Predictors of optimal virological response to potent antiretroviral therapy.

BACKGROUND: Current potent antiretroviral therapy (using a protease inhibitor and two nucleoside reverse transcriptase inhibitors) produces a durable suppression of HIV replication in less than 75% of treated patients. Identification of predictors of successful therapy might allow the development of improved strategies to increase response rates. METHODS: We analyzed retrospectively the results from a multicenter, randomized, double-blind Phase III study of combination anti-HIV therapy with nelfinavir, zidovudine, and lamivudine to evaluate the relationship between virological response over 48 weeks of treatment to variables which could potentially serve as early predictors of long-term response. The goal was to produce long-term suppression of viral load to sensitive (<400 copies HIV RNA/ml) and ultrasensitive (<50 copies HIV RNA/ml) limits of quantification with the Amplicor PCR assay. FINDINGS: Baseline viral load, the change in viral load over the first 4 weeks of treatment, the 2 h post-dose nelfinavir levels and the time to respond to HIV RNA levels of <400 copies/ml and <50 copies/ml have the best predictive value in determining response and response duration. Patients who achieved very low viral nadirs (<50 copies HIV RNA/ml) had significantly longer responses than those who achieved nadirs of 50-400 copies HIV RNA/ml. INTERPRETATION: Parameters that can be measured easily at baseline or early after therapy is started can identify patients at high risk of failure with standard treatment. Such patients may be candidates for more aggressive therapy or for alternative strategies designed to improve outcome. In addition, these results support the use of ultra-sensitive HIV RNA assays to predict long-term outcome of anti-HIV therapy.

Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate.

In vitro studies with human liver microsomes and P450 probe substrates were performed to characterize selectivity and mechanism of cytochrome P450 inhibition by nelfinavir mesylate. At therapeutic concentrations (steady-state plasma concentrations approximately 4 microM), nelfinavir was found to be a competitive inhibitor of only testosterone 6beta-hydroxylase (CYP3A4) with a Ki concentration of 4. 8 microM. At supratherapeutic concentrations, nelfinavir competitively inhibited dextromethorphan O-demethylase (CYP2D6), S-mephenytoin 4-hydroxylase (CYP2C19), and phenacetin O-deethylase (CYP1A2) with Ki concentrations of 68, 126, and 190 microM, respectively. Nelfinavir did not appreciably inhibit tolbutamide 4-hydroxylase (CYP2C9), paclitaxel 6alpha-hydroxylase (CYP2C8), or chlorzoxaxone 6beta-hydroxylase (CYP2E1) activities. The inhibitory potency of nelfinavir toward CYP3A4 suggested the possibility of in vivo inhibition of this isoform, whereas in vivo inhibition of other P450s was considered unlikely. In a one-sequence crossover study in 12 healthy volunteers, nelfinavir inhibited the elimination of the CYP3A substrate terfenadine and the carboxylate metabolite of terfenadine. The 24-hr urinary recoveries of 6beta-hydroxycortisol were reduced by an average of 27% during nelfinavir treatment, consistent with CYP3A inhibition by nelfinavir. Inhibition of CYP3A4 by nelfinavir in vitro was NADPH-dependent requiring the catalytic formation of a metabolite or a metabolic intermediate. The catechol metabolite of nelfinavir (M3) was considered unlikely to be responsible for inhibition as the addition of catechol O-methyl transferase, S-adenosyl methionine, and ascorbic acid to the preincubation mixture did not protect against the loss of testosterone 6beta-hydroxylase activity. Also, the addition of M3 to human liver microsomes did not inhibit CYP3A4. Although incubations with nelfinavir showed a time- and concentration-dependent loss of CYP3A4 activity, the partial or complete recovery of enzyme activity upon dialysis indicated that inhibition was reversible. Microsomal incubations with nelfinavir and NADPH did not result in a loss of spectral P450 content compared with the NADPH control. Glutathione, N-acetylcysteine, and catalase did not attenuate CYP3A4 inhibition by nelfinavir. Collectively, these results suggest that the probable mechanism for CYP3A4 inhibition by nelfinavir is a transient metabolic intermediate or stable metabolite that coordinates tightly but reversibly to the heme moiety of the P450.

Sex difference in risk of torsade de pointes with d,l-sotalol.

BACKGROUND: The present study was undertaken to test the hypothesis that women are more prone than men to develop torsade de pointes (TdP) in a defined cohort of patients exposed to the QT-prolonging antiarrhythmic drug d,l-sotalol. METHODS AND RESULTS: In a database derived from 22 clinical trials involving 3135 adult patients who received oral d,l-sotalol (median follow-up, 164 days), TdP developed in 44 (1.9%) of 2336 men and in 33 (4.1%) of 799 women (P < .001). Logistic regression analysis identified female sex (P < .0001), presenting arrhythmia of sustained ventricular tachycardia or fibrillation (P < .0001), history of congestive heart failure (P < .001), and d,l-sotalol dose > 320 mg/d (P < .001) as factors most predictive of TdP; in addition to these, a serum creatinine > 1.4 mg/dL in women and > 1.6 mg/dL in men was weakly predictive (P < .05). After adjustment for these risk factors, women had threefold greater odds of developing TdP than men. The sex difference in TdP risk was age independent and could not be explained by differential dose-related bradycardic responses in women versus men. CONCLUSIONS: Women are at increased risk of developing TdP during-administration of d,l-sotalol. This finding needs to be taken into account, together with other TdP risk factors, when patients are treated with this antiarrhythmic agent. Given the consistency between the present and other recent observations, greater caution in women regarding use of QT-prolonging drugs, in general, is advisable.

