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Background: The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines., Methods: We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021., Results: One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7-29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4-33.4%) in the control group. The absolute difference in 10-week mortality was -3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p < 0.001)., Conclusions: In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource-limited settings., Objectives: To determine the accuracy of simple measures of ART adherence (including patient self-report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non-suppressed viral load in people living with HIV and receiving ART treatment., Search Methods: The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African-Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases., Selection Criteria: We included studies of all designs that evaluated a simple measure of adherence (index test) such as self-report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity., Data Collection and Analysis: We screened studies, extracted data, and assessed risk of bias using QUADAS-2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta-analysis or comparison of adherence measures. We explored heterogeneity using pre-defined subgroup analysis., Main Results: We included 51 studies involving children and adults with HIV, mostly living in low- and middle-income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self-report. - Self-report questionnaires (25 studies, 9211 participants; very low-certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%. - Self-report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low-certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%. - Tablet counts (12 studies, 3466 participants; very low-certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%. - Electronic monitoring devices (3 studies, 186 participants; very low-certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%. - Pharmacy records or secondary databases (6 studies, 2254 participants; very low-certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%. - Composite measures (9 studies, 1513 participants; very low-certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%. Across all included studies, the ability of adherence measures to detect viral non-suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision. The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results., Authors' Conclusions: We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non-suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Objectives: Renal dysfunction is a significant cause of morbidity and mortality among HIV-positive individuals. This study evaluated renal dysfunction in a cohort of adults who started antiretroviral treatment (ART) regardless of CD4 count at three Department of Health (DOH) clinics included in the HIV Prevention Trials Network 071 (HPTN 071) Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART) trial., Methods: A retrospective cohort analysis of routine data for HIV-positive individuals starting ART between January 2014 and November 2015 was completed. Incident renal dysfunction was defined as an estimated glomerular filtration rate (eEGFR) < 60 mL/min after ART initiation among individuals with a baseline (pre-ART) eGFR ≥ 60 mL/min., Results: Overall, 2423 individuals, with a median baseline CD4 count of 328 cells/μL [interquartile range (IQR) 195-468 cells/μL], were included in the analysis. Forty-seven individuals had a baseline eGFR < 60 mL/min. Among 1634 nonpregnant individuals started on a tenofovir-containing ART regimen and with a baseline eGFR ≥ 60 mL/min, 27 developed an eGFR < 60 mL/min on ART. Regression analysis showed lower odds of baseline eGFR < 60 mL/min at baseline CD4 counts of > 500 cells/μL [adjusted odds ratio (aOR) 0.29; 95% confidence interval (CI) 0.11-0.80], 351-500 cells/μL (aOR 0.22; 95% CI 0.08-0.59) and 201-350 (aOR 0.48; 95% CI: 0.24-0.97) compared with baseline CD4 counts < 200 cells/μL., Conclusions: This study showed low rates of renal dysfunction at baseline and on ART, with lower rates of baseline renal dysfunction among individuals with baseline CD4 counts > 200 cells/μL. Strategies that use baseline characteristics, such as age, to identify individuals at high risk of renal dysfunction on ART for enhanced eGFR monitoring may be effective and should be the subject of future research., (© 2019 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Cryptococcal meningitis is a severe fungal infection that occurs primarily in the setting of advanced immunodeficiency and remains a major cause of HIV-related deaths worldwide. The best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis is unclear, particularly in resource-limited settings where management of drug-related toxicities associated with more potent antifungal drugs is a challenge., Objectives: To evaluate the best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis; to compare side effect