When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and

Piperine, the active principle of Piper longum, Piper nigrum and Zingiber officinalis, has been reported to enhance the oral bioavailability of phenytoin in human volunteers. The objective of this study was to explore the effect of a single dose of piperine in patients with uncontrolled epilepsy on the steady-state pharmacokinetics of phenytoin. Two groups of 10 patients each receiving either a 150 mg or 200 mg twice daily dose of phenytoin were selected. Twelve hours after the night dose, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h after administration of phenytoin. On the next study day, piperine 20 mg was administered along with phenytoin and samples were collected similarly. The mean plasma drug concentrations at different time points and the pharmacokinetic parameters before and after piperine administration were compared by Student's t-test. Piperine increased significantly the mean plasma concentration of phenytoin at most of the time points in both dose groups. There was a significant increase in AUC((0-12h)) (p < 0.01), C(max) (p < 0.001) and K(a) (p < 0.05) whereas the changes in K(el) and t(max) were not significant. The results showed that piperine enhanced the bioavailability of phenytoin significantly, possibly by increasing the absorption.

Piperine, the active principle of piper species, is commonly used as a spice and adjuvant in various traditional systems of medicine. It has been known as a bioavailability-enhancer. The present study aimed at evaluating the effect of piperine on the steady-state pharmacokinetics of a single dose of carbamazepine in poorly controlled epilepsy patients on carbamazepine monotherapy. Patients (n = 10 each) receiving either 300 mg or 500 mg dose of carbamazepine twice daily were selected. After administration of carbamazepine, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h. Subsequently, piperine (20 mg p.o.) was administered along with carbamazepine and samples were collected similarly. The pharmacokinetic parameters were compared by Students t-test. Piperine significantly increased the mean plasma concentrations of carbamazepine at most of the time points in both dose groups. There was a significant increase in AUC(0-12hr) (p < 0.001), average C(ss) (p < 0.001), t(1\2el) (p < 0.05) and a decrease in K(el) (p < 0.05), in both the dose groups, whereas changes in K(a) and t(1\2a) were not significant. Cmax (p < 0.01) and t(max) (p < 0.01) were increased significantly following piperine administration in the 500 mg dose group; however, these parameters were not significant in the lower dose group. Piperine could significantly enhance the oral bioavailability of carbamazepine, possibly by decreasing the elimination and/or by increasing its absorption.

Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Coadministration of nirmatrelvir/ritonavir with immunosuppressive drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. Although a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejec-tion. Here, we provide some general recommendations for therapeutic drug monitoring of ISDs and dosing recommendations when coadministered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day 1, whereas cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug related events include ADRs, events due to patient or physician noncompliance, drug overdosage and drug interactions.• Economic burden of management of drug related events are substantial and include both direct and indirect costs.• Some data regarding cost of treatment of ADR exist from south and western India. WHAT THIS STUDY ADDS• An approximate cost of management of drug related events presenting to the emergency medical department in a tertiary care hospital over a period of 4 months.• Compares the cost incurred in a public sector hospital to the projected cost of management of same events in a private sector hospital.• Gives a rough estimate of economic burden on the health care system due to adverse drug events. AIMSDrug related events (DREs) contribute significantly to hospital admissions. These are largely preventable events and require optimum use of the therapeutic agents. The study was conducted to analyze the cost of treatment of DREs. PATIENTS & METHODSAll visits to medical emergency department of a tertiary care public sector hospital in northern India were recorded in a prospective, non-interventional manner over a period of 4 months. DREs were recognized and were followed up till their stay in the hospital. Data about the cost generating components of direct and indirect costs of treatment of DREs were collected. The projected cost of treatment of the same DREs in a private sector hospital was estimated and compared. RESULTSOut of 1833 admissions, 92(5.01%) were due to DREs. Maximum cases were due to non compliance (66%) followed by ADR (28%) and drug overdose(6%). The common DREs leading to ED visits were cerebrovascular accident(19.44%), followed by accelerated hypertension(18.36%) and diabetic ketoacidosis(14.04%). Total cost of management of all the 92 DREs in our hospital was calculated to be INR17,37,339(€30,215). The direct cost was INR1,72,961(€3008) and the approximate indirect cost was INR15,64, 378(€27, 206). The projected cost of management of all the 92 DREs was estimated to be INR63,63,872(€1,01, 676) in a private sector hospital. CONCLUSIONThe study shows that ADEs leading to emergency department visits and hospitalizations constitute a significant economic burden. Training of the patients and the prescribers may lessen the economic burden on the patient as well as the health care system.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?• Different strategies have been evaluated for their efficacy in reducing stent thrombosis and restenosis in patients undergoing percutaneous coronary intervention (PCI).• Triple antiplatelet therapy is one such strategy that has been shown to improve the efficacy outcomes associated with PCI.• Cilostazol is an antiplatelet agent that is being prescribed as a component of triple-therapy regimen in various centres in our country, and the beneficial effect of cilostazol addition to other antiplatelet regimens has been observed. • However, the extent of the efficacy is not uniformly in favour of the triple therapy compared with dual therapy. • Moreover, the use of this agent with bare metal stents (commonly used in developing countries) and drug-eluting stents has not been separately looked into. WHAT THIS STUDY ADDS• Triple antiplatelet therapy, with cilostazol as a component, reduces restenosis rates and repeat revascularizations post PCI without any significant increase in bleeding risk.• The beneficial effect of cilostazol is more evident with drug-eluting stents.• Its use with bare metal stents needs to be explored further. AIMSOutcomes of patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and bare metal stents (BMS) have not been evaluated separately for specific dual and triple antiplatelet agent use. The purpose of this meta-analysis was to determine whether triple antiplatelet therapy (combination of clopidogrel, aspirin and cilostazol) has any advantage in efficacy compared with standard dual antiplatelet therapy (aspirin and clopidogrel) in patients undergoing PCI. METHODSElectronic and printed sources were searched till May 2008 for randomized controlled clinical trials (RCTs) of cilostazol in combination with aspirin and clopidogrel. Pooled weighted mean difference (WMD) and pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. RESULTSA total of four RCTs including 1457 patients with a median follow-up period of 6-9 months were included in the analysis. The rates of major adverse cardiac and/or cerebrovascular events (MACE/MACCE), stent thrombosis and bleeding were not significantly different between triple and dual antiplatelet therapy groups. Pooled analysis showed that cilostazol was associated with significantly decreased incidence of in segment restenosis (ISR) (OR 0.51, 95% CI 0.38, 0.68; P < 0.00001), increased minimum luminal diameter (MLD) (WMD 0.16, 95% CI 0.10, 0.22; P < 0.00001) for both DES and BMS and also individually. However, the rates of target vessel revascularization (OR 0.45, 95% CI 0.25, 0.83; P = 0.01 and late lumen loss (pooled WMD 0.14, 95% CI 0.2, 0.07; P = 0.001) were decreased significantly only in the DES group receiving triple therapy. CONCLUSIONSCilostazol appears to be effective in reducing the rates of ISR without any significant benefit for MACE/MACCE.

The aim of this research is to study the effects of nimodipine, gabapentin, ketamine and imipramine in the partial sciatic nerve transection (PST) model of neuropathic pain in rats. PST was produced in young Wistar rats of either sex by partial destruction of the sciatic nerve. A decrease in the latency to paw withdrawal reaction on the hot plate was considered as development of neuropathy. The drugs were given daily from the third day of the procedure, and evaluation was done on days 7, 14, 21 and 28. There was a significant decrease (p < 0.05) in the paw withdrawal response in the nimodipine group from day 14 onward when compared with the control group. In the ketamine and imipramine group, this response was seen from day 21 onward. The effect persisted till the end of the study. There was no improvement in the gabapentin group. The results of our study show that nimodipine (dihydropyridine calcium channel blocker), ketamine (NMDA antagonist) and imipramine (tricyclic antidepressant) modulated hyperalgesia and allodynia in the PST model of neuropathy. Gabapentin (an alpha-2 delta calcium subunit blocker) did not show any effect in this model of neuropathy. The widespread use of gabapentin in various types of neuropathic pain thus needs to be reevaluated.

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