Search Results (47)

Background/Objectives: P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated that filapixant would cause fewer taste-related side effects compared to the unselective P2X3/P2X2/3 antagonist gefapixant and the less selective P2X3 antagonist eliapixant. This study assessed the tolerability, safety and PK of filapixant, the effect of food on PK and relative BA of a tablet vs. solution. Methods: This study (NCT03212586) followed a randomized, double-blind single-ascending-dose design. A total of 72 healthy male subjects received a solution (6–60 mg) or immediate-release tablets (120–1250 mg) of filapixant or corresponding placebo in fasted state. The subjects at 60 mg were re-dosed with 60 mg tablets in both fasted and fed states. The endpoints included PK parameters, dose proportionality, adverse events, and taste assessments (taste strips; dysgeusia questionnaire). Results: Filapixant showed dose-proportional PK with a half-life (about 10–15 h), supporting once-daily dosing. Food minimally affected PK and BA was comparable between tablet and solution. Filapixant was well tolerated; however, the number of taste side effects was unexpectedly high. Comparing the results observed across clinical filapixant studies, the threshold for such side effects seems to be well below the in vitro IC₅₀ for P2X2/3. Conclusions: Treatment with filapixant was safe and well tolerated. Filapixant showed dose-proportional PK, bioavailability similar to that of a solution and a tablet, and a minor effect of food on PK. The number of taste side effects was unexpectedly high considering the high in vitro P2X3 receptor selectivity. Factors other than selectivity are needed to explain taste profile differences between P2X3 antagonists. Full article

Background: The antidiabetic drug gliclazide is often taken with antacids due to its gastrointestinal side effects. However, patients rarely report antacid use, making drug–drug interactions a potential cause of therapy failure. Therefore, this study aimed to investigate the in vitro effects of various antacids on gliclazide permeability and to explore the underlying mechanisms. Methods: The permeability of gliclazide alone and in the presence of antacids (sodium bicarbonate, calcium carbonate, aluminum hydroxide, hydrotalcite and calcium carbonate/magnesium carbonate) was investigated using the parallel artificial membrane permeability assay (PAMPA) in four media (buffers pH 1.2, pH 4.5, pH 6.8 and water). The permeability coefficients were calculated, and the effect of pH on gliclazide permeability was also evaluated. Results: At simulated fasting gastric conditions (pH 1.2), groups with calcium carbonate, hydrotalcite and the combination of calcium carbonate/magnesium carbonate showed significantly higher permeability of gliclazide than the control group. At fed-state gastric conditions (pH 4.5), only hydrotalcite did not significantly change the permeability of gliclazide. Sodium bicarbonate, aluminum hydroxide and hydrotalcite significantly reduced the gliclazide permeability in comparison to the control group at pH 6.8 as a representative of fasted-state intestinal fluid. Conclusions: Antacids significantly impact the permeability of gliclazide at different pH values, potentially influencing its bioavailability. Gliclazide permeability is mainly influenced by pH-dependent ionization, though complex or salt formation may also play a role. Since both gliclazide and antacids are taken with food, and gliclazide is primarily absorbed in the small intestine, calcium- and magnesium-based antacids can be considered the most suitable choice. Full article

The food-induced viscosity of the media can alter tablet disintegration and eventually the release of the drug it contains. The extent of this retardation depends on tablet formulation factors, such as the solubility of its excipients. Objectives: This research aimed to study the effect of filler solubility on the disintegration and dissolution of tablets under different testing conditions. Methods: Tablet formulations containing acetaminophen (as a model compound), mixtures of different ratios of fillers, and other excipients were directly compressed using uniform manufacturing parameters. These formulations were investigated under fasted- and fed-state conditions to determine the influence of viscosity on their disintegration, inspired by the liquid penetration ratio (LPR) theoretical framework. Disintegration and dissolution tests were performed using both compendial and novel testing apparatuses. Results: The soluble fillers in the tablets affected their disintegration and dissolution in the simulated fed-state medium, while fasted-state conditions affected the tablets only marginally. The testing devices showed partially contrasting results, which appeared to be due to the hydrodynamics of the testing media used. The novel CNC (computed numerical control) apparatus offered 3D motion and effectively exposed the tablets to the viscous testing media, unlike the compendial paddle apparatus. Conclusions: This study explored the impact of filler solubility on the disintegration and dissolution of tablets. As the LPR framework revealed, fillers with a higher solubility have positive effects on the disintegration and dissolution of tablets in viscous conditions. Additionally, the proportion of soluble filler used is also inversely correlated with the disintegration time. Further investigation of the formulation parameters, as well as the testing conditions, would provide additional insights into the effects of food on these tablets. Full article

