Low Risk Of Drug-drug Interactions Research Articles

New once-daily formulation for trospium in overactive bladder

AIMS We examined the relative efficacy and safety of trospium 20 mg bid and 60 mg extended release formulations and position this drug against other antimuscarinic agents. Data were identified on the pharmacology and pharmacokinetics of trospium chloride. Key publications on trospium 20-mg and 60-mg clinical studies in patients with overactive bladder (OAB) were identified and efficacy and safety compared between these formulations as well as other antimuscarinic agents. Trospium offers the principal advantage over other antimuscarinic agents that, as it is a quaternary amine, it does not cross the blood-brain barrier and is therefore less likely to cause central nervous system effects observed with several other agents. Moreover, with its minimal liver metabolisation, independent of the main cytochrome pathways, trospium has a low risk of drug-drug interaction in patients taking multiple pharmacological agents. Trospium 60 mg ER is as effective as trospium 20 mg bid in improving the key outcome parameters associated with OAB, but with a lower rate of dry mouth, the most common side effect of these agents. Trospium has comparable efficacy and safety to the other antimuscarinic agents currently marketed. Good patient persistence with treatment has been reported with trospium. There are currently a large number of antimuscarinic drugs on the market without clear evidence to distinguish one agent from another in terms of efficacy, provided that an adequate dose is used in the clinical setting. The new formulation of trospium is certainly worth considering as a pharmacological treatment of patients with OAB, particularly in the elderly, in whom one wants to avoid the potential for cognitive dysfunction.

Inhibition of human liver microsomal CYP by nateglinide

Nateglinide is metabolized by CYP2C9 and CYP3A4, therefore drug-drug interactions through cytochrome P450 (CYP) inhibition may occur. In this study, we examined the inhibitory effects of nateglinide and its major metabolite N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine (M1) on various CYP isoforms in human liver microsomes. We used typical substrates (7-ethoxyresorufin for CYP1A1/2, tolbutamide for CYP2C9, S-mephenytoin for CYP2C19, bufuralol for CYP2D6, chlorzoxazone for CYP2E1 and midazolam for CYP3A4) in the evaluation of the inhibitory effects, and examined the possibility of mechanism-based inhibition (MBI) by evaluating the influence of pre-incubation in the inhibition. The results showed that nateglinide inhibited CYP2C9 and CYP2C19 with an IC50(app) (apparent value of the 50% inhibitory concentration) of 125 micromol/l and 946 micromol/l, respectively, while M1 did not inhibit any of the CYP isoforms. The inhibition constant (K(i)) value of the inhibitory effect of nateglinide on CYP2C9 and the 1 + I(in,max,u)/K(i) value were estimated (where I(in,max,u)= the maximum unbound concentration of nateglinide). The 1 + I(in,max,u)/K(i) value was 1.02 (close to 1), suggesting a low risk of drug-drug interactions. The influence of pre-incubation on the inhibition by nateglinide of CYP3A4, CYP2C9 and CYP2C19 was examined. The results revealed that the inhibition of CYP by nateglinide was not influenced by pre-incubation, and that the possibility of MBI is very low. The possibility of drug-drug interactions involving nateglinide that might be attributable to CYP inhibition is low.

Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models

Among the known antimalarial drugs, chloroquine (CQ) and other 4-aminoquinolines have shown high potency and good bioavailability. Yet complications associated with drug resistance necessitate the discovery of effective new antimalarial agents. ADMET prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug-drug interactions, and desirable pharmacokinetic profiles. Both 18 and 4 are highly potent antimalarial compounds, with IC(50) values of 5.6 and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (for CQ, IC(50) = 382 nM). When tested in mice, these compounds were found to have biological half-lives and plasma exposure values similar to or higher than those of CQ; they are therefore desirable candidates to pursue in future clinical trials.

Onychomycosis and diabetes

This study aims to discuss factors specific to diabetics in the diagnosis and treatment of onychomycosis. Onychomycosis has the potential to cause severe complications in diabetics and should be treated promptly. The existence of comorbid conditions and potential for drug-drug interactions complicates the selection of an appropriate treatment regimen. The role of Candida in onychomycosis is controversial but may be of increased significance in the diabetic population due to an underlying vulnerability to this organism. Terbinafine is an excellent choice in diabetics due to its low risk of drug-drug interaction and proven efficacy against the typical pathogens that cause onychomycosis. Itraconazole, while an effective treatment for onychomycosis, is not a first-choice therapy due to its black-box cardiac warning and numerous drug interactions. Larger studies are needed in diabetics to determine the frequency of candidal nail infections.