profiles of different therapies., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE (PubMed), Embase (Ovid), LILACS (BIREME), African Index Medicus, and Index Medicus for the South-East Asia Region (IMSEAR) from 1 January 1980 to 9 July 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry; and abstracts of select conferences published between 1 July 2014 and 9 July 2018., Selection Criteria: We included randomized controlled trials that compared antifungal induction therapies used for the first episode of HIV-associated cryptococcal meningitis. Comparisons could include different individual or combination therapies, or the same antifungal therapies with differing durations of induction (less than two weeks or two or more weeks, the latter being the current standard of care). We included data regardless of age, geographical region, or drug dosage. We specified no language restriction., Data Collection and Analysis: Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardized forms. The main outcomes included mortality at 2 weeks, 10 weeks, and 6 months; mean rate of cerebrospinal fluid fungal clearance in the first two weeks of treatment; and Division of AIDS (DAIDS) grade three or four laboratory events. Using random-effects models we determined pooled risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean differences (MD) and 95% CI for continuous outcomes. For the direct comparison of 10-week mortality, we assessed the certainty of the evidence using the GRADE approach. We performed a network meta-analysis using multivariate meta-regression. We modelled treatment differences (RR and 95% CI) and determined treatment rankings for two-week and 10-week mortality outcomes using surface under the cumulative ranking curve (SUCRA). We assessed transitivity by comparing distribution of effect modifiers between studies, local inconsistency through a node-splitting approach, and global inconsistency using design-by-treatment interaction modelling. For the network meta-analysis, we applied a modified GRADE approach for assessing the certainty of the evidence for 10-week mortality., Main Results: We included 13 eligible studies that enrolled 2426 participants and compared 21 interventions. All studies were carried out in adults, and all but two studies were conducted in resource-limited settings, including 11 of 12 studies with 10-week mortality data.In the direct pairwise comparisons evaluating 10-week mortality, one study from four sub-Saharan African countries contributed data to several key comparisons. At 10 weeks these data showed that those on the regimen of one-week amphotericin B deoxycholate (AmBd) and flucytosine (5FC) followed by fluconazole (FLU) on days 8 to 14 had lower mortality when compared to (i) two weeks of AmBd and 5FC (RR 0.62, 95% CI 0.42 to 0.93; 228 participants, 1 study), (ii) two weeks of AmBd and FLU (RR 0.58, 95% CI 0.39 to 0.86; 227 participants, 1 study), (iii) one week of AmBd with two weeks of FLU (RR 0.49, 95% CI 0.34 to 0.72; 224 participants, 1 study), and (iv) two weeks of 5FC and FLU (RR 0.68, 95% CI 0.47 to 0.99; 338 participants, 1 study). The evidence for each of these comparisons was of moderate certainty. For other outcomes, this shortened one-week AmBd and 5FC regimen had similar fungal clearance (MD 0.05 log 10 CFU/mL/day, 95% CI -0.02 to 0.12; 186 participants, 1 study) as well as lower risk of grade three or four anaemia (RR 0.31, 95% CI 0.16 to 0.60; 228 participants, 1 study) compared to the two-week regimen of AmBd and 5FC.For 10-week mortality, the comparison of two weeks of 5FC and FLU with two weeks of AmBd and 5FC (RR 0.92, 95% CI 0.69 to 1.23; 340 participants, 1 study) or two weeks of AmBd and FLU (RR 0.85, 95% CI 0.64 to 1.13; 339 participants, 1 study) did not show a difference in mortality, with moderate-certainty evidence for both comparisons.When two weeks of combination AmBd and 5FC was compared with AmBd alone, pooled data showed lower mortality at 10 weeks (RR 0.66, 95% CI 0.46 to 0.95; 231 participants, 2 studies, moderate-certainty evidence).When two weeks of AmBd and FLU was compared to AmBd alone, there was no difference in 10-week mortality in pooled data (RR 0.94, 95% CI 0.55 to 1.62; 371 participants, 3 studies, low-certainty evidence).One week of AmBd and 5FC followed by FLU on days 8 to 14 was the best induction therapy regimen after comparison with 11 other regimens for 10-week mortality in the network meta-analysis, with an overall SUCRA ranking of 88%., Authors' Conclusions: In resource-limited settings, one-week AmBd- and 5FC-based therapy is probably superior to other regimens for treatment of HIV-associated cryptococcal meningitis. An all-oral regimen of two weeks 5FC and FLU may be an alternative in settings where AmBd is unavailable or intravenous therapy cannot be safely administered. We found no mortality benefit of combination two weeks AmBd and FLU compared to AmBd alone. Given the absence of data from studies in children, and limited data from high-income countries, our findings provide limited guidance for treatment in these patients and settings.

