Comparative efficacy of new investigational agents against Helicobacter pylori.

BACKGROUND: Emergence of antibiotic resistant Helicobacter pylori has necessitated the identification of alternate therapies for the treatment of this infection. AIM: To assess the in vitro efficacy of two investigational agents: DMG-MINO CL 344 (a N,N-dimethylglycylamido derivative of minocycline), and davercin, a cyclic carbonate of erythromycin A as compared to older antibiotics (clarithromcyin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, cefixime) against clinical isolates of H. pylori. METHODS: Testing was performed using the agar dilution method approved by the NCCLS subcommittee on antimicrobial susceptibility testing, Helicobacter pylori working group. Under these guidelines, Mueller-Hinton agar containing 5% aged sheep blood was used. All incubations were done under CampyPak Plus conditions for 72 h at 37 degrees C. The drug concentrations in the agar ranged from 0.016 to 16 microg/mL. Twenty-one clarithromycin-resistant and 16 clarithromycin-susceptible clinical isolates of H. pylori obtained from patients with duodenal ulcer were used. H. pylori ATCC 43504 was used as the control in all determinations. RESULTS: Against clarithromycin susceptible isolates, all antimicrobial agents except the fluoroquinolones were highly effective. Against clarithromycin-resistant H. pylori, the MIC50/MIC90 values showed that the tetracyclines and cefixime were the most efficacious agents. The fluoroquinolones and macrolides were ineffective. Macrolide cross-resistance was detected. CONCLUSION: Macrolide cross-resistance prevents the use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients.

Assessment of coagulation system activation using spot urine measurements.

Coagulation system activation is most commonly assessed by measuring levels of one or more proteins in peripheral blood. Because faulty blood-drawing can cause activation of the coagulation system, artifactual elevations of such markers have been reported. We have therefore investigated the possibility of using randomly collected ('spot') urine samples as a non-invasive means of assessing the state of coagulation system activation. Using a commercially available enzyme-linked immunosorbent assay kit designed to measure plasma levels of fragment 1 + 2, we found immunoreactive fragment 2 in healthy control subjects, and significantly increased levels in diabetic and non-diabetic pregnant subjects, and patients with venous thromboembolism, prostate cancer, and diabetes. Measurements of excretion of immunoreactive fragment 2 are worth further study as an adjunct or alternative to plasma-based assays designed to detect or quantify coagulation system activation.

Pharmacokinetic interaction between ritonavir and didanosine when administered concurrently to HIV-infected patients.

The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (<10%) with concurrent administration of ddI compared with those of ritonavir alone. In contrast, ddI concentrations were lower with concurrent administration compared with those of ddI alone; maximum concentration and area under the concentration-time curve were reduced by about 15% (p < .05). The ddI elimination rate constant was unaffected by ritonavir, suggesting no change in ddI's systemic metabolism. Adverse events were similar between regimens. The relatively minor changes in ritonavir and ddI pharmacokinetics are probably not clinically relevant; therefore, dosage adjustment of either compound appears unnecessary when administered concurrently. However, the combination regimen of ddI and ritonavir continue to be evaluated clinically.

Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients.

The oxidative metabolism of delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is mediated in part by cytochrome P450 3A. The influence of rifabutin, an inducer of certain human cytochrome P450 isozymes, on the steady-state pharmacokinetics of delavirdine was investigated in 12 HIV-positive patients with CD4 counts ranging from 75 to 671/mm3. Both the control group (n = 5) and the rifabutin group (n = 7) received 400 mg delavirdine mesylate every 8 h for 30 days; subjects in the rifabutin group took a 300 mg, once-daily dose of rifabutin on study days 16-30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations using a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifabutin by HPLC. Delavirdine mesylate alone or in combination with rifabutin was well-tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (P < 0.046). After coadministration of rifabutin and delavirdine mesylate for 2 weeks, oral clearance of delavirdine increased five-fold, resulting in lower steady-state plasma delavirdine concentrations. Rifabutin pharmacokinetic parameters were similar to those previously reported. Concomitant use of delavirdine and rifabutin at the recommended dose for each drug is discouraged. Maintaining therapeutic concentrations of delavirdine in patients on both medications may require dose modification.

Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

OBJECTIVE: To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. DESIGN: Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). SETTING: Clinical Pharmacology Unit within a teaching hospital. MAIN OUTCOME MEASURES: Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. RESULTS: Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. CONCLUSIONS: These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

The effect of co-administration of zolpidem with fluoxetine: pharmacokinetics and pharmacodynamics.

Since early treatment of depression with Selective Serotonin Reuptake Inhibitor (SSRI) can be associated with insomnia, daytime antidepressive therapy with SSRI is often combined with nighttime administration of a hypnotic. This study attempted to evaluate the pharmacokinetic and pharmacodynamic interactions between zolpidem 10 mg, a short-acting hypnotic, and fluoxetine 20 mg, an SSRI. Twenty-seven healthy male volunteers (mean age 23.5 years, range 20 - 29) received zolpidem and fluoxetine in the following open design: zolpidem on night 1, a morning dose of fluoxetine daily from day 2 through day 18 and zolpidem on night 18. Using HPLC, plasma levels of zolpidem, fluoxetine, and norfluoxetine were determined throughout night 1 for zolpidem, night 18 for zolpidem, fluoxetine, and norfluoxetine on days 16 and 17 for fluoxetine and norfluoxetine. Morning psychomotor tests were performed on days 1, 2, 18, and 19. Statistical analysis of data consisted of repeated measures of ANOVA. There was no significant difference in AUC, C(max), and T1/2 of zolpidem plasma concentrations between night 1 (zolpidem) and night 18 (zolpidem and fluoxetine). There was a significantly higher zolpidem plasma level at 0.5 hours after dosing together with a significantly shorter T(max) on night 18 compared to night 1. There was no significant difference in C(min) of plasma fluoxetine and norfluoxetine levels between day 16 and 17 of fluoxetine dosing, and there was no difference in T(max) between day 17 (fluoxetine) and day 18 (fluoxetine and zolpidem). There was a 3 - 4% increase in AUC and C(max) of fluoxetine and norfluoxetine plasma concentrations in the presence of zolpidem. There was no difference in the next morning performance tests after nighttime treatment of zolpidem alone after 17 consecutive days of fluoxetine treatment, or after zolpidem in the presence of steady-state plasma concentrations of fluoxetine. Both zolpidem and fluoxetine were well tolerated alone or in combination. It is concluded that the onset of action of zolpidem may possibly be shortened in the presence of fluoxetine, but no other significant pharmacokinetic or pharmacodynamic interactions occurred between zolpidem and fluoxetine.

Pharmacokinetics of tacrolimus in liver transplant patients.

OBJECTIVE: To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients. METHODS: Patients (n = 16) were assessed during and after 1- to 3-day intravenous infusions followed by a 2-week course of oral dose therapy. Plasma and whole blood data were fitted simultaneously with equations accounting for nonlinear drug binding by red blood cells to generate clearance (CL) and volume of distribution (V). RESULTS: The maximum blood/plasma ratio of tacrolimus was 55.5 +/- 26.8 (SD) and half-life averaged 12.1 +/- 4.7 hours. The CL and V were relatively high based on plasma concentrations (CL, 1.7 L/hr/kg; V, 30 L/kg) and low based on whole blood (CL, 54 ml/hr/kg; V, 0.9 L/kg), with moderate variability (coefficient of variation, 34% to 49%) among the patients. Correlations of plasma CL and V with maximum blood/plasma ratios (ranging from 13 to 114) were strong (r = 0.65 and r = 0.73). Blood binding affects the disposition of tacrolimus, and plasma concentrations are indirectly and inversely related to red cell binding. The oral dose data for tacrolimus yielded a brief absorption lag time (tlag, 0.39 hour), a variable first-order absorption rate constant (ka, 4.5 +/- 3.0 hr-1), and consistent bioavailability (F, 25% +/- 10%). The area under the concentration-time curve versus 12-hour minimum concentration relationships for both whole blood and plasma were nearly linear, confirming the utility of trough values for monitoring drug exposure. CONCLUSION: This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.

Pharmacokinetics and acute cardiovascular effects of menogaril in patients with metastatic tumors.

The new anthracyclin, menogaril [7-(R)-0-methylnogarol], is reported to produce less cardiotoxicity than doxorubicin after multiple doses. This study was designed to assess acute hemodynamic changes during the first administration of menogaril and to relate these changes to plasma concentrations. Menogaril (200 mg/mg) was infused over 90 minutes to 4 patients with metastatic colon or prostate cancer. Cardiac output (CO) and stroke volume (SV) were measured noninvasively by Doppler ultrasound. Menogaril plasma concentrations were measured by HPLC and a 3-compartment mammillary model was used for pharmacokinetic analysis of the results. Steady-state volume of distribution, elimination clearance, and elimination half-life averaged 1,114 +/- 340 l/m2, 38 +/- 16 l/h/m2 and 40.3 +/- 30.3 hours, respectively. All patients were normotensive (baseline blood pressure = 135 +/- 10/73.5 +/- 8 mmHg) and ejection fractions were in normal range (EF = 68 +/- 7%). Transient increase in mean arterial pressure (MAP) from 93 +/- 3 to 107 +/- 4 mmHg (p < or = 0.001) were seen during and shortly after the end of menogaril infusion in all patients. Heart rate (78 +/- 5 min-1) remained constant. CO fell slightly and total peripheral resistance (TPR) increased by 36.8% in the last 2 patients. The increase in MAP was analyzed by a linear-effect model and averaged 0.028 +/- 0.017 mmHg per ng/ml of menogaril in the hypothetical biophase. The half-life for menogaril equilibration between plasma and this biophase was 41 +/- 22 minutes. We conclude that during acute administration of menogaril, blood pressure increases transiently secondary to an increase in TPR.(ABSTRACT TRUNCATED AT 250 WORDS)

A concurrent audit of high digoxin plasma levels.

A concurrent audit was made of 92 patients with plasma or serum digoxin levels of 3.0 ng/ml or more. Evidence of digoxin toxicity was present in 44 of these patients, and premature blood sampling accounted for the high levels in 30 nontoxic patients. Another 14 patients tolerated high digoxin levels without apparent adverse effects. Impaired renal function appeared to increase the risk of digoxin toxicity, even though digoxin levels were similar in patients with and without toxicity. Pharmacokinetic predictions based on patient weight and creatinine clearance often deviated considerably from measured digoxin levels even when these were drawn appropriately.

Activation of renin-angiotensin system does not cause skeletal muscle cramps during hemodialysis.

Activation of the renin-angiotensin system usually occurs during hemodialysis and in hemodialyzed normal dogs parallels reductions in blood flow to a tissue group that is largely composed of skeletal muscle. To determine if excessive activation of this system might cause dialysis-associated skeletal muscle cramps in some patients, we conducted a double-blind, randomized and balanced trial in which 5 patients with frequent dialysis-associated cramps were each given either a 25 mg oral dose of captopril or placebo 1 h before 8 consecutive dialyses. Captopril increased the frequency of dialyses complicated by skeletal muscle cramps in 1 patient and did not affect cramp frequency in the other 4 patients. Predialysis plasma renin activity (PRA) averaged 3.9 ng/ml/h (+/- SD) and was the same as in unselected hemodialysis patients. Following captopril, PRA increased by an average of 2.2 +/- 0.7 times, similar to the 2.6-fold increase that was reported when this drug was used to prevent dialysis-associated hypertensive crises. However, hemodialysis by itself did not activate the renin-angiotensin system as consistently in patients with frequent dialysis-associated skeletal muscle cramps as in unselected hemodialysis patients and the ratio of post- to predialysis PRA averaged 1.0 +/- 0.6. We conclude that the renin-angiotensin system does not mediate, and that its activation during hemodialysis may actually help prevent, dialysis-associated skeletal muscle cramps.

Pharmacokinetics of N-acetylprocainamide in patients profiled with a stable isotope method.

