Current trends in drug treatment of obsessive–compulsive disorder

This article aims to highlight current trends in the pharmacologic management of obsessive–compulsive disorder (OCD). A systematic search of the electronic database MEDLINE was conducted. The first case report of clomipramine efficacy in the management OCD more than 40 years ago gave new hope for the treatment of this debilitating disorder. Selective serotonin reuptake inhibitors (SSRIs) proved to have a similar efficacy profile compared with clomipramine but had a superior tolerability profile. While many patients with OCD respond to SSRIs or clomipramine, the treatment of those with refractory OCD remains challenging. Different augmentation agents in treatment-resistant OCD have been explored, with antipsychotic agents having the largest supporting evidence base. Nevertheless, new pharmacologic treatment options are required and are under investigation

Treatment of HIV associated neurocognitive disorders

Background Human immunodeficiency virus (HIV) invades the central nervous system (CNS) as early as 8 days after HIV infection, causing a wide spectrum of neuropathological changes including HIV associated neurocognitive disorders (HAND). HAND is a spectrum of cognitive impairment, which in its most severe form cause marked interference with day-to-day functioning (HIV-associated dementia). Antiretroviral therapy (ART) has substantially reduced the incidence of HIV-associated dementia, but has not had an impact on the overall prevalence of HAND. The prevalence of milder stages of HAND in ART experienced individuals varies from 15 - 50%. Transporters expressed in the blood brain barrier and blood cerebrospinal fluid (CSF) barrier affect influx and efflux of drugs including antiretrovirals. Antiretrovirals that have better penetration into the CNS may result in improved cognitive function in patients with HAND, however this has not yet been conclusively shown. On the other hand, prolonged CNS exposure to high antiretroviral concentrations has been proposed as a cause of secondary decline in cognitive function as several antiretrovirals are neurotoxic. Efavirenz in particular, but also tenofovir and emtricitabine, have been shown to have direct neurotoxicity in preclinical models. Polymorphisms in genes that encode these enzymes or transporters may therefore affect antiretroviral CSF concentrations. Africans are the most genetically diverse population worldwide and South Africa has the world’s largest ART programme, with most of patients currently receiving efavirenz-tenofovir-emtricitabine. The impact of pharmacogenetic polymorphisms on the pharmacokinetics of efavirenz-tenofovir-emtricitabine CNS penetration are lacking. A number of adjunctive pharmacotherapies for HAND have been studied, including lithium. Multiple mechanisms have been suggested for the potential beneficial cognitive effect of lithium, including the inhibition of glycogen synthase kinase-3- beta, which mediates inflammation signaling pathways and neuronal apoptosis. Lithium has been used in mood disorders and other neuropsychiatric conditions for more than 40 years. In addition, lithium is a low-cost drug and widely available in public service settings in low and middle-income countries. There is a need for controlled data to evaluate the efficacy of lithium as adjunctive therapy for HAND. Finally, it is unknown whether lithium causes additive nephrotoxicity in combination with tenofovir. Methods We conducted a 24-week randomised placebo-controlled trial of lithium as adjunctive pharmacotherapy in participants with moderate to severe HAND established on ART for at least 6 months, with suppressed viral loads. We randomised 66 participants to lithium (n=32) or placebo (n= 34). Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, while our secondary endpoint was the change in proton magnetic resonance spectroscopy (1 H-MRS) brain metabolite concentrations. We collected paired plasma-CSF samples in 47 adult participants with and without HAND treated with efavirenz-tenofovir-emtricitabine. We considered 2049 single-nucleotide polymorphisms (SNPs), including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. We investigated genetic polymorphisms associated with CSF exposure of efavirenz and its metabolites, tenofovir and emtricitabine. The secondary objective was to explore the pharmacokineticpharmacodynamic relationships with neurocognitive performance. Finally, we investigated the change in estimated glomerular filtration rate (eGFR) in participants who received concomitant tenofovir and lithium. Results The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95% CI -0.26, 0.15); p = 0.716. The improvement remained similar when analysed according to age, severity of impairment, CD4+ count, time on ART and ART regimen. Standard 1 H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. There was no statistically significant difference in the reduction in eGFR or in potassium between the two arms during the 24 weeks. A model that included the composite CYP2B6 15582/516/983 genotype in univariate analyses best predicted the log10-transformed concentrations of plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 8-hydroxyefavirenz-to-efavirenz ratio and CSF efavirenz. Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742, ABCB1 rs115780656 and CYP2A6 -48A→C. The CYP2A6 -48A→C polymorphism was independently associated with higher CSF 8-hydroxy-efavirenz-to-efavirenz ratio. The CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenzto-efavirenz ratio in univariate on multivariate analyses adjusting for CYP2B6 516G→T and 983T→C. No polymorphisms were associated with CSF-to-plasma ratios of all 3 drugs, plasma or CSF 8-hydroxy-efavirenz, tenofovir or emtricitabine concentrations, or neurocognitive performance. Conclusion Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment. We found that 24-week treatment of HIV-infected patients with lithium and tenofovir did not result in increased nephrotoxicity. We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz-to-efavirenz ratio, plasma 8-hydroxy-efavirenz-to-efavirenz ratio, CSF 8-hydroxy-efavirenz-to-efavirenz ratio and CSF efavirenz

