko

Sci. Pharm. 2016, 84(3), 497-506; doi:10.3390/scipharm84030497

Received: 27 December 2015 / Accepted: 2 February 2016 / Published: 18 April 2016

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Abstract

In continuing the search for new analgesics among derivatives of 2,1-benzothiazines, a series of corresponding toluidides and xylidides of 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid has been synthesized by the reaction of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with equimolar amounts of mono-

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In continuing the search for new analgesics among derivatives of 2,1-benzothiazines, a series of corresponding toluidides and xylidides of 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid has been synthesized by the reaction of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with equimolar amounts of mono- and dimethyl-substituted anilides in boiling dry xylene. Their structure has been confirmed by the data of elemental analysis, nuclear magnetic resonance (NMR) spectroscopy (¹Н and ¹³С), as well as mass spectrometry. All compounds obtained were subjected to pharmacological screening to identify their analgesic properties. Testing was carried out in male rats using the standard model of the thermal tail-flick (tail immersion test) in parallel and in comparison with the structurally related drugs meloxicam and piroxicam. Among the substances studied, highly active oral painkillers have been found; they exceed the analgesic effect of the reference drugs using the same dose. Interesting structural and biological regularities have been described; they will be useful in further research on creating promising new analgesics based on 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamides. Full article

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Open AccessArticle Metabolite Profiles in Various Plant Organs of Justicia gendarussa Burm.f. and Its in Vitro Cultures

by Putu Indrayoni, Diah Intan Purwanti, Suwidji Wongso, Bambang E.W. Prajogo and Gunawan Indrayanto

Sci. Pharm. 2016, 84(3), 555-566; doi:10.3390/scipharm84030555

Received: 24 November 2015 / Accepted: 4 April 2016 / Published: 13 April 2016

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Abstract

Metabolite profiles of plant organs and their in vitro cultures of Justicia gendarussa have been studied by using Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight-Mass Spectrometry (UPLC-Qtof-MS). Samples of leaves, stems, roots, and shoot cultures showed similar patterns of metabolites, while samples of root cultures

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Metabolite profiles of plant organs and their in vitro cultures of Justicia gendarussa have been studied by using Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight-Mass Spectrometry (UPLC-Qtof-MS). Samples of leaves, stems, roots, and shoot cultures showed similar patterns of metabolites, while samples of root cultures gave very different profiles. Concentrations of secondary metabolites in shoot cultures were relatively low compared to those in the leaves and roots of the plants. The results suggested that secondary metabolites in J. gendarussa were biosynthetized in the leaves, then transported to the roots. Full article

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Open AccessArticle Benzotriazole-Mediated Synthesis and Antibacterial Activity of Novel N-Acylcephalexins

by Khalid A. Agha, Nader E. Abo-Dya, Tarek S. Ibrahim, Eatedal H. Abdel-Aal and Wael A. Hegazy

Sci. Pharm. 2016, 84(3), 484-496; doi:10.3390/scipharm84030484

Received: 13 December 2015 / Accepted: 18 February 2016 / Published: 13 April 2016

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Abstract

Cephalexin (1) was acylated using N-acylbenzotriazoles (3a–k′) derived from various carboxylic acids including aromatic, heterocyclic and N-Pg-α-amino acid to afford N-acylcephalexins in excellent yields (82%–96%). Antibacterial screening of the novel cephalosporins revealed that all

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Cephalexin (1) was acylated using N-acylbenzotriazoles (3a–k′) derived from various carboxylic acids including aromatic, heterocyclic and N-Pg-α-amino acid to afford N-acylcephalexins in excellent yields (82%–96%). Antibacterial screening of the novel cephalosporins revealed that all targets (4a–j) retained the antibacterial activity of cephalexin against Staphylococcus aureus (ATCC 6538). N-Nicotinylcephalexin (4c) and N-(3,4,5-trimethoxybenzoyl)cephalexin (4g) exhibited a broader spectrum of antibacterial activity towards standard strains of Staphylococcus aureus (ATCC 6538), Paenibacillus polymyxa (ATCC 842), and Escherichia coli (ATCC 10536) as well as a resistant strain of Pseudomonas aeruginosa (ATCC 27853). Full article

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Open AccessReview Estrogen Receptor Ligands: A Review (2013–2015)

by Shabnam Farzaneh and Afshin Zarghi

Sci. Pharm. 2016, 84(3), 409-427; doi:10.3390/scipharm84030409

Received: 24 November 2015 / Accepted: 17 January 2016 / Published: 13 April 2016

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Abstract

Estrogen receptors (ERs) are a group of compounds named for their importance in both menstrual and estrous reproductive cycles. They are involved in the regulation of various processes ranging from tissue growth maintenance to reproduction. Their action is mediated through ER nuclear receptors.

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Estrogen receptors (ERs) are a group of compounds named for their importance in both menstrual and estrous reproductive cycles. They are involved in the regulation of various processes ranging from tissue growth maintenance to reproduction. Their action is mediated through ER nuclear receptors. Two subtypes of the estrogen receptor, ERα and ERβ, exist and exhibit distinct cellular and tissue distribution patterns. In humans, both receptor subtypes are expressed in many cells and tissues, and they control key physiological functions in various organ systems. Estrogens attract great attention due to their wide applications in female reproductive functions and treatment of some estrogen-dependent cancers and osteoporosis. This paper provides a general review of ER ligands published in international journals patented between 2013 and 2015. The broad physiological profile of estrogens has attracted the attention of many researchers to develop new estrogen ligands as therapeutic molecules for various clinical purposes. After the discovery of the ERβ receptor, subtype-selective ligands could be used to elicit beneficial estrogen-like activities and reduce adverse side effects, based on the different distributions and relative levels of the two ER subtypes in different estrogen target tissues. Therefore, recent literature has focused on selective estrogen ligands as highly promising agents for the treatment of some types of cancer, as well as for cardiovascular, inflammatory, and neurodegenerative diseases. Estrogen receptors are nuclear transcription factors that are involved in the regulation of many complex physiological functions in humans. Selective estrogen ligands are highly promising targets for treatment of some types of cancer, as well as for cardiovascular, inflammatory and neurodegenerative diseases. Extensive structure-activity relationship studies of ER ligands based on small molecules indicate that many different structural scaffolds may provide high-affinity compounds, provided that some basic structural requirements are present. Full article

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Open AccessArticle Scientia Pharmaceutica, Autorenhinweise 2016

by Sci. Pharm. Editorial Office

Sci. Pharm. 2016, 84(1), 219-230; doi:10.3797/scipharm.aut-16-01 (registering DOI)

Received: 5 September 2015 / Accepted: 15 December 2015 / Published: 14 February 2016

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Abstract Die Zeitschrift Scientia Pharmaceutica (www.scipharm.at) erscheint vierteljährlich jeweils am Quartalsende und ist ein Medium zur Publikation von Originalarbeiten, Kurzmit-teilungen und ausgewählten Übersichtsarbeiten aus allen wissenschaftlichen Disziplinen der Pharmazie und angrenzenden Gebieten sowie der pharmazeutischen Praxis.[...] Full article

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