A phase I trial of paclitaxel plus carboplatin in untreated patients with advanced non-small cell lung cancer.

This Phase I study was designed to determine the maximally tolerated doses of paclitaxel (given as an outpatient 3-h infusion) plus carboplatin in advanced, untreated non-small cell lung cancer. Secondary objectives were to determine the response rate, response duration, and survival. Fifty-six patients were accrued, and all were evaluable for toxicity; 50 patients were assessable for response. Paclitaxel doses ranged from 135-250 mg/m2, whereas carboplatin dosing started at 250 mg/m2 and was escalated to 400 mg/m2. Patients received therapy on day 1 every 21 days for a maximum of six cycles. Prophylactic granulocyte colony-stimulating factor was not given initially but was allowed if grade 4 neutropenia developed. Neutropenia was the major toxicity observed (41% of patients; 16% of courses) and was dose related. However, febrile neutropenia was uncommon (4%), and no patient receiving growth factor developed subsequent grade 4 neutropenia. Only one patient developed grade 4 thrombocytopenia. No grade 4 neuropathy or grade 3 or 4 myalgias/arthralgias were reported. Grade 4 allergic reactions occurred in three patients (5%), and two patients sustained grade 4 cardiac toxicity (4%). Partial responses were observed in 13 of 50 patients (26%). One of 13 patients (8%) receiving paclitaxel at 135 mg/m2 and carboplatin (250-350 mg/m2) responded versus 12 of 37 patients (32%) receiving paclitaxel doses >/= 175 mg/m2 with carboplatin doses of 350-400 mg/m2. The median time to progression, median survival, and 1-year survival rates seemed to be dose related, with median times to progression of 6, 18, and 27 weeks; median survival of 13, 29, and 39 weeks; and 1-year survival rates of 15, 28, and 41% for the 135, 175-200, and 225-250 mg/m2 groups. We conclude that full doses of both paclitaxel and carboplatin can be given safely on an outpatient basis with 3-h paclitaxel infusions. Neutropenia is the most common toxicity; response rates and survival at higher dose levels were encouraging. Phase III trials to determine the optimal dose and infusion schedule of this combination are warranted, as are trials to compare paclitaxel/carboplatin to other active single agents or combination regimens.

The effect of concurrent oral administration of propranolol and disopyramide on cardiac function in healthy men.

Sixteen healthy men were evaluated for left ventricular performance changes and beta-blockade after therapeutic oral doses of disopyramide and propranolol administered alone and concurrently. The volunteers were randomly assigned to receive one of two drug treatment regimens that differed in the sequence and duration of administration of the drugs. Left ventricular function was assessed by echocardiographically determined ejection fraction (EF) and systolic time intervals. Beta-blockade was assessed by changes in exercise heart rate. Both disopyramide and propranolol exhibited negative inotropic activity, as evidenced by significant, although clinically inconsequential, decreases in EF and increases in the ratio of preejection period to left ventricular ejection time. The negative inotropic effects of a single 200-mg dose of disopyramide and an 80-mg dose of propranolol were comparable, while chronic disopyramide therapy (200 mg every 6 hours for 1 week) had a greater negative inotropic effect than chronic propranolol therapy (80 mg every 8 hours for 1 week). Only propranolol had beta-adrenoceptor blocking activity. When the drugs were administered concurrently, the negative inotropic effects of oral propranolol and disopyramide were neither additive nor synergistic.

Single- and multiple-dose kinetics of oral lorazepam in humans: the predictability of accumulation.

Six healthy volunteers participated in single- and multiple-dose pharmacokinetic studies of oral lorazepam. Following single 4-mg oral doses, peak plasma lorazepam concentrations ranging from 40 to 70 ng/ml were reached within 3 hr of the dose. Values of absorption half-life averaged 25 min (range 10.3-42.7 min), and elimination half-life (t1/2 beta) averaged 14.2 hr (range 8.4-23.9 hr). During 15 consecutive days of 3 mg per day administered in divided doses, accumulation to the steady-state condition was complete within several days of the initiation of therapy. Values of accumulation half-life (mean 21.1 hr) were slightly longer than t1/2beta, and the two were not well correlated. Observed accumulation ratios (mean 1.88) were very close to those predicted from the single-dose study (mean 1.77), but the correlation between the two (r = 0.51) was not significant in the small sample size. "Washout" half-life values (mean 14.9 hr) were highly correlated with t1/2beta (r = 0.92). Clearance of a single intravenous dose of antipyrine determined prior to the multiple-dose lorazepam study (mean 0.86 ml/min/kg) was essentially identical to that determined after the study (mean 0.87 ml/ min/kg). Overall, the rate and extent of lorazepam accumulation during multiple dosage were reasonably well predicted by the single-dose kinetic study. However, accurate prediction for any specific individual was not always achieved. Stimulation or inhibition by lorazepam of its own clearance probably does not explain imprecise prediction, since single-dose t1/2beta and washout half-life values were essentially identical. Furthermore, chronic lorazepam exposure has no apparent effect on hepatic hydroxylation capacity as measured by clearance of exogenously administered antipyrine.