Background: Policy makers, health staff and communities recognise that health services in lower- and middle-income countries need to improve people's access to HIV treatment and retention to treatment programmes. One strategy is to move antiretroviral delivery from hospitals to more peripheral health facilities or even beyond health facilities. This could increase the number of people with access to care, improve health outcomes, and enhance retention in treatment programmes. On the other hand, providing care at less sophisticated levels in the health service or at community-level may decrease quality of care and result in worse health outcomes. To address these uncertainties, we summarised the research studies examining the risks and benefits of decentralising antiretroviral therapy service delivery., Objectives: To assess the effects of various models that decentralised HIV treatment and care to more basic levels in the health system for initiating and maintaining antiretroviral therapy., Search Methods: We conducted a comprehensive search to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress) from 1 January 1996 to 31 March 2013, and contacted relevant organisations and researchers. The search terms included 'decentralisation', 'down referral', 'delivery of health care', and 'health services accessibility'., Selection Criteria: Our inclusion criteria were controlled trials (randomised and non-randomised), controlled-before and after studies, and cohorts (prospective and retrospective) in which HIV-infected people were either initiated on antiretroviral therapy or maintained on therapy in a decentralised setting in lower- and middle-income countries. We define decentralisation as providing treatment at a more basic level in the health system to the comparator., Data Collection and Analysis: Two authors applied the inclusion criteria and extracted data independently. We designed a framework to describe different decentralisation strategies, and then grouped studies against these strategies. Data were pooled using random-effects meta-analysis. Because loss to follow up in HIV programmes is known to include some deaths, we used attrition as our primary outcome, defined as death plus loss to follow-up. We assessed evidence quality with GRADE methodology., Main Results: Sixteen studies met the inclusion criteria, all but one were from Africa, comprising two cluster randomised trials and 14 cohort studies. Antiretroviral therapy started at a hospital and maintained at a health centre (partial decentralisation) probably reduces attrition (RR 0.46, 95% CI 0.29 to 0.71, 4 studies, 39 090 patients, moderate quality evidence). There may be fewer patients lost to care with this model (RR 0.55, 95% CI 0.45 to 0.69, low quality evidence).We are uncertain whether there is a difference in attrition for antiretroviral therapy started and maintained at a health centre (full decentralisation) compared to a hospital at 12 months (RR 0.70, 95% CI 0.47 to 1.02; four studies, 56 360 patients, very low quality evidence), but there are probably fewer patients lost to care with this model (RR 0.3, 95% CI 0.17 to 0.54, moderate quality evidence).When antiretroviral maintenance therapy is delivered at home by trained volunteers, there is probably no difference in attrition at 12 months (RR 0.95, 95% CI 0.62 to 1.46, two trials, 1453 patients, moderate quality evidence)., Authors' Conclusions: Decentralisation of HIV care aims to improve patient access and retention in care. Most data were from good quality cohort studies but confounding between site of treatment and outcomes cannot be excluded. Nevertheless, this review found that attrition appears to be lower in partial decentralisation models of treatment, where antiretrovirals were started at hospital and continued in the health centre; with antiretroviral drugs started and continued at health centres, no difference in attrition was detected, but there were fewer patients lost to care. For antiretroviral therapy provided at home by trained volunteers, no difference in outcomes were detected when compared to facility-based care.

