Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study.

OBJECTIVES: To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain. METHODS: A prospective, open-label, observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV-associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score ≥4, who received ≤6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using "bedside tests" and Brief Pain Inventory (question 5). RESULTS: Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12. CONCLUSIONS: Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.

Pharmacokinetics of the co-administration of boceprevir and St John's wort to male and female healthy volunteers.

BACKGROUND: St John's wort (SJW; Hypericum perforatum) induces CYP3A4 that is involved in the metabolism of the hepatitis C virus (HCV) protease inhibitor boceprevir. Reduced boceprevir exposure and efficacy would contribute to therapeutic failure and increase the risk for resistance development. Boceprevir is co-administered with interferon/ribavirin, and depression has been described frequently in patients undergoing HCV treatment. Patients may purchase over-the-counter herbals to manage depression, and knowing the interaction between SJW and boceprevir is desirable. METHODS: This Phase I, open-label, three-period, cross-over pharmacokinetic study enrolled healthy males and females who, following consent and screening procedures, were randomized to receive SJW on days 1-14, SJW plus boceprevir (SJW on days 22-35 and together on days 31-35) and boceprevir on days 52-56, separated by 7 day washout periods, or the same treatment in the opposite order. Pharmacokinetic sampling was performed at the end of each phase. RESULTS: Seventeen (11 female) subjects completed the study and no serious adverse events were reported. Geometric mean ratios (GMRs) and 90% CIs for boceprevir (with SJW versus alone) AUC(0-8), C(max) and C8 were 0.91 (0.87-0.96), 0.94 (0.82-1.07) and 1.00 (0.79-1.27), respectively. GMRs and 90% CIs for hypericin, the active component of SJW, (with boceprevir versus alone) AUC(0-8), C(max) and C(8) were 1.23 (1.10-1.38), 1.32 (1.16-1.52) and 1.37 (1.19-1.58), respectively. CONCLUSIONS: SJW did not have a clinically significant effect on boceprevir plasma concentrations (or those of its metabolite), suggesting that SJW and boceprevir can be safely co-administered.

Coadministration of atazanavir-ritonavir and zinc sulfate: impact on hyperbilirubinemia and pharmacokinetics.

Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0-24) were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients.

The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial.

BACKGROUND: Hypertriglyceridemia is common in patients with HIV treated with highly active antiretroviral therapy (HAART). OBJECTIVE: The goal of this study was to investigate the effect of the polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) 460 mg/eicosapentaenoic acid (EPA) 380 mg on hypertriglyceridemia in HIV-treated patients. METHODS: A double-blind, placebo-controlled, randomized, multicenter pilot study was undertaken in 48 evaluable HIV-infected patients undergoing HAART, with fasting triglyceride levels of 3.39 to 11.3 mmol/L. Patients were allowed fibrate or niacin but not statins and were randomized to PUFA 4 g daily versus placebo for 12 weeks. The primary end point was mean fasting triglyceride levels. RESULTS: The study included 48 patients; 23 in the PUFA group (mean age, 46.1 years) and 25 in the placebo group (mean age, 43.6 years). All except one were male. All patients in the PUFA group were white; in the placebo group, 20 were white, 4 Asian, and 1 black. The PUFA group had a mean body mass index of 24.7 kg/m(2); the placebo group, 24.1 kg/m(2). All patients were receiving concomitant fibrate therapy. Median baseline triglyceride levels were 5.58 (1.76-10.6) mmol/L for the PUFA group and 4.29 (1.81-6.14) mmol/L for the placebo group. PUFA reduced triglycerides by a median of 1.75 mmol/L versus a 0.41 mmol/L increase for the placebo group (baseline-corrected percentage change relative to placebo [95% CI, -69.48% to -6.53%; P = 0.019). No effect was seen on biochemical or virologic safety parameters. No severe treatment-emergent adverse events (TEAEs) occurred. Mild and moderate TEAEs occurred in 20 PUFA-treated patients versus 19 patients receiving placebo. Five were adjudged treatment related, and one was due to cholelithiasis, which led to early discontinuation. Most TEAEs affected the gastrointestinal tract (DHA/EPA, n = 7; placebo, n = 4) and comprised diarrhea, nausea, and flatulence (DHA/EPA vs placebo: 3, 2, and 2 vs 2, 0, and 0, respectively). CONCLUSIONS: PUFA therapy with DHA/EPA reduced triglyceride levels significantly compared with placebo in HIV-infected patients with HAART-associated hypertriglyceridemia.