Miconazole en comprimé gingival muco-adhésif (Loramyc ® 50 mg)

Depressed patients are at increased risk of cardiovascular (CV) disease (CVD) and those with concomitant depression and CVD are at increased risk of death. The safety and efficacy of antidepressants in patients with CVD varies greatly between the agent used and type of disease. This review will summarize the CV adverse effect and drug interaction profile of antidepressants and discuss the use of antidepressants in CVD patients.We searched MEDLINE, PubMed, CINAHL, Web of Science, PsycINFO, and The Cochrane Library from inception to June 2014 to identify studies relevant to antidepressant use in patients with CVD. Primary references from the identified articles were also evaluated for inclusion. Descriptive analysis was performed for the included studies in this review.Orthostatic hypotension was more common with tricyclic antidepressants (TCAs), trazodone and monoamine oxidase inhibitors (MAOIs). Hypertension can be significant with serotonin norepinephrine reuptake inhibitors (SNRIs) and MAOIs. The potential for QT prolongation is present with TCAs, certain selective serotonin reuptake inhibitors (SSRIs), certain SNRIs and mirtazapine. Due to its low risk of drug-drug interactions, adverse effect profile and potential for beneficial antiplatelet activity, sertraline could be considered the choice antidepressant for patients with ischemic heart disease. SSRIs and potentially SNRIs are relatively safe and effective options for patients with heart failure. In patients at high risk for ventricular arrhythmias, bupropion has the overall lowest risk for QT prolongation. TCAs and MAOIs should be avoided in patients with concomitant CVD. In conclusion, due to the increased morbidity and mortality associated with comorbid CVD and depression, practitioners should readily assess and initiate management of depression in such patients. The choice of antidepressant should take into account the potential CV impact of the various agents balancing safety and efficacy.

Practical Issues with Amisulpride in the Management of Patients with Schizophrenia

Amisulpride is an atypical antipsychotic with a significantly greater effect size than first-generation, typical antipsychotics, and efficacy at least similar to that of olanzapine and risperidone in large-scale clinical trials in schizophrenia. Amisulpride provides greater improvement in positive and negative symptoms of schizophrenia, a better long-term outcome than typical antipsychotics, and distinct tolerability advantages over typical antipsychotics, which are reported to cause extrapyramidal symptoms (EPS) in 20-50% of patients. In addition, amisulpride is associated with significantly less weight gain than olanzapine and risperidone, does not increase body mass index, and favourably influences lipid profiles. In many patients with schizophrenia, adverse events impair adherence to treatment, and switching from typical or atypical antipsychotic therapy to amisulpride may be clinically appropriate. Observational drug-utilization studies suggest that many physicians switch to amisulpride because of fewer EPS and/or less weight gain and improved patient adherence. Cross-tapering (over 4 weeks), rather than abrupt cessation of pre-switch treatment, is preferred. Amisulpride has a low risk of drug-drug interactions, and, during cross-tapering, patients can remain on concurrent treatments (e.g. anticholinergics and antiparkinsonian agents) until the effective dosage has been reached. An appropriate amisulpride starting dose is 800 mg/day for patients with acute psychotic exacerbations, 400-800 mg/day for patients with predominantly positive symptoms, and 100-300 mg/day for predominantly negative symptoms. Amisulpride may be particularly suitable for clozapine-augmentation therapy in patients with refractory schizophrenia. Indeed, amisulpride is more effective than quetiapine as augmentation therapy in patients partially responsive to clozapine, and several prospective open-label studies and case series have reported promising results for amisulpride/clozapine combination therapy. In three prospective studies, addition of amisulpride 200-800 mg/day to clozapine significantly reduced mean scores on the Brief Psychiatric Rating Scale (BPRS) total (-33% to -35%), Clinical Global Impression (CGI)-Severity scale (-31%), Positive and Negative Syndrome Scale total (-22%), and Scale for the Assessment of Negative Symptoms (-34%). The proportion of responders (CGI score > or =3 or BPRS improvement >20%) was 71-86%. Retrospective case-series analyses have also reported improved psychopathological state, reduced adverse events, and lower clozapine dosage requirement with use of this combination. The pharmacological and clinical profiles of amisulpride suggest that this agent is a viable clinical option when a change of antipsychotic therapy is required in patients with schizophrenia because of lack of efficacy, adverse events and poor adherence to treatment, or for augmentation of clozapine in treatment-resistant illness.