Posttraumatic stress disorder (PTSD) symptoms, exposure to traumatic stressors, and health care utilization were examined in 84 women attending a primary health care clinic in Mogadishu, Somalia. The Somalia-Posttraumatic Diagnostic Scale was used in this active warzone to measure symptoms. Nearly all women reported high levels of confrontations with violence; half described being exposed to a potentially traumatizing event. Nearly one third had significant PTSD symptoms. Compared to those who did not, women who reported exposure to a traumatic stressor reported more confrontations with violence (7.1 vs. 3.3; p < . 001), health complaints (3.8 vs. 2.9; p = .03), and nearly 3 times as much (p = .03) health service utilization. A potentially traumatizing event was found to be a simplified proxy for assessing mental health distress in women attending a primary health care facility in highly insecure, unpredictable, resource-limited settings., (Copyright © 2011 International Society for Traumatic Stress Studies.)

Background: Multiple births are increasing, and may be associated with birth defects., Methods: To explore this relationship, data from the Virginia birth defects registry (VaCARES) was analyzed., Results: During 1989-1998, a total of 44505 children from singleton births and 2258 children from multiple births were born with birth defects in Virginia. The risk of birth defects was significantly increased in children from multiple births as compared to singleton births (birth defect rate per 10000 live births: singleton 482.3, twin 922.0, triplet 1300.0, and quadruplet or higher 2222.2). Increased risk was observed for 39 of 86 diagnoses. The five diagnoses with the highest risk ratio per 10000 live births (RR) were: neurofibromatosis (RR, 12.80), retrolental fibroplasia (RR, 9.96), microphthalmos (RR, 5.24), pulmonary valve anomalies (RR, 5.00), and patent ductus arteriosus (RR, 4.68). A significantly reduced risk ratio for congenital hip dislocation was found in these children (RR, 0.54). In most multiple births, only one child was born with birth defects (81% in twin births, 71% in triplet births, and 56% in quadruplet and higher births). The diagnosis of birth defects might be concordant or discordant for children in which all siblings had birth defects. The children from multiple births who had birth defects were generally preterm and had significantly lower birth weight. A higher fatality and mortality rate and longer hospital stay were also observed., Conclusions: Overall, children from multiple births have an increased risk of birth defects., (Copyright 2003 Wiley-Liss, Inc.)

An open-label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1-12 years) and adolescents (13-16 years) with hypertension. Patients received single once-daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (+/- nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high-performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day 1, and up to 48 hours after the final dose. The plasma concentration-time profiles were similar between the 6- to 12-year and the 13- to 16-year age groups and to that previously determined from a study of adult subjects receiving approximately 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and may be a treatment option for pediatric hypertensive patients.

Background and Objective: Nefazodone inhibits CYP3A; therefore coadministration with CYP3A substrates such as terfenadine or loratadine may result in increased exposure to these drugs. A potential pharmacodynamic consequence is electrocardiographic QTc prolongation, which has been associated with torsade de pointes cardiac arrhythmia. Therefore a clinical pharmacokinetic-pharmacodynamic evaluation of this potential interaction was conducted., Methods: A randomized, double-blind, double-dummy, parallel group, multiple-dose design was used. Healthy men and women who were given doses of 60 mg of terfenadine every 12 hours, 20 mg of loratadine once daily, and 300 mg of nefazodone every 12 hours were studied. Descriptive pharmacokinetics (time to maximum concentration, maximum concentration, and area under the plasma concentration-time curve) were used for the examination of interactions among the respective parent drugs and metabolites. QTc prolongation (mean value over the dosing interval) was the pharmacodynamic parameter measured. Kinetic and dynamic analysis was used for the examination of pooled concentration and QTc data with the use of a linear model., Results: Concomitant nefazodone treatment markedly increased the dose interval area under the plasma concentration-time curve of both terfenadine (mean value, 17.3 +/- 8.5 ng. mL/h versus 97.4 +/- 48.9 ng. mL/h; P <.001) and carboxyterfenadine (mean value, 1.69 +/- 0.48 microg. h/mL versus 2.88 +/- 0.53 microg. h/mL; P <.001) and moderately increased the dose interval area under the plasma concentration-time curve of both loratadine (mean value, 31.5 +/- 27.9 ng. h/mL versus 43.7 +/- 25.9 ng. h/mL; P <.014) and descarboethoxyloratadine (mean value, 73.4 +/- 54.9 ng. h/mL versus 81.9 +/- 26.2 ng. h/mL; P <.002). The mean QTc was unchanged with terfenadine alone; however, it was markedly prolonged with concomitant nefazodone and terfenadine (mean [90% confidence interval] prolongation 42.4 ms [34.2, 50.6 ms]; P <.05). Similarly, the mean QTc was unchanged with loratadine alone; however, it was prolonged with concomitant nefazodone and loratadine (21.6 ms [13.7, 29.4 ms]; P <.05). Nefazodone alone did not change mean QTc. QTc was positively correlated with terfenadine plasma concentration (r (2) = 0.21; P =.0001). Similarly, QTc was positively correlated with loratadine plasma concentration (r (2) = 0.056; P =.0008) but with a flatter slope. There was no relationship between QTc and nefazodone plasma concentration during treatment with nefazodone alone (r (2) = 0.002, not significant)., Conclusions: In healthy men and women, concomitant nefazodone treatment at a therapeutic dose increases exposure to both terfenadine and carboxyterfenadine. This increased exposure is associated with marked QTc prolongation, which is correlated with terfenadine plasma concentration. A similar interaction occurs with loratadine, although it is of lesser magnitude. Concomitant administration of nefazodone with terfenadine may have predisposed individuals to the arrhythmia associated with QTc prolongation, torsade de pointes, when terfenadine was available for clinical use. However, a new finding is that in the context of higher than clinically recommended daily doses (20 mg) of loratadine concomitant administration with a metabolic inhibitor such as nefazodone can also result in QTc prolongation.