Quantitation of lidocaine and its deethylated metabolites in plasma and urine by gas chromatography-mass fragmentography.

A sensitive, precise and accurate method for simultaneous quantitation of lidocaine and its deethylated metabolites by gas chromatography-mass fragmentography has been developed. Propyl derivatives of the deethylated metabolites are formed directly in either plasma or urine by treatment with propionaldehyde and sodium cyanoborohydride. The propyl derivatives and unchanged lidocaine are extracted, separated by gas chromatography and quantitated by mass fragmentography using mepivacaine as the internal standard. Quantitation of these compounds to levels as low as 50 ng/ml body fluid has been achieved with coefficients of variation less than 10%.

Impairment of antipyrine clearance in humans by propranolol.

The effect of propranolol on antipyrine clearance in humans was evaluated in six healthy volunteers who received single 1.4 to 1.5 g doses of intravenous antipyrine on two occasions. The first (control) antipyrine trial was without concurrent drug administration; the second trial was done during treatment with therapeutic doses of propranolol (40 mg every 4 to 6 hours). Antipyrine elimination half-life (t1/2), volume of distribution (Vd), and total clearance were determined after each trial. In all subjects isoproterenol sensitivity decreased markedly during propranolol treatment, indicating a high degree of beta blockade produced by the drug. Mean antipyrine t1/2 during the propranolol treatment period was significantly prolonged, and total clearance significantly reduced, over the control values. Twenty-four-hour urinary excretion of 4-hydroxyantipyrine, the major metabolite of antipyrine, likewise was reduced from 23.6% of the dose on the control trial to 14.8% of the dose during propranolol coadministration (0.1 less than P less than 0.2). Vd however, was nearly identical during both trials (0.62 L/kg). Thus propranolol prolongs the half-life and reduces the clearance or biotransformation rate of antipyrine, a drug whose clearance is independent of hepatic blood flow. Propranolol may influence the activity of hepatic microsomal enzymes responsible for drug hydroxylation.

Quantitation of N-demethylantipyrine in biological samples and isolation and characterization of its glucuronic acid conjugate.

An improved method for quantitating N-demethylantipyrine (N-DEM-AP) in urine by gas chromatography or gas chromatography-mass spectrometry has been developed. Recovery of greater than 90% of N-DEM-AP was achieved by extraction of the sample at pH 1 after addition of 3-amino-1-phenyl-2-pyrazolin-5-one. The coefficient of variation of replicate analyses was 8%. N-DEM-AP was excreted in the urine as a glucuronic acid conjugate. This conjugate was isolated from the urine of an individual receiving antipyrine and purified. The NMR and mass-spectral data are consistent with the conjugate being an O-glucuronide of N-DEM-AP in its enol form.

Digoxin in hyperthyroidism.

A patient with chronic atrial fibrillation developed hyperthyroidism. Increasing doses of digoxin were required to maintain satisfactor ventricular rate control. The systemic availability of oral digoxin was decreased in this patient. The metabolism of digoxin was studied in the hyperthyroid rats. The plasma digoxin concentrations were significantly decreased in the hyperthyroid rats. A threefold increase in digoxin excretion in the bile of the hyperthyroid rats was associated with these changes in plasma digoxin concentrations. Conversely, hypothyroid rats excreted less digoxin in the bile when compared with control and hyperthyroid rats. Thus, changes in digoxin absorption and its biliary excretion result, in part, in a decreased therapeutic effect of digoxin based on dose in hyperthyroidism.

Metabolic disposition of antipyrine in patients with lung cancer.

The metabolism of antipyrine (10 mg/kg i.v.) was studied in nine patients with cancer of the lung and in a cancer-free control group matched for age, sex, drug intake, and smoking and drinking history. The mean plasma clearance of antipyrine was 0.0475 +/- 0.009 liter/kg/hr in the tumor group and 0.0557 +/- 0.007 liter/kg/hr in the control group (p greater than 0.05). The antipyrine plasma elimination half-life was longer in the group with tumors (9.5 +/- 1.3 hr) compared to the control group (7.7 +/- 1.3 hr), but the difference was not statistically significant (p greater than 0.05). There was no difference between the groups in the excretion of two major antipyrine metabolites, 4-hydroxyantipyrine and N-demethylantipyrine, in a 48-hr urine sample. Thus, the presence of lung cancer in humans does not significantