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Pharmaceuticals, Volume 6, Issue 10 (October 2013) – 6 articles , Pages 1170-1334

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252 KiB  
Article
Loss of Response to Long-Term Infliximab Therapy in Children with Crohn’s Disease
by Oliver Gouldthorpe, Anthony G. Catto-Smith, George Alex and Di Simpson
Pharmaceuticals 2013, 6(10), 1322-1334; https://doi.org/10.3390/ph6101322 - 16 Oct 2013
Cited by 13 | Viewed by 6093
Abstract
Secondary loss of response (LoR) often precludes further use of infliximab in children with Crohn’s disease. Immunomodulators may reduce the incidence of LoR but their combination with infliximab presents safety concerns. We aimed to determine the long-term durability of infliximab response in paediatric [...] Read more.
Secondary loss of response (LoR) often precludes further use of infliximab in children with Crohn’s disease. Immunomodulators may reduce the incidence of LoR but their combination with infliximab presents safety concerns. We aimed to determine the long-term durability of infliximab response in paediatric Crohn’s, effect of immunomodulators on LoR, and secondarily the effect of infliximab on growth. We retrospectively audited patients on maintenance infliximab at a single centre. Data included height and weight, Paediatric Crohn’s Disease Activity Index (PCDAI), and immunomodulator use. 71 children (32% female, mean age 14.4 years) had been commenced on maintenance infliximab before July 2011. 89% had been on immunomodulators concurrently with infliximab. LoR occurred in 20 (28%), with a median time to LoR of 4.31 years. LoR was significantly increased in children who did not enter remission (PCDAI ≤ 10) after induction (p < 0.05). LoR occurred more frequently in the 72% who ceased immunomodulators, but this failed to reach statistical significance (p = 0.300). Height and weight SDS improved significantly on infliximab. Infliximab is a durable long-term therapy for paediatric Crohn’s refractory to conventional therapy. A large-magnitude increase in the rate of loss of response after immunomodulator cessation was not observed. Full article
(This article belongs to the Special Issue Biologics)
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145 KiB  
Review
Drug Repositioning: An Opportunity to Develop Novel Treatments for Alzheimer’s Disease
by Anne Corbett, Gareth Williams and Clive Ballard
Pharmaceuticals 2013, 6(10), 1304-1321; https://doi.org/10.3390/ph6101304 - 11 Oct 2013
Cited by 40 | Viewed by 7765
Abstract
Alzheimer’s Disease (AD) is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There [...] Read more.
Alzheimer’s Disease (AD) is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery. Full article
(This article belongs to the Special Issue Drug Repositioning)
144 KiB  
Review
Glibenclamide for the Treatment of Acute CNS Injury
by David B. Kurland, Cigdem Tosun, Adam Pampori, Jason K. Karimy, Nicholas M. Caffes, Volodymyr Gerzanich and J. Marc Simard
Pharmaceuticals 2013, 6(10), 1287-1303; https://doi.org/10.3390/ph6101287 - 11 Oct 2013
Cited by 65 | Viewed by 8428
Abstract
First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor [...] Read more.
First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options. Full article
(This article belongs to the Special Issue CNS-Drugs and Therapy)
328 KiB  
Review
The Use of Central Nervous System Active Drugs During Pregnancy
by Bengt Källén, Natalia Borg and Margareta Reis
Pharmaceuticals 2013, 6(10), 1221-1286; https://doi.org/10.3390/ph6101221 - 10 Oct 2013
Cited by 118 | Viewed by 12535
Abstract
CNS-active drugs are used relatively often during pregnancy. Use during early pregnancy may increase the risk of a congenital malformation; use during the later part of pregnancy may be associated with preterm birth, intrauterine growth disturbances and neonatal morbidity. There is also a [...] Read more.
CNS-active drugs are used relatively often during pregnancy. Use during early pregnancy may increase the risk of a congenital malformation; use during the later part of pregnancy may be associated with preterm birth, intrauterine growth disturbances and neonatal morbidity. There is also a possibility that drug exposure can affect brain development with long-term neuropsychological harm as a result. This paper summarizes the literature on such drugs used during pregnancy: opioids, anticonvulsants, drugs used for Parkinson’s disease, neuroleptics, sedatives and hypnotics, antidepressants, psychostimulants, and some other CNS-active drugs. In addition to an overview of the literature, data from the Swedish Medical Birth Register (1996–2011) are presented. The exposure data are either based on midwife interviews towards the end of the first trimester or on linkage with a prescribed drug register. An association between malformations and maternal use of anticonvulsants and notably valproic acid is well known from the literature and also demonstrated in the present study. Some other associations between drug exposure and outcome were found. Full article
(This article belongs to the Special Issue CNS-Drugs and Therapy)
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1457 KiB  
Review
MicroRNAs as Molecular Targets for Cancer Therapy: On the Modulation of MicroRNA Expression
by Pedro M. Costa and Maria C. Pedroso de Lima
Pharmaceuticals 2013, 6(10), 1195-1220; https://doi.org/10.3390/ph6101195 - 30 Sep 2013
Cited by 93 | Viewed by 10552
Abstract
The discovery of small RNA molecules with the capacity to regulate messenger RNA (mRNA) stability and translation (and consequently protein synthesis) has revealed an additional level of post-transcriptional gene control. MicroRNAs (miRNAs), an evolutionarily conserved class of small noncoding RNAs that regulate gene [...] Read more.
The discovery of small RNA molecules with the capacity to regulate messenger RNA (mRNA) stability and translation (and consequently protein synthesis) has revealed an additional level of post-transcriptional gene control. MicroRNAs (miRNAs), an evolutionarily conserved class of small noncoding RNAs that regulate gene expression post-transcriptionally by base pairing to complementary sequences in the 3' untranslated regions of target mRNAs, are part of this modulatory RNA network playing a pivotal role in cell fate. Functional studies indicate that miRNAs are involved in the regulation of almost every biological pathway, while changes in miRNA expression are associated with several human pathologies, including cancer. By targeting oncogenes and tumor suppressors, miRNAs have the ability to modulate key cellular processes that define the cell phenotype, making them highly promising therapeutic targets. Over the last few years, miRNA-based anti-cancer therapeutic approaches have been exploited, either alone or in combination with standard targeted therapies, aiming at enhancing tumor cell killing and, ideally, promoting tumor regression and disease remission. Here we provide an overview on the involvement of miRNAs in cancer pathology, emphasizing the mechanisms of miRNA regulation. Strategies for modulating miRNA expression are presented and illustrated with representative examples of their application in a therapeutic context. Full article
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Review
Safety of Immunosuppressive Drugs Used as Maintenance Therapy in Kidney Transplantation: A Systematic Review and Meta-Analysis
by Celline Cardoso Almeida, Micheline Rosa Silveira, Vânia Eloisa De Araújo, Livia Lovato Pires De Lemos, Juliana De Oliveira Costa, Carlos Augusto Lins Reis, Francisco De Assis Acurcio and Maria Das Gracas Braga Ceccato
Pharmaceuticals 2013, 6(10), 1170-1194; https://doi.org/10.3390/ph6101170 - 30 Sep 2013
Cited by 93 | Viewed by 8351
Abstract
To evaluate the safety of regimens containing calcineurin inhibitors (CNI), proliferation signal inhibitors (TOR-I) and antimetabolites, we conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies. A total of 4,960 citations were identified in our electronic search and 14 additional articles [...] Read more.
To evaluate the safety of regimens containing calcineurin inhibitors (CNI), proliferation signal inhibitors (TOR-I) and antimetabolites, we conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies. A total of 4,960 citations were identified in our electronic search and 14 additional articles were identified through hand searching. Forty-eight articles (11,432 participants) from 42 studies (38 RCTs and four cohorts) met the inclusion criteria. Meta-analysis results revealed the following: (i) tacrolimus was associated with an increased risk for diabetes and lower risk of dyslipidemia, compared to cyclosporine; (ii) mycophenolate mofetil (MMF) was associated with increased risk for total infections, abdominal pain, diarrhea and vomiting, compared with azathioprine; (iii) sirolimus was associated with higher risk of anemia, diabetes, dyslipidemia, lymphoceles and withdrawal compared to tacrolimus or cyclosporine, and cyclosporine was associated with an increased risk of CMV infection; (iv) the combination of CNI with antimetabolites was associated with more adverse events than CNI alone; (v) TOR-I was related to more adverse events than MMF. The data observed in this meta-analysis are similar to those describe by others authors; thus, the choice of treatment must be made by the clinical staff based on specific patient characteristics. Full article
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