N-Acetylprocainamide (NAPA) absorption and disposition were profiled in five patients with ventricular arrhythmias by the simultaneous intravenous administration of NAPA-13C and oral administration of a 500 mg NAPA hydrochloride tablet. NAPA distribution was modeled with a three compartment mammillary system. The central compartment volume of 14.1 +/- 2.6 L (mean +/- SD) was similar to expected intravascular space, corrected for NAPA partitioning between erythrocytes and plasma. Other compartment volumes, intercompartmental and nonrenal clearances, and the steady-state distribution volume of 1.45 +/- 0.09 L/kg were similar to normal subject values. The least-squares estimate of 1.67 for the NAPA renal clearance/creatinine clearance ratio was similar to the value of 1.68 previously reported for functionally anephric patients and showed the expected age-associated decrease. The oral NAPA dose was 78.0% +/- 11.7% absorbed and interindividual variation in NAPA absorption was correlated with fast intercompartmental clearance (r = 0.89, p = 0.045). Because fast intercompartmental clearance partly reflects splanchnic blood flow, hemodynamic changes may affect NAPA bioavailability, as has been found for procainamide.

Comparison of the pharmacokinetic and pharmacodynamic properties of procainamide and N-acetylprocainamide.

Although procainamide (PA) has been widely used to treat patients with both ventricular and supraventricular arrhythmias since 1951, more than twenty years elapsed before N-acetylprocainamide (NAPA) was identified as a major PA metabolite and shown in PA-treated patients to have plasma concentrations generally equaling or being 2 to 3 times greater than those of the parent drug. Numerous investigations have been conducted since then to characterize the pharmacokinetics and pharmacodynamics of NAPA and to compare these properties with those of PA. Salient differences have been that the elimination half-life of NAPA is 2.5 times that of PA, even when renal function is normal; that NAPA has a spectrum of electrophysiologic action that differs from PA in that NAPA only prolongs action potential duration; and that NAPA is less likely than PA to cause a syndrome resembling systemic lupus erythematosus. Although these properties have provided an impetus for the development of NAPA as an antiarrhythmic drug in its own right, emphasis is placed in this review on the implications of these findings for individualizing PA therapy.

Effect kinetics of N-acetylprocainamide-induced QT interval prolongation.

We attempted to correlate clinical response with the effects of N-acetylprocainamide (NAPA) on the QT interval in five patients with stable chronic ventricular arrhythmias. A 15 mg/kg dose of NAPA was administered and a pharmacokinetic-pharmacodynamic model was used to relate plasma NAPA concentrations to changes in corrected QT interval (QTc). NAPA volume of distribution, elimination clearance, and elimination half-life averaged 1.37 +/- 0.19 L/kg, 174 +/- 63 ml/min, and 8.2 +/- 1.4 hours, respectively (mean +/- SD), and NAPA renal clearance averaged 1.9 +/- 0.6 times creatinine clearance. QTc prolongation was characterized by a linear-effect model in the first four patients and averaged 2.4 msec for every microgram per milliliter NAPA in a hypothetic biophase. QTc prolongation in patient 5 was exaggerated and was analyzed with an Emax model. Nonetheless, NAPA did not control this patient's arrhythmia. Conversely, patient 1 subsequently developed torsade de pointes even though QTc prolongation in this patient was comparable to that in patients 2 through 4, who responded satisfactorily to NAPA. We conclude that QT interval changes during initial NAPA administration do not reliably predict subsequent clinical response.

Torsade de pointes induced by N-acetylprocainamide.

N-Acetylprocainamide (NAPA), a class III antiarrhythmic drug, caused torsade de pointes in a 72 year old woman who had this arrhythmia on two previous occasions while being treated with quinidine and disopyramide. Initial evaluation with an intravenous infusion of NAPA indicated a favorable antiarrhythmic response. The QTC interval was prolonged, but the 2.4 ms/microgram per ml incremental QTC interval lengthening caused by NAPA was not greater than usual. During subsequent oral therapy with NAPA, torsade de pointes developed at plasma levels of this drug that appeared to be well tolerated during the initial evaluation.