The gastrointestinal microbiota of medicinal leeches is particularly interesting due to their blood-feeding habits, increasing medical use, and risk of pathogen transmission. Three groups of Hirudo verbana were used to study the leech microbiota: farmed leeches fasting for a long time, farmed leeches recently fed with bovine blood, and wild specimens fed with amphibian blood. The microbiota of the leeches’ mouth, pharynx, crop, and intestine was analyzed. Metasequencing analyses were performed using amplification of the 16S rRNA V3-V4 region on a NovaSeq Illumina platform. The relative abundance of bacterial microbiota included environmental bacteria from the families Rhizobiaceae, Comamonadaceae, Sphingobacteriaceae, Phreatobacteraceae, Myxococcaceae, Chitinophagaceae, Rhodospirillaceae, and Bdellovibrionaceae, as well as symbiotic/probiotic bacteria such as Mucinivorans, Aeromonas, Vagococcus, Lactobacillales, and Morganella. Significant differences were found in the different regions of the digestive system among the three groups of leeches, and environmental bacteria were present in all groups to varying degrees. A negative correlation was found between the dominant environmental and the symbiotic/probiotic bacteria. In contrast, a positive correlation was found between environmental and symbiotic/probiotic bacteria, indicating their association with host factors. Microbiota diversity, abundance, and bacterial correlations may be influenced by factors such as the leech’s fasting state, blood meal source, and environmental conditions. The identified opportunistic pathogens, such as Rickettsia, Anaplasma, and Treponema, identified for the first time in H. verbana, should be taken into consideration when using this leech in hirudotherapy. Our results show that extensive screening for opportunistic and pathogenic agents should be performed on leeches intended for medical use. Long-fasting leeches and leeches cultured in specialized farms are recommended for hirudotherapy. Full article

Background/Objectives: A sustained-release formulation of fenofibrate while enhancing drug dissolution with minimal food effect is critical for maximizing the therapeutic benefits of fenofibrate. Therefore, this study aimed to develop an effective solid dispersion formulation of fenofibrate for simultaneous enhancement in the extent and duration of drug exposure. Methods: Fenofibrate-loaded solid dispersions (FNSDs) were prepared using poloxamer 407 and Eudragit^® RSPO at varied ratios via solvent evaporation. In vitro/in vivo characteristics of FNSDs were examined in comparison with untreated drugs. Results: Based on dissolution profiles of FNSDs in aqueous media, the weight ratio of fenofibrate: poloxamer 407: Eudragit^® RSPO at 1:1:4 (FNSD2) was selected as the optimal composition for achieving sustained drug release while maximizing the drug dissolution. The enhanced and sustained drug release of FNSD2 was also confirmed in a buffer transition system mimicking the pH change in the gastrointestinal tract. FNSD2 achieved approximately 66% drug release over 12 h, while pure drug exhibited only 12%. Furthermore, FNSD2 maintained similar release rates under fed and fasted conditions, while the entire drug dissolution slightly increased in the fed state. Structural analysis by x-ray diffraction showed that fenofibrate remained crystalline in FNSD2. Pharmacokinetic studies in rats revealed that orally administered FNSD2 significantly improved the extent and duration of systemic drug exposure. Compared to pure drugs, the FNSD2 formulation increased the oral bioavailability of fenofibrate by 22 folds with the delayed T_max of 4 h in rats. Conclusion: FNSD2 formulation is effective in improving the extent and duration of drug exposure simultaneously. Full article

Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, although commercial 20 mg TD-loaded tablets (TD-TAB, Cialis^® tablet) may be taken with or without food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936–1.105 and 1.012–1.153, respectively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the C_max T/R of 0.610–0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851–0.998 of TD-TAB and TDF. The predictive diffusion direction model for physical digestion of TD-TAB and TDF in the stomach after the first and second meal intake was successfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions. Full article

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal^® SR 200 mg capsules have higher drug release rates than Cilostan^® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC_0-t, and AUC_0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal^® SR 200 mg capsules compared with Cilostan^® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal^® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan^® CR 200 mg tablets. Full article