Clinical potential of a new HIV protease inhibitor.

AIDS: Based on favorable results from a phase I study of AG1343 using oral doses of 800 mg and 400 mg, a new study assessed a 300 mg dose regimen as the starting dose for a 1-month pilot phase II trial in HIV-positive patients with CD4 counts between 200 and 500. One patient was assessed who had been diagnosed in 1994 with HIV and had no prior HIV therapy or current medications. Results from HIV RNA titers, p24 antigen levels, and CD4 counts over a 9 to 14 day period showed increases in CD4 counts and decreases in viral load.^ieng

Multicenter trial of sotalol compared with procainamide in the suppression of inducible ventricular tachycardia: a double-blind, randomized parallel evaluation. Sotalol Multicenter Study Group.

Sotalol is the prototype class III agent that combines beta-blocking properties with the propensity to prolong the effective refractory period by lengthening the action potential duration. Its precise effect on the prevention of ventricular tachycardia-ventricular fibrillation (VTVF) compared to class I agents has not been evaluated in a blinded study. In a double-blind parallel-design multicenter study, the electrophysiologic and antiarrhythmic effects of intravenous and oral sotalol (n = 55) and procainamide (n = 55) were therefore compared in patients with VTVF inducible by programmed electric stimulation. Sotalol produced a greater effect on lengthening the ventricular effective refractory period (VERP). It prevented the inducibility of VTVF in 30% versus 20% for procainamide, but this was not significantly different. In an alternate therapy group (n = 41) of similar patients previously refractory to or intolerant of procainamide, intravenous sotalol prevented inducibility in 32%. The pooled overall sotalol efficacy rate was 31%. There was a significant relation between the increase in the VERP and the prevention of inducibility of VTVF (n = 56; p < 0.02). VERP of > or = 300 msec was critical for the prevention of VTVF inducibility. Thirteen sotalol and 6 procainamide responders from the randomized group and 30 from the nonrandomized groups completed 1 year of oral sotalol therapy follow-up. Life-table analysis of these patient in each group showed a trend in favor of sotalol; however, statistical analysis was not possible because of the small numbers of patients. Both sotalol and procainamide were well tolerated. In the randomized group there was one case of sudden death during treatment with sotalol and two cases of nonfatal torsades de pointes in the procainamide group and two in the sotalol group; in the nonrandomized alternate therapy group, there were 6 cases of nonfatal torsades de pointes. The data support the emerging role of sotalol in the control of symptomatic ventricular tachycardia and fibrillation.

Treatment of ectopic atrial arrhythmias and premature atrial complexes in adults with encainide.

Few studies of the antiarrhythmic effects of encainide have included patients with primary atrial tachycardias and premature atrial contractions (PACs). In this review, 11 patients with primary atrial tachycardia and 10 patients with symptomatic PACs were abstracted from all studies known to have been performed. These patients had been shown to be highly resistant to prior antiarrhythmic treatments. Intravenous encainide terminated a primary atrial tachycardia in 4 of 4 patients, 3 of whom had an incessant arrhythmia, and oral encainide was effective or partially effective in 6 of 10 patients treated for an average of 2.9 years with a mean dosage of 156 mg/day. Intravenous encainide was effective or partially effective in 8 of 10 patients with symptomatic PACs, and oral encainide was effective or partially effective in 6 of 9 patients treated for an average of 1.8 years with a mean dosage of 114 mg/day. The median number of PACs per hour on Holter recording was reduced from a baseline rate of 1,139/hour to 166/hour at 3 to 5 months of treatment (p = 0.001). Adverse effects were modest. The mechanism of action of encainide in these arrhythmias appears to be depression of ectopic pacemaker activity.

The use of N-acetylcysteine long after an acetaminophen overdose in mice.

N-Acetylcysteine (NAC), given to mice 5 h after an LD50 dose of acetaminophen, decreased 24-h survival to 33%. The reduction in survival observed for late NAC is significantly lower than the survival observed for the LD50 dose alone (53%), and is in sharp contrast to the 100% survival reported for the early use of NAC.

Drug interaction studies and encainide use in renal and hepatic impairment.