The pharmacokinetics of lopinavir in HIV-infected adults receiving rifampicin with adjusted doses of lopinavir

Includes bibliographical references.Globally Sub-Saharan Africa carries the biggest burden of patients infected with human immunodeficiency virus (HIV). Tuberculosis is the most common opportunistic infection in patients infected with HIV. Although antiretroviral therapy (ART) has decreased the burden of tuberculosis in HIV-infected patients, the incidence of tuberculosis remains higher than in the general population. HIV-tuberculosis co-infection requires dual treatment with ART and tuberculosis treatment, exposing patients to multiple drug-drug interactions. As ART programs mature, more patients will be changed from first-line to second-line ART. In South Africa, the adult second-line ART consists of the protease inhibitor (PI) lopinavir/ritonavir (LPV/r) and 2 nucleoside reverse transcriptase inhibitors (NRTls). This review will focus on the data of the drug-drug interactions between the PIs and rifampicin, with an emphasis on LPV/r

Dosage adjustment in medical patients with renal impairment at Groote Schuur Hospital

BACKGROUND: Many drugs are eliminated by the kidneys and therefore may require dose adjustment in patients with renal impairment. The need for dose adjustment is frequently neglected by prescribers. METHODS: We reviewed folders of patients admitted to the Groote Schuur Hospital general medical wards between January and March 2008. Patients with renal impairment, defined as an estimated glomerular filtration rate (eGFR) or = 1 day after renal function tests were performed. We determined what proportion of these prescriptions required dose adjustment and whether drug doses were appropriately adjusted. RESULTS: We found renal impairment in 32% (97/301) of medical admissions. There were 615 prescription entries for the 97 patients with renal impairment. Dose adjustment was required in 19% (117/615) of prescription entries, and only 32% (37/117) of these prescription entries were correctly dose adjusted. Of 97 patients, 69 received one or more drugs that required dose adjustment (median 1, range 1 - 5). All drug doses were correctly adjusted in 12% (8/69) of patients. Importantly, in the majority of patients (59% (41/69)) no doses had been correctly adjusted. CONCLUSION: Consistent with international studies, drug dose adjustment in patients with renal impairment in a South African hospital was frequently neglected. Strategies to alert clinicians of the need for dose adjustment in renal impairment should be considered, including automated eGFR reporting and computerised aids to guide drug dosing, that account for renal impairment

Renal safety of lithium in HIV-infected patients established on tenofovir disoproxil fumarate containing antiretroviral therapy: analysis from a randomized placebo-controlled trial