Avitriptan (BMS-180048) is a 5-HT1-like receptor agonist for the treatment of migraine. This double-blind, placebo-controlled, randomized, parallel-group study evaluated the pharmacokinetics, safety, and preliminary efficacy of avitriptan in patients with migraine during migrainous and pain-free states. Patients met the IHS criteria for migraine with or without aura and suffered one to six migraines per month for at least 1 year. Patients in a clinic experiencing a migraine headache received avitriptan 75 mg, 150 mg, or 200 mg or matching placebo capsules. Blood samples were obtained before and 0.25, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours after dosing. Headache intensity was rated before and up to 6 hours after dosing. Seven to 30 days after the inclinic treatment, patients returned in a pain-free state for the same study medication. All pharmacokinetic and safety measures were repeated. Forty-eight patients (9 men and 39 women) participated. Peak plasma concentrations of avitriptan were achieved 1 to 2 hours following dosing in migraine and pain-free states for all doses. The pharmacokinetics of avitriptan were proportional to dose during a migraine attack over the 75- to 200-mg dose range. The 150- and 200-mg doses of avitriptan demonstrated a greater decrease in headache intensity scores at 2 hours postdose. The most common adverse event was paresthesia. Thus, avitriptan was rapidly absorbed, well tolerated, and demonstrated preliminary efficacy in this population.

The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single- and multiple-dose (7 consecutive days) administration to normotensive subjects in an open-label, multiple-dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half-life (t1/2), area under the plasma concentration-time curve (AUC), apparent oral clearance (Cl(t)/F), renal clearance (Cl(r)), and accumulation index (AI). Steady-state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild-to-moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy subjects. In this single-center, placebo-controlled, double-blind within dose group, sequential, dose-ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days. The values for plasma area under the concentration-time curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no significant differences between the dose groups in time to maximum concentration (tmax) or half-life (t1/2) after single and multiple doses. After multiple doses, urinary recovery was significantly lower in the 600-mg and 900-mg dose groups compared with the 150-mg and 300-mg dose groups. Steady-state concentrations of irbesartan were achieved within 3 days of administration with no clinically important accumulation. Irbesartan produced dose-dependent increases in plasma renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in blood pressure without orthostatic symptoms were observed at irbesartan doses of 300 mg or higher. These results demonstrated the dose-proportionality of irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well tolerated.

In the course of evaluating the safety and efficacy of an investigational compound for acute migraine headaches, a large number of patients received placebo at a single site, offering the opportunity to characterize subjective and clinical physiologic responses of migraine patients to placebo in a controlled environment. In a single-site, double-blind, placebo-controlled study, 67 patients reported to the clinic while suffering a moderate to severe acute migraine headache and received oral placebo. For 6 hours after treatment, a continuous electrocardiogram (ECG) was performed, and headache severity, adverse events, and vital signs were recorded. Patients returned and repeated the procedure when free from pain. A headache was considered to be improved if its severity dropped to "mild" or "none." Twenty-five patients (37%; 95% CI: 26% to 50%) experienced headache improvement within 2 hours of receiving placebo, and 32 patients (48%: 36% to 60%) improved within 4 hours. There were no clinically important ECG changes during the migraine visit, and there were no clinically relevant differences in vital signs between the migraine and pain-free visits. Thus, a substantial placebo response occurs in migraine headache. Hemodynamic and ECG parameters are unchanged between migraine and pain-free states.