The effect of encainide administration on steady-state plasma digoxin levels was evaluated in 17 patients receiving stable doses of digoxin. A paired t test, comparing plasma digoxin levels (mean +/- standard error) before encainide therapy (1.05 +/- 0.14 ng/ml) and after 2 weeks of encainide, 100 mg/day (1.03 +/- 0.11 ng/ml) or 200 mg/day (1.2 +/- 0.2 ng/ml), indicates no significant (p greater than 0.05) change in digoxin levels. These results were confirmed in a second study of 10 patients with severe congestive heart failure. Also, no difference in efficacy of either drug was observed and changes in dosing of digoxin were not required. Plasma concentrations of encainide and its 2 major metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide, significantly increased by 31.6%, 43.1% and 35.6% after concomitant cimetidine administration in 13 healthy adult men receiving 75 mg/day of encainide. However, a retrospective evaluation of 33 patients receiving both drugs did not reveal any clinically significant interactions. Retrospective evaluation of patients enrolled in clinical studies who received concomitant digoxin (268), antiarrhythmics (118), anticoagulants (78), antidiabetics (40), antipsychotics (23), beta blockers (88), calcium-channel blockers (24) or diuretics (229) did not reveal any clinically significant interactions with encainide. Similarly, in vitro protein binding studies did not reveal any clinically significant interactions with encainide or its major metabolites. Six patients with moderate to severe renal impairment (creatinine clearance 10 to 38 ml/min) received 25 mg of encainide, 3 times/day, for 7 doses. Plasma encainide, ODE and 3-methoxy-O-demethyl concentrations were similar to those observed in normal subjects who had received twice the dose of encainide, and steady-state apparent oral clearance of encainide was reduced by 66% with renal impairment. Based on these data it is recommended that in patients with moderate to severe renal impairment encainide be initiated at one-third the normal dose, or 25 mg once a day. Doses may be elevated in small increments at 1-week intervals if needed for efficacy. The effect of hepatic impairment on the pharmacokinetics of encainide was studied in 7 patients with clinically documented cirrhosis. Compared with normal subjects studied using a similar protocol, the plasma concentrations of encainide were elevated significantly due to a 6-fold decrease in oral clearance. However, since plasma concentrations of the active metabolite ODE were correspondingly lower, specific encainide dosing instructions for patients with hepatic impairment are not indicated.

Relation of blood level and metabolites to the antiarrhythmic effectiveness of encainide.

Encainide is a potent new antiarrhythmic agent with 2 major active metabolites and 2 distinct phenotypes for metabolism, extensive (approximately 92%) and nonextensive (8%). Encainide is an active compound with close correlation of plasma levels with antiarrhythmic effectiveness and electrocardiographic changes in nonextensive metabolizers. Its metabolites, O-demethyl-encainide and 3-methoxy-O-demethyl-encainide, are active against experimental and clinical arrhythmias. They have longer half-lives than and equal or greater potency than the parent compound. All 3 compounds contribute to the antiarrhythmic profile in extensive metabolizers. There is no readily apparent relation between encainide and its metabolites, blood levels and efficacy because of the complexity of the 3 active compounds and individual variation in pharmacokinetic and arrhythmia responsiveness. Encainide has been given for up to 2 years in 140 patients with sustained ventricular tachycardia or ventricular fibrillation. The survival curves are similar to historical control data from patients reported by Graboys and Swerdlow. The survival curves for long-term administration in patients with frequent ventricular premature complexes (greater than 30/min) are comparable to data from Califf. While these data must be viewed cautiously, it seems fair to conclude that encainide is as effective as any combination of drugs for preventing sudden death in patients with life-threatening ventricular arrhythmias.

The effect of alcohol on the toxicity of acetaminophen in mice.

A previous study with human subjects has shown that a low dose of alcohol, consumed prior to the ingestion of a therapeutic dose of acetaminophen, significantly reduced the excretion of acetaminophen-mercapturic acid. This study suggested that alcohol may be of value as an antidote in cases of acetaminophen overdose, by inhibiting the oxidative metabolism of acetaminophen. The present report describes our results in using alcohol as an antidote for acetaminophen overdose in the mouse model. We have observed that 0.2 ml per animal of 19% alcohol, given at 3 - 4 hours after an LD50 dose of acetaminophen, produced a 24 hour survival of 92%. N Acetyl-cysteine produced 100% survival. Changes in either the dose or timing of the alcohol produced smaller increases in survival (75%), and in no case of alcohol treatment was survival less than control levels (50%). Alcohol thus appears to be an effective antidote for acetaminophen overdose in the mouse model, when given at an appropriate time and dose. It remains to be determined whether these results are applicable to human subjects.

The effect of mild alcohol consumption on the metabolism of acetaminophen in man.

Previous studies with human subjects have shown that chronic alcohol consumption increases the risk of hepatotoxic effects from an overdose of acetaminophen (APAP). Recent studies in humans and with animal models have shown, on the other hand, that an acute dose of alcohol inhibits the development of hepatotoxic effects from an APAP overdose. Our studies in human subjects show that low doses of alcohol consumption may also provide some protection from the hepatotoxicity of APAP overdose. Specifically, we observe that a small dose of alcohol (the equivalent of 1 ounce of ethanol), consumed over a period of one hour prior to the ingestion of APAP, leads to a reduction in APAP-mercapturic acid excretion. The reduction in the excretion of this metabolite extends for a period of up to 12 hours after APAP ingestion, which is longer than the half-life of the alcohol consumed. The changes in APAP-mercapturic acid excretion are easily detected by our chromatography system via a colorimetric reaction with diphenylpicrylhydrazyl (DPPH).