BACKGROUND: The prevalence of bipolar disorder in HIV-infected patients is higher than the general population. Lithium is the most effective mood stabiliser, while tenofovir disoproxil fumarate (TDF) is frequently used as part of combination antiretroviral therapy (ART). Both TDF and lithium are associated with renal tubular toxicity, which could be additive, or a pharmacokinetic interaction may occur at renal transporters with a decrease in TDF elimination. OBJECTIVE: We report on the change in estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease formula in participants who received ART including TDF and were enrolled in a 24 week randomised trial of lithium versus placebo in patients with HIV-associated neurocognitive impairment. METHODS: We included HIV-infected adults with cognitive impairment established on ART for at least 6 months with a suppressed viral load attending public sector ART clinics in Cape Town, South Africa. We excluded participants with an eGFR <60 mL/min and treated with medications predisposing to lithium toxicity. We reviewed participants weekly for the first month for adverse events followed by 4 weekly visits for renal function assessment, adverse event monitoring and adherence. Lithium dose was titrated to achieve the maintenance target plasma concentration of between 0.6 and 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo. RESULTS: We included 23 participants allocated to the lithium arm and 30 participants allocated to the placebo arm. Baseline characteristics were not statistically different with a mean age of 37.7 and 40.8 years, a median time on ART of 33 and 40 months and an eGFR of 139.3 and 131.0 mL/min in the lithium and placebo arms respectively. There was no statistical significant difference in the reduction in eGFR or increase in potassium between the two arms during the 24 weeks. CONCLUSIONS: We found that 24-week treatment of HIV-infected patients with lithium and TDF did not result in increased nephrotoxicity. Trial registration The study was registered on the Pan African Clinical Trials Registry (PACTR) with the identifier number PACTR201310000635418. Registered 11 October 2013 before the first participant was enrolled

Dosage adjustment in medical patients with renal impairment at Groote Schuur Hospital

Background. Many drugs are eliminated by the kidneys and therefore may require dose adjustment in patients with renal impairment. The need for dose adjustment is frequently neglected by prescribers. Methods. We reviewed folders of patients admitted to the Groote Schuur Hospital general medical wards between January and March 2008. Patients with renal impairment, defined as an estimated glomerular filtration rate (eGFR) ≤50 ml per minute per 1.73 m2, were identified. In-patient prescriptions were captured if they were written after clinical notes indicated impaired renal function, or ≥1 day after renal function tests were performed. We determined what proportion of these prescriptions required dose adjustment and whether drug doses were appropriately adjusted. Results. We found renal impairment in 32% (97/301) of medical admissions. There were 615 prescription entries for the 97 patients with renal impairment. Dose adjustment was required in 19% (117/615) of prescription entries, and only 32% (37/117) of these prescription entries were correctly dose adjusted. Of 97 patients, 69 received one or more drugs that required dose adjustment (median 1, range 1 - 5). All drug doses were correctly adjusted in 12% (8/69) of patients. Importantly, in the majority of patients (59% (41/69)) no doses had been correctly adjusted. Conclusion. Consistent with international studies, drug dose adjustment in patients with renal impairment in a South African hospital was frequently neglected. Strategies to alert clinicians of the need for dose adjustment in renal impairment should be considered, including automated eGFR reporting and computerised aids to guide drug dosing, that account for renal impairment

Pharmacokinetics of Antimicrobials in Children with Emphasis on Challenges Faced by Low and Middle Income Countries, a Clinical Review

Effective antimicrobial exposure is essential to treat infections and prevent antimicrobial resistance, both being major public health problems in low and middle income countries (LMIC). Delivery of drug concentrations to the target site is governed by dose and pharmacokinetic processes (absorption, distribution, metabolism and excretion). However, specific data on the pharmacokinetics of antimicrobials in children living in LMIC settings are scarce. Additionally, there are significant logistical constraints to therapeutic drug monitoring that further emphasize the importance of understanding pharmacokinetics and dosing in LMIC. Both malnutrition and diarrheal disease reduce the extent of enteral absorption. Multiple antiretrovirals and antimycobacterial agents, commonly used by children in low resource settings, have potential interactions with other antimicrobials. Hypoalbuminemia, which may be the result of malnutrition, nephrotic syndrome or liver failure, increases the unbound concentrations of protein bound drugs that may therefore be eliminated faster. Kidney function develops rapidly during the first years of life and different inflammatory processes commonly augment renal clearance in febrile children, potentially resulting in subtherapeutic drug concentrations if doses are not adapted. Using a narrative review approach, we outline the effects of growth, maturation and comorbidities on maturational and disease specific effects on pharmacokinetics in children in LMIC.</p

The Safety, Effectiveness and Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin-Based Antitubercular Therapy

Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment.Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month.18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1-9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable.Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate