Antiabsence effects of carbenoxolone in two genetic animal models of absence epilepsy (WAG/Rij rats and lh/lh mice)

Carbenoxolone (CBX), the succinyl ester of glycyrrhetinic acid, is an inhibitor of gap junctional intercellular communication. We have tested its possible effects upon two genetic animal models of epilepsy (WAG/Rij rats and lethargic (lh/lh) mice). Systemic administration of CBX was unable to significantly affect the occurrence of absence seizures in WAG/Rij rats. In particular, intravenous (5-40 mg/kg) or intraperitoneal (i.p.; 10-80 mg/kg) administration of CBX was unable to significantly modify the number and duration of spike-wave discharges (SWDs) in WAG/Rij rats, whereas the bilateral microinjection (0.05, 0.1, 0.5 and 1 microg/0.5 microl) of CBX into nucleus reticularis thalami (NRT) and nucleus ventralis posterolateralis (VPL) thalami produced a decrease in the duration and the number of SWDs. Bilateral microinjection of CBX into nucleus ventroposteromedial (VPM) thalami did not produce any significant decrease in the number and duration of SWDs. On the contrary, i.p. (5-40 mg/kg) or intracerebroventricular (0.5, 1, 2 and 4 microg/2 microl) administration of CBX in lh/lh mice induced a marked decrease in the number and duration of SWDs in a dose-dependent manner. At the doses used no movement disorders, or other behavioural changes, were recorded in both WAG/Rij rats and lh/lh mice. No effects were observed in both animal models following systemic or focal administration of glycyrrhizin into the same brain areas where CBX was shown to be effective

Exploring Off-Targets and Off-Systems for Adverse Drug Reactions via Chemical-Protein Interactome — Clozapine-Induced Agranulocytosis as a Case Study

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs

Serum homocysteine levels in men with and without erectile dysfunction: A systematic review and meta-analysis

Objectives. Elevated levels of serum homocysteine (Hcy) have been associated with cardiovascular diseases and endothelial dysfunction, conditions closely associated with erectile dysfunction (ED). This meta-analysis was aimed to assess serum Hcy levels in subjects with ED compared to controls in order to clarify the role of Hcy in the pathogenesis of ED. Methods. Medline, Embase, and the Cochrane Library were searched for publications investigating the possible association between ED and Hcy. Results were restricted by language, but no time restriction was applied. Standardized mean difference (SMD) was obtained by random effect models. Results. A total of 9 studies were included in the analysis with a total of 1320 subjects (489 subjects with ED; 831 subjects without ED). Pooled estimate was in favor of increased Hcy in subjects with ED with a SMD of 1.00, 95% CI 0.65-1.35, p < 0.0001. Subgroup analysis based on prevalence of diabetes showed significantly higher SMD in subjects without diabetes (1.34 (95% CI 1.08-1.60)) compared to subjects with diabetes (0.68 (95% CI 0.39-0.97), p < 0 0025 versus subgroup w/o diabetes). Conclusions. Results from our meta-analysis suggest that increased levels of serum Hcy are more often observed in subjects with ED; however, increase in Hcy is less evident in diabetic compared to nondiabetic subjects

Iatrogenic Delirium in an Elderly Patient: When Drugs are Harmful

Delirium is a global disorder of cognition that represents a medical emergency and, particularly in elderly, is often unrecognized or misdiagnosed and commonly mistaken for dementia, depression, mania, or an acute schizophrenic reaction. Drug-induced delirium is a common matter in the elderly and in this paper we report the onset of delirium induced by -drug interaction in a previously health elderly patient

Interactions among Low Dose of Methotrexate and Drugs Used in the Treatment of Rheumatoid Arthritis

Methotrexate (MTX) is a nonbiological disease-modifying antirheumatic drug that has shown both a good control of clinical disease and a good safety. Usually drug-drug interactions (DDIs) represent the most limiting factor during the clinical management of any disease, in particular when several drugs are coadministered to treat the same disease. In this paper, we report the interactions among MTX and the other drugs commonly used in the management of rheumatoid arthritis. Using Medline, PubMed, Embase, Cochrane libraries, and Reference lists, we searched for the articles published until June 30, 2012, and we reported the most common DDIs between MTX and antirheumatic drugs. In particular, clinically relevant DDIs have been described during the treatment with MTX and NSAIDs, for example, diclofenac, indomethacin, or COX-2 inhibitors, and between MTX and prednisone or immunosuppressant drugs (e.g., leflunomide and cyclosporine). Finally, an increase in the risk of infections has been recorded during the combination treatment with MTX plus antitumor necrosis factor-α agents. In conclusion, during the treatment with MTX, DDIs play an important role in both the development of ADRs and therapeutic failure

New Insights into Signal Detection of the Effects of Exposures during Pregnancy

There is inadequate information on the fetal safety of drugs during pregnancy for the majority of marketed drugs. It is challenging to examine the safety and efficacy of drugs during pregnancy due to the ethical issues of exposing unborn babies to these chemicals. It often takes many years before associations between a drug and its safety, efficacy, and toxicity in pregnancy can be established. This thesis will examine strategies in signal detection of the effects of drug exposures during pregnancy. Meta-analyses have become useful in the area of clinical teratology. Observational studies provide the main source of information in these meta-analyses. Although the quality of meta-analysis of small observational studies is challenging, it is an effective strategy, as shown in the present study, in predicting correct signals to estimate teratogenicity years before large cohort studies become available. Results of retrospective pregnancy registries are commonly reported in regulatory documentations. However, little data are available on the precision of the estimates from such registries. The present study confirms a consistent bias against the null hypothesis in a retrospective registry which needs to be considered when interpreting such data as a strategy in generating safety/risk signals of new drugs. H1 antihistamines are used for the treatment of nausea and vomiting during pregnancy as well as the symptomatic relief of allergy. Although they are felt to be safe, several studies have challenged this assumption. By using meta-analysis, the safety of antihistamines has been confirmed in this thesis with over 1.3 million exposed and control subjects. Typically, after experimental animal studies, novel therapeutic modalities are tested by randomized controlled trials. Cumulative meta-analysis is an effective strategy to detect a possible time- dependent effect and potential bias against the null hypothesis, whether antioxidant treatment decreases the rates of preeclampsia. I have shown that the initial favorable effect seen in the first studies is nullified as the sample sizes and number of studies is increased. There is a need to continue using and developing the above strategies to study the safety and efficacy of drugs to improve maternal-fetal health