Current Clinical Pharmacology - Volume 7, Issue 1, 2012

Recent investigations of pain mechanisms leading to the induction and maintenance of long-term potentiation (LTP) in the spinal cord have identified a huge number of molecular targets that might be appropriate for therapeutically intervention. In this short review we summarize recently published studies investigating drugs that affect LTP in the spinal cord. After providing an overview of spinal pain pathways and of the respective methods for their investigation, molecular targets for possible pharmacological interventions are discussed.

Antidepressant use during the gestational period remains a controversial issue. The objective of this study was to appraise the quality of the available clinical practice guidelines (CPGs) that includes recommendations for antidepressant use during pregnancy. We systematically searched for documents published between January 2000 and September 2010 in MEDLINE / TRIP database and on clearinghouses and main scientific societies' websites. Four appraisers evaluated each guideline using the Appraisal of Guidelines for Research and Evaluation tool (AGREE II). Intra-class correlation coefficients (ICC) with 95% confidence intervals (CI) were calculated as an overall indicator of agreement. Twelve CPGs were included from a total of 539 references. Only two guidelines were specifically addressed to pregnant women. The overall agreement among reviewers was high (ICC: 0.94, 95% CI: 0.86-0.98). The mean scores and standard deviation (SD) for each of the AGREE II domains were: scope and purpose: 84.4% (12); stakeholder involvement: 67.4% (29.8); rigor of development: 68.6% (19.8); clarity and presentation: 83.4% (17.4); applicability: 44% (37.3); and editorial independence: 62.1% (30.4). After standardizing the scores of the 12 guidelines, 5 were considered as being “recommended”, 5 as “recommended with modifications, and 2 as “not recommended”. Among the five recommended guidelines, two were specifically conceived to the gestational period. CPGs containing recommendations for antidepressant use during pregnancy were of moderate to high quality. Future guidelines should take into account the observed drawbacks in some domains, and specifically focus a more in depth approach of depression during pregnancy.

Structure-activity relationships (SARs) refer to the relation between chemical structure and pharmacologic activity for a series of compounds. Since the pioneering work of Crum-Brown and Fraser in 1868, they have been increasingly used in the pharmaceutical, chemical and cosmetic industries, especially for drug and chemical design purposes. Structure-activity relationships may be based on various techniques, ranging from considerations of similarity or diversity of molecules to mathematical relationships linking chemical structures to measured activities, the latter being referred to as quantitative SAR or QSAR. This review aims at briefly reviewing the history of SARs and highlighting their interest in delayed and immediate drug allergy using selected examples from the literature. Studies of SAR are commonly conducted in the area of contact dermatitis, a delayed hypersensitivity reaction, to determine the allergenic potential of a given compound without animal testing. In immediate, immunoglobulin E-mediated drug hypersensitivity, this kind of approach remains rather confidential. It has been mainly applied to neuromuscular blocking drugs (muscle relaxants) and betalactam antibiotics (penicillins, cephalosporins). This review shows that SARs can prove useful to (i) predict the allergenic potential of a chemical or a drug, (ii) help identify putative antigenic determinants for each patient or small group of patients sharing the same cross-reactivity pattern, and (iii) predict the likelihood of adverse reactions to related molecules and select safe alternatives.

Aminoglycoside antibiotics are usually administered by multiple short intravenous infusions at fixed intervals. Today, equations reported 35 years ago by Sawchuk and Zaske are still the cornerstone of methods used for determination of patient-specific pharmacokinetic parameters of aminoglycosides and individualization of drug dosage regimens in many clinical settings. Additionally, these methods are included in many clinical pharmacology curricula in pharmacy and other related fields. However, there are a few issues with regard to the application and/or modification of this method in clinical settings, which may result in some confusion among novice clinicians. For example, serum samples collected from different intervals at steady state, instead of samples obtained during the same interval, require special manipulation of sampling time before they can be used for estimation of pharmacokinetic parameters. Furthermore, there are various ways that the original equations are modified or simplified, which can result in some degree of error in the estimates of pharmacokinetic parameters and ensuing dosage regimen calculations. Simulation data presented here indicate that in some cases, these errors may be substantial, depending on the length of short infusion, half life of the drug, and the dosage interval. For instance, using equations developed for intravenous bolus mode of administration, ignoring the short infusion, may result in ≥ 25% error for a typical patient and dosing scenario. Although experts may use modified equations, understanding their error ramifications, these modifications may be confusing to the novice clinician. Therefore, it is recommended that exact equations developed specifically for multiple intravenous infusions be used without any modification, particularly in settings where clinicians are being trained.

As bacterial vaginosis (BV) is a potential cause of obstetric complications and gynecological disorders, there is substantial interest in establishing the most effective treatment. Standard treatment - metronidazole or clindamycin, by either vaginal or oral route - is followed by relapses in about 30% of cases, within a month from treatment completion. This inability to prevent recurrences reflects our lack of knowledge on the origins of BV. Atopobium vaginae has been recently reported to be associated with BV in around 80% of the cases and might be involved in the therapeutic failures. This review looks at the potential benefits of nifuratel against A. vaginae compared to the standard treatments with metronidazole and clindamycin. In vitro, nifuratel is able to inhibit the growth of A. vaginae, with a MIC range of 0.125-1 μg/mL; it is active against G. vaginalis and does not affect lactobacilli. Metronidazole is active against A. vaginae only at very high concentrations (8-256 μg/mL); it is partially active against G. vaginalis and also has no effect on lactobacilli. Clindamycin acts against A. vaginae with an MIC lower than 0.125 μg/mL and is active on G. vaginalis but it also affects lactobacilli, altering the vaginal environment. These observations suggest that nifuratel is probably the most valid therapeutic agent for BV treatment.

We hypothesized that a high concentration of nifedipine (1 μM), known to inhibit at least 75%of L-type Ca++ current, might counteract proarrhythmic dose-dependent effects of ondansetron (0.1 to 10 μM) in rabbit Purkinje fibers. Ondansetron is a 5-HT3 receptor antagonist commonly prescribed to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery but may increase the risk of developing prolongation of the QT interval of the electrocardiogram, which can lead to an abnormal and potentially fatal heart rhythm and recently raised FDA concerns and warnings. Neostigmine, a quaternary nitrogen agent that was also used clinically concomitant to antiemetics after anesthesia was further investigated dose-dependently (0.1 to 10 μM) and at fixed concentration (10 μM) with 0.1 to 10 μM ondansetron. The protocol included use-dependent (1 to 0.33 Hz) studies. APD durations, triangulation and early after depolarization (EAD) incidence were assessed. Ondansetron increased APD50, APD70 and APD90 (0.01>p<0.05) dose-dependently. APD90 averaged 102±1%of baseline to 302±49%dose-dependently (p<0.001) and, at the highest dose, increased to 511±73%reverse use-dependently (p<0.001). EAD were seen at top concentrations (33%) which were increased at lower rates (50%). Neostigmine induced reverse use-dependent APD changes (p<0.05) but no EAD. In preparations treated by nifedipine and ondansetron, APD90 changes averaged 101±2%of baseline to 151±8%dose-dependently (p<0.01) and to 193±13%reverse use-dependently (p<0.05) and no EAD were seen. Thus nifedipine significantly shortened ondansetron-induced APD changes (p<0.01), whereas neostigmine only slightly shortened ondansetron-induced APD changes (p<0.05). There was a tendency for increased incidence of EAD (p<0.06) in the ondansetron and neostigmine group vs. neostigmine alone. It is concluded that inhibition of L-type Ca++ current by high concentration nifedipine may counteract the ondansetron effects on APD changes.

Background: In Arab and Muslim-dominated countries, spirituality and religiosity shape the belief and practices toward chronic illnesses. No previous studies were published to assess adherence to and satisfaction with antipsychotic medications in persons with schizophrenia in the Arab world. Objective: To assess medication adherence and treatment satisfaction with antipsychotics in a sample of Palestinian people with schizophrenia. Methodology: Medication adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8). Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4). Psychiatric symptoms were assessed using the expanded Brief Psychiatric Rating Scale (BPRS-E). Data were entered and statistically analyzed using SPSS 16 for windows. Results: A convenience sample of 131 persons with schizophrenia was studied. Based on MMAS-8, 44 persons (33.6%) had a low rate, 58 (44.3%) had a medium rate and 29 (22.1%) had a high rate of adherence. Age was significantly correlated (P=0.028) with adherence score. However, variables like use of monotherapy or atypical or depot antipsychotics were not significantly associated with higher adherence. The means of satisfaction with regard to effectiveness, side effects, convenience and global satisfaction were 72.6 ± 20.5, 67.9 ± 31.47, 63.2 ± 14.3 and 63.1 ± 18.8 respectively. There was a significant difference in the means of effectiveness (P<0.01), convenience (P<0.01), global satisfaction (P<0.01), but not side effects domains (P=0.1) among persons with different levels of adherence. Furthermore, there was a significant difference in the means of positive symptom score (P<0.01), manic (P<0.01) and depression (P<0.01) but not negative symptom score (P=0.4) among persons with different levels of adherence. Conclusions: Medication nonadherence was common and was associated with low treatment satisfaction scores and poor psychiatric scores. Medication related factors had insignificant effects on adherence scores.

Objective: The objective of this systematic review is to summarize the literature to date on the rates of infusion reactions (IR) associated with chemotherapies and monoclonal antibody (mAb) drug therapies used for the treatment of metastatic colorectal cancer (mCRC) and the associated clinical and economic impact. Methods: This study searched Medline, Medline (R) In-Process, Embase and Cochrane Library databases for studies on IRs associated with chemotherapy and mAbs in mCRC patients from 2000-2011. Results: For chemotherapy, the incidence of IRs ranged from 0-71% for all grades and 0-15% for grade 3-4. Rates of all grade IRs associated with cetuximab ranged from 7.6-33% and grade 3-4 IR rates were 0-22%. Rates of all grade IRs associated with panitumumab ranged from 0-4% and rates of grade 3-4 IRs ranged from 0-1%. The overall rate of IRs associated with bevacizumab ranged from 1.6-11%, with a rate of 0-4% for grade 3-4 IRs. A range of 50-100% of patients with grade 3-4 IRs terminated chemotherapy, and 34-100% of cetuximab patients with grade 3-4 IRs discontinued cetuximab therapy. No data were reported for bevacizumab or panitumumab. Only one study evaluated the economic impact of IRs. The study compared cetuximab administrations without an IR to those with an IR requiring resource utilization and found that mean costs were $9308 and $1725 higher for those with an IR requiring an emergency room visit or hospitalization and for those with an IR requiring outpatient treatment, respectively. Conclusions: The incidence of IRs varies among different mAbs; and IRs may cause treatment disruption and require costly medical interventions.

Migraine is a common disorder with a female prevalence of 17% and a male prevalence of 9%. Migraine is most often disabling and the patients need treatment of the attacks. The introduction of triptans has been a revolution for many migraine patients but only a minority of patients use these specific drugs. The pharmacokinetics and efficacy and tolerability of triptans are reviewed. The triptans can most likely with advantage be combined with NSAIDs and prokinetic drugs. Among future drugs, CGRP receptor antagonists are the most promising. These drugs have shown excellent tolerability with no more adverse events than placebo, but only one quarter of migraine patients have been pain-free after 2 hours in phase III studies. The development of current CGRP antagonists has been stopped.