A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy.

INTRODUCTION: Effective treatment of HIV-associated distal sensory polyneuropathy remains a significant unmet therapeutic need. METHODS: In this randomized, double-blind, controlled study, patients with pain due to HIV-associated distal sensory polyneuropathy received a single 30-minute or 60-minute application of NGX-4010--a capsaicin 8% patch (n = 332)--or a low-dose capsaicin (0.04%) control patch (n = 162). The primary endpoint was the mean percent change from baseline in Numeric Pain Rating Scale score to weeks 2-12. Secondary endpoints included patient global impression of change at week 12. RESULTS: Pain reduction was not significantly different between the total NGX-4010 group (-29.5%) and the total control group (-24.5%; P = 0.097). Greater pain reduction in the 60-minute (-30.0%) versus the 30-minute control group (-19.1%) prevented intended pooling of the control groups to test individual NGX-4010 treatment groups. No significant pain reduction was observed for the 30-minute NGX-4010 group compared with 30-minute control (-26.2% vs.-19.1%, respectively, P = 0.103). Pain reductions in the 60-minute NGX-4010 and control groups were comparable (-32.8% vs. -30.0%, respectively; P = 0.488). Posthoc nonparametric testing demonstrated significant differences favoring the total (P = 0.044) and 30-minute NGX-4010 groups (P = 0.035). Significantly, more patients in the total and 30-minute NGX-4010 group felt improved on the patient global impression of change versus control (67% vs. 55%, P = 0.011 and 65% vs. 45%, P = 0.006, respectively). Mild to moderate transient application site pain and erythema were the most common adverse events. CONCLUSIONS: Although the primary endpoint analyses were not significant, trends toward pain improvement were observed after a single 30-minute NGX-4010 treatment.

Overcoming resistance to existing therapies in HIV-infected patients: the role of new antiretroviral drugs.

Resistance to available antiretroviral (ARV) agents is of increasing concern, and development of novel agents that address this problem has been identified as a major public health priority. As ARV resistance becomes more prevalent with extended use of existing agents, individuals with HIV infection resistant to all three traditional classes of ARVs, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), find themselves increasingly limited with regard to effective treatment options. The need for tolerable new drug regimens that effectively suppress viral replication while being simple to adhere to is increasingly pressing. This article reviews the epidemiology of antiretroviral drug resistance, the factors that contribute to the emergence of resistance, and presents data that support the need for early detection of resistance and maximal virologic suppression in order to delay treatment failure and reduce mortality. Healthcare providers are encouraged to optimize therapy through the use of new agents from existing drug classes, which can minimize cross-resistance, as well as agents with novel mechanisms of action, in order to realize the potential for greater viral containment and to forestall development of resistance mutations. This article evaluates several emerging therapies that are in late-stage clinical development and promise to expand treatment options for highly treatment-experienced patients with the goal of improving outcomes for HIV-infected individuals whose options for sustained antiviral efficacy are increasingly limited.

Anaemia in persons with HIV infection: prognostic marker and contributor to morbidity.

Human immunodeficiency virus (HIV)-infected patients experience a range of haematological complications including anaemia, neutropenia, lymphopenia and thrombocytopenia. Anaemia is a prognostic marker of future disease progression or death, independent of CD4 and viral load. Recovery from anaemia reduces the risk of disease progression to approximately the same level as seen among patients who have never had anaemia. Additionally, anaemia impacts a range of dimensions of quality of life, most commonly through fatigue. Anaemia can be caused by a range of mechanisms including infections, neoplasms, dietary deficiencies, blood loss and medication. Histologically, bone marrow hypoproliferation and dysplasia are the most commonly seen. Both AZT and d4T induce macrocytosis, however, AZT, but not d4T, has broader myelosuppressive effects both in vitro and in vivo. The management of anaemia typically includes correction of the underlying cause(s) and blood transfusion or erythropoietin. However, blood transfusions and iron supplementation may activate HIV expression and possibly worsen immunosuppression. Recombinant human erythropoietin (rHuEPO) is an effective means of improving haemoglobin and reducing transfusion requirements in patients who have low (< 500 IU/L) endogenous erythropoietin levels.