The prevalence of gastric disorders in high-performance horses, especially gastric ulceration, ranges from 50 to 90%. These pathological conditions have negative impacts on athletic performance and health. This study was designed to evaluate changes in gastric pH during a 24 h period and to compare gastrin concentrations at different time points in horses undergoing general inhalation anesthesia and dorsal recumbency. Twenty-two mixed-breed mares weighing 400 ± 50 kg and aged 8 ± 2 years were used. Of these, eight were fasted for 8 h and submitted to 90 min of general inhalation anesthesia in dorsal recumbency. Gastric juice samples were collected prior to anesthesia (T0), and then at 15 min intervals during anesthesia (T15–T90). After recovery from anesthesia (45 ± 1 min), samples were collected every hour for 24 h (T1 to T24) for gastric juice pH measurement. During this period, mares had free access to Bermuda grass hay and water and were fed a commercial concentrate twice (T4 and T16). In a second group (control), four non-anesthetized mares were submitted to 8 h of fasting followed by nasogastric intubation. Gastric juice samples were then collected at T0, T15, T30, T45, T60, T75, and T90. During this period, mares did not receive food or water. After 45 min, mares had free access to Bermuda grass hay and water, and gastric juice samples were collected every hour for four hours (T1 to T4). In a third group comprising ten non-fasted, non-anesthetized mares with free access to Bermuda grass hay and water, gastric juice samples were collected 30 min after concentrate intake (T0). In anesthetized mares, blood gastrin levels were measured prior to anesthesia (8 h fasting; baseline), during recovery from anesthesia, and 4 months after the anesthetic procedure, 90 min after the morning meal. Mean values of gastric juice pH remained acidic during general anesthesia. Mean pH values were within the physiological range (4.52 ± 1.69) and did not differ significantly between time points (T15–T90; p  >  0.05). After recovery from anesthesia, mean gastric pH values increased and remained in the alkaline range throughout the 24 h period of evaluation. Significant differences were observed between T0 (4.88 ± 2.38), T5 (7.08 ± 0.89), T8 (7.43 ± 0.22), T9 (7.28 ± 0.36), T11 (7.26 ± 0.71), T13 (6.74 ± 0.90), and T17 (6.94 ± 1.04) (p  <  0.05). The mean gastric juice pH ranged from weakly acidic to neutral or weakly alkaline in all groups, regardless of food and water intake (i.e., in the fasted, non-fasted, and fed states). Mean gastric pH measured in the control group did not differ from values measured during the 24 h post-anesthesia period or in the non-fasted group. Gastrin concentrations increased significantly during the post-anesthetic period compared to baseline (20.15 ± 7.65 pg/mL and 15.15 ± 3.82 pg/mL respectively; p  <  0.05). General inhalation anesthesia and dorsal recumbency did not affect gastric juice pH, which remained acidic and within the physiological range. Gastric juice pH was weakly alkaline after recovery from anesthesia and in the fasted and fed states. Serum gastrin levels increased in response to general inhalation anesthesia in dorsal recumbency and were not influenced by fasting. Preventive pharmacological measures are not required in horses submitted to general anesthesia and dorsal recumbency. Full article