Multimodal Approaches to the Management of Neuropathic Pain: The Role of Topical Analgesia

Because of their localized activity and low systemic absorption, topical analgesics have a favorable safety profile and a low risk for drug-drug interactions. There is a growing body of evidence on the efficacy and safety of these agents in a variety of pain disorders, including the most prevalent neuropathic pain conditions. The molecular basis for the usage of peripheral analgesics in neuropathic pain and the available clinical trial evidence for a wide variety of topical agents are reviewed.

Placebo-controlled relapse prevention trials in unipolar depression

Depressed patients are at increased risk of cardiovascular (CV) disease (CVD) and those with concomitant depression and CVD are at increased risk of death. The safety and efficacy of antidepressants in patients with CVD varies greatly between the agent used and type of disease. This review will summarize the CV adverse effect and drug interaction profile of antidepressants and discuss the use of antidepressants in CVD patients.We searched MEDLINE, PubMed, CINAHL, Web of Science, PsycINFO, and The Cochrane Library from inception to June 2014 to identify studies relevant to antidepressant use in patients with CVD. Primary references from the identified articles were also evaluated for inclusion. Descriptive analysis was performed for the included studies in this review.Orthostatic hypotension was more common with tricyclic antidepressants (TCAs), trazodone and monoamine oxidase inhibitors (MAOIs). Hypertension can be significant with serotonin norepinephrine reuptake inhibitors (SNRIs) and MAOIs. The potential for QT prolongation is present with TCAs, certain selective serotonin reuptake inhibitors (SSRIs), certain SNRIs and mirtazapine. Due to its low risk of drug-drug interactions, adverse effect profile and potential for beneficial antiplatelet activity, sertraline could be considered the choice antidepressant for patients with ischemic heart disease. SSRIs and potentially SNRIs are relatively safe and effective options for patients with heart failure. In patients at high risk for ventricular arrhythmias, bupropion has the overall lowest risk for QT prolongation. TCAs and MAOIs should be avoided in patients with concomitant CVD. In conclusion, due to the increased morbidity and mortality associated with comorbid CVD and depression, practitioners should readily assess and initiate management of depression in such patients. The choice of antidepressant should take into account the potential CV impact of the various agents balancing safety and efficacy.

Management of symptons associated with advanced cancer: olanzapine and mirtazapine

Advanced cancer patients are polysymptomatic and often receive multiple medications for symptom relief. Common symptoms include anorexia, weight loss, delirium and depression. Olanzapine and mirtazapine may have several advantages over older agents despite increased acquisition costs. Both medications can treat several symptoms with a low risk for drug-drug interactions and with only once- or twice-daily dosing. Drug side effects are low, compared with more conventionally used agents. The pharmacokinetics and pharmacodynamics of both agents are unique and explain many of the benefits. More research and clinical experience will be necessary to define their role in the palliation of advanced cancer.

In vitro interactions between a potential muscle relaxant E2101 and human cytochromes P450.

E2101 or N-methyl-[1-[1-(2-fluorophenethyl)piperidine-4-yl]-1H-indol-6-yl] acetamide, an antagonist of 5-hydroxytryptamine receptor subtypes 1A and 2, is currently under development for the potential treatment of skeletal muscle associated spasticity. Here we characterized the in vitro metabolism of E2101 using human liver enzymes including human liver microsomal preparations, human liver S9 fractions, and individual forms of recombinant cytochromes P450 (P450s). Our results showed that E2101 was metabolized by P450s to form monohydroxylated (M1 and M2), dihydroxylated (M3), and N-dealkylated metabolites (M4). The structures of these major microsomal metabolites were proposed based on LC/MS/MS analyses. All four metabolites, M1-M4, were formed by CYP3A4. Metabolites, M1, M2, and M4, were also formed by CYP2C19 and M2 and M3 by CYP2D6. The potential P450 inhibition and induction of E2101 were also evaluated. E2101 was determined to be a competitive inhibitor of CYP2C19 and CYP2D6 with K(i) of 15 and 48 microM, respectively, as determined by both Dixon plots and simultaneously nonlinear regression analyses. Induction of major P450 expression was not detected immunochemically after 72-h exposure to 10 or 50 microM E2101 in primary hepatocyte cultures obtained from three subjects. Taken together, E2101 is expected to metabolically interact with major human P450 enzymes including CYP2C19, CYP2D6, and CYP3A4, and a low risk of drug-drug interaction would be anticipated in clinical studies.