Purpose: An open-label, multiple-dose, parallel-group study was conducted to evaluate the pharmacokinetics of the angiotensin II receptor antagonist irbesartan in subjects with varying degrees of renal function., Methods: Forty subjects were divided into four treatment groups on the basis of 24-hour creatinine clearance (CLCR): normal renal function (> 75 ml/min/1.73 m2), mild to moderate renal impairment (30 to 74 ml/min/1.73 m2), severe renal impairment (< 30 ml/min/1.73 m2), and maintenance hemodialysis. Subjects received 100 mg irbesartan daily for 8 days (or 300 mg daily for 9 days for the hemodialysis group). Serial blood and urine samples were collected for 24 hours after the first and last of eight successive daily doses. In addition, arterial and venous blood samples were collected during two hemodialysis sessions from subjects requiring maintenance hemodialysis., Results: There was no statistically significant linear relationship between CLCR and maximum plasma concentrations, dose-adjusted area under the plasma concentration time curve values on days 1 or 8, or any other pharmacokinetic parameters among the renal function groups studied. There was no indication of drug accumulation with repetitive dosing. In the subjects receiving hemodialysis, arterial-venous concentration differences for irbesartan were negligible, suggesting that this compound is not cleared through hemodialysis. In addition, irbesartan was well tolerated., Conclusion: Based on pharmacokinetic parameters, no starting dose adjustment is necessary in subjects with mild to severe renal impairment, inclusive of hemodialysis. Subjects with volume depletion may have an exaggerated response to an initial dose of irbesartan and, under such circumstances, volume depletion should be corrected or a lower starting dose of irbesartan should be considered.

A case of posttraumatic stress disorder is described in which a favorable response to the anticonvulsants carbemazepine and sodium valproate occurred. The literature on the use of anticonvulsants in this disorder is reviewed.

Five patients with NYHA Class III CHF received 5 mg of fosinopril on each of 4 days. Hemodynamics were measured with a Swan-Ganz catheter after dosing on day 1. Measurements of plasma fosinoprilat, ACE activity, renin, and aldosterone were obtained. An Emax model was used to fit the effect-site concentration and mean arterial pressure change. A linear model was used to fit the effect-site concentration and the pulmonary artery wedge pressure (PAWP) change. At steady state on day 4, AUC0-24 was 1668 +/- 476 ng.hr/mL and Cmax was 143.5 +/- 33.6 ng/mL. The mean elimination half-life of fosinoprilat was 11.3 +/- 0.7 hours, and median Tmax occurred at 3 hours, corresponding to maximum plasma ACE inhibition. Plasma renin activity was unchanged, and mean plasma aldosterone level declined. Emax modeling using fosinoprilat concentrations and mean arterial pressure showed good prediction of the pharmacodynamic effects from the effect-site concentration. A linear relationship was observed between the effect-site concentrations of fosinoprilat and PAWP. When expressed in an Emax model, the pharmacodynamic actions of fosinopril in patients with CHF are a reflection of its pharmacokinetics.

The single-dose and steady-state pharmacokinetics of the angiotensin-converting enzyme (ACE) inhibitor fosinopril and its active diacid, fosinoprilat, were evaluated in 6 healthy volunteers and 12 patients with alcoholic cirrhosis. Fosinopril was administered at a dosage of 10 mg once daily for 14 days. Results in the two groups were similar, with no evidence of accumulation of fosinoprilat in hepatically impaired patients. Mean (+/- SD) maximum observed plasma concentrations of fosinoprilat in the healthy subjects were 112.0 +/- 67.2 ng/mL after the first dose and 144.1 +/- 61.7 ng/mL at steady-state. Corresponding values for the hepatically impaired patients were 111.4 +/- 40.1 ng/mL and 140.2 +/- 50.9 ng/mL. The area under the serum concentration versus time curve for healthy volunteers was 790.7 +/- 431.0 ng.hr/mL after the first dose and 940.3 +/- 400.4 ng.hr/mL at steady-state. Similar values were noted in hepatically impaired patients: 926.0 +/- 293.9 ng.hr/mL and 1,255.4 +/- 434.0 ng.hr/mL for first dose and steady-state, respectively. No statistically significant differences were detected in fosinoprilat pharmacokinetic values between healthy and hepatically impaired subjects. Absence of accumulation can be attributed to the dual route of elimination of fosinoprilat reported in previous studies. Renal excretion of fosinoprilat in hepatically impaired patients prevents increased accumulation. The present findings suggest that the starting dose of fosinopril used in hypertensive patients with normal renal and hepatic function can also be used in patients with hepatic impairment secondary to cirrhosis.