The objectives of the present research were to investigate (1) the nutritional quality through the Protein Digestibility-Corrected Amino Acid Score (PDCAAS); (2) the apparent viscosity under simulated in vitro gastric conditions of two pea protein isolates named NUTRALYS^® pea protein and NUTRALYS^® S85 Plus. In the first study, the in vivo protein digestibility was measured according to the methodology recommended by the FAO/WHO in 1991. Growing rats were fed a diet containing 10% proteins or a protein-free diet during a minimum of a 5-day balance period with daily collection of faeces. The true digestibility was measured using the rats’ nitrogen intake and fecal nitrogen. PDCAAS was calculated using the amino acid profile and the protein digestibility. In the second study, in vitro gastric digestion was simulated using the NIZO SIMPHYD model. The profiles of “fast-” or “slow-digested” proteins were evaluated and compared to whey and casein proteins by measuring the evolution of the viscosity in these conditions. Both of the tested proteins displayed a balanced amino acid profile with high concentrations of arginine, branched-chain amino acids, lysine and glutamic acid. The true protein digestibility of NUTRALYS^® pea protein and NUTRALYS^® S85 Plus were 97% ± 2 and 96% ± 3, respectively. According to the FAO/WHO requirement profile (2007) mainly used in Europe for adults or the profile from 1991 mainly used in the United States for all age groups except infants, the PDCAAS results of NUTRALYS^® pea protein were 93 and 81, respectively. The PDCAAS scores of NUTRALYS^® S85 Plus were 92 and 81, respectively (Study 1). The digestion of NUTRALYS^® pea protein resulted in a clear increase in viscosity during the gastric acidification and a sudden drop in viscosity after the addition of the gastric enzymes. The viscosity profile of NUTRALYS^® S85 Plus did not change during digestion (Study 2). The range of pea proteins evaluated in these studies displayed a high nutritional quality profile. NUTRALYS^® pea protein is an “intermediate-fast protein” and NUTRALYS^® S85 Plus is a “fast-digested protein”, meaning that these ingredients can be adapted to specific nutritional needs. These results show that plant-based proteins, like those of the NUTRALYS^® range, may allow us to design high-quality protein. Full article

Because of the importance of gastric emptying for pharmacokinetics, numerous methods have been developed for its determination. One of the methods is the salivary tracer technique, which utilizes an ice capsule containing caffeine as a salivary tracer. Despite the ice capsule’s advantage in labeling ingested fluids with caffeine for subsequent salivary detection, its risk of premature melting before swallowing, and its complicated storage and preparation, limit its application, particularly in special populations (e.g., older people). For this reason, here, a compression-coated tablet was developed and validated against the ice capsule in a cross-over clinical trial. The two dosage forms were administered simultaneously to 12 volunteers in an upright position under fasted and fed state conditions. To distinguish the caffeine concentrations in saliva from each dosage form, regular type of caffeine (¹²C) was added to the tablet, while for the ice capsule ¹³C₃ labelled caffeine was used. The salivary caffeine concentrations showed no statistically significant differences for the pharmacokinetic parameters t_max and AUC_0→60 (p > 0.05). Thus, the new formulation is a useful tool for determining gastric emptying that can also be used in special populations. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition characterized by the impairment of alveolar epithelial cells. Despite continued research efforts, the effective therapeutic medication is still absent due to an incomplete understanding of the underlying etiology. It has been shown that rhythmic alterations are of significant importance in the pathophysiology of IPF. However, a comprehensive understanding of how metabolite level changes with circadian rhythms in individuals with IPF is lacking. Here, we constructed an extensive metabolite database by utilizing an unbiased reference system culturing with ¹³C or ¹⁵N labeled nutrients. Using LC-MS analysis via ESI and APCI ion sources, 1300 potential water-soluble metabolites were characterized and applied to evaluate the metabolic changes with rhythm in the lung from both wild-type mice and mice with IPF. The metabolites, such as glycerophospholipids and amino acids, in WT mice exhibited notable rhythmic oscillations. The concentrations of phospholipids reached the highest during the fast state, while those of amino acids reached their peak during fed state. Similar diurnal variations in the metabolite rhythm of amino acids and phospholipids were also observed in IPF mice. Although the rhythmic oscillation of metabolites in the urea cycle remained unchanged, there was a significant up-regulation in their levels in the lungs of IPF mice. ¹⁵N-ammonia in vivo isotope tracing further showed an increase in urea cycle activity in the lungs of mice with IPF, which may compensate for the reduced efficiency of the hepatic urea cycle. In sum, our metabolomics database and method provide evidence of the periodic changes in lung metabolites, thereby offering valuable insights to advance our understanding of metabolic reprogramming in the context of IPF. Full article

Cannabinoids: cannabidiol (CBD), cannabidiolic acid (CBDA), and cannabichromene (CBC) are lipophilic compounds with limited water solubility, resulting in challenges related to their bioavailability and therapeutic efficacy upon oral administration. To overcome these limitations, we developed co-dispersion cannabinoid delivery systems with the biopolymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) and magnesium aluminometasilicate (Neusilin US2) to improve solubility and permeability. Recognizing the potential therapeutic benefits arising from the entourage effect, we decided to work with an extract instead of isolated cannabinoids. Cannabis sativa inflorescences (Henola variety) with a confirming neuroprotective activity were subjected to dynamic supercritical CO₂ (scCO₂) extraction and next they were combined with carriers (1:1 mass ratio) to prepare the co-dispersion cannabinoid delivery systems (HiE). In vitro dissolution studies were conducted to evaluate the solubility of CBD, CBDA, and CBC in various media (pH 1.2, 6.8, fasted, and fed state simulated intestinal fluid). The HiE-Soluplus delivery systems consistently demonstrated the highest dissolution rate of cannabinoids. Additionally, HiE-Soluplus exhibited the highest permeability coefficients for cannabinoids in gastrointestinal tract conditions than it was during the permeability studies using model PAMPA GIT. All three cannabinoids exhibited promising blood-brain barrier (BBB) permeability (P_app higher than 4.0 × 10⁻⁶ cm/s), suggesting their potential to effectively cross into the central nervous system. The improved solubility and permeability of cannabinoids from the HiE-Soluplus delivery system hold promise for enhancement in their bioavailability. Full article

Doubly fed induction generators (DFIGs) are widely applied in wind energy conversion systems, where the harsh service environment and long-lasting operation can bring about motor parameter deviations, deteriorating the system performance. In this paper, an extended state observer (ESO)-based deadbeat control strategy that enhances the system parameter robustness is proposed. Firstly, the effects of motor parameter inaccuracy are analyzed to reflect the control errors and degradation of the system performance. Secondly, a lumped disturbance represented by an additional state extended from the system mathematical model is derived with the parameter inaccuracy taken into consideration. Finally, the parameter robustness enhanced deadbeat control method with the ESO-based disturbance estimation is developed to realize accurate prediction and control, even when the inductance of DFIG deviates under various operation conditions. To verify the effectiveness of the proposed method, simulations are carried out in MATLAB/Simulink for a 1.5 MW DFIG with a 30% stator and rotor inductance deviation. Compared to the conventional control method, smooth and fast dynamic performance is maintained, and the current ripple for the proposed control strategy can be reduced by approximately 40%, where the steady-state tracking performance and parameter robustness of the system are significantly enhanced. Full article

A database consisting of 163 data on the uranium content and ²³⁴U/²³⁸U initial activity ratio of 15 Italian travertine and calcareous tufa sites was created using data from the relevant literature. Using a graphical method, data were interpreted considering the U geochemistry in natural environments as well as the geological, hydrogeological and hydrogeochemical settings of each site. The U content and ²³⁴U/²³⁸U initial activity ratio in travertine and tufa appear to be affected by different factors, such as the availability of U in the aquifer rocks, the redox state of the waters, and the alpha-active radionuclide recoil phenomenon. The data allow the identification of four groups of travertines/tufas: (i) those precipitated from circulating groundwater, with a short/fast flow path, in volcanic rocks with a high radionuclide content; (ii) those precipitated from circulating groundwater, with a long, deep flow path in carbonate/evaporite formations with a relatively low radionuclide content; and (iii) those precipitated from cold waters associated with riverine systems, which are characterized by oxidizing conditions and fed by high-discharge springs recharged by carbonate aquifers. The fourth group represents the intermediate situations frequently occurring due to the mixing of waters from different aquifers. The results suggest an interpretative model that might contribute to the paleo-environmental reconstruction of fossil travertine and calcareous tufa depositing systems. Full article

This randomized food effect study in healthy adult participants examined dispersible tablet formulations of fixed-dose combinations of dolutegravir/abacavir/lamivudine (TRIUMEQ) and dolutegravir/lamivudine (DOVATO). While adult tablet formulations of these combinations are currently approved for the treatment of human immunodeficiency virus, alternate formulations for children are urgently needed to facilitate appropriate pediatric dosing for patients who may have difficulty swallowing a conventional tablet. This study compared the effect of a high-fat, high-calorie meal on the pharmacokinetics, safety, and tolerability of dispersible tablet (DT) formulations of the two-drug and three-drug regimens, with administration under fasting conditions. Both the two-drug and three-drug dispersible tablet formulations, administered under fasting conditions and following a high-fat, high-calorie meal, were well tolerated in healthy participants. There were no clinically relevant differences in drug exposure for either regimen when administered with a high-fat meal as compared to under fasting conditions. Safety observations were similar for both treatments, either in the fed or fasted state. Both TRIUMEQ DT and DOVATO DT formulations can be administer with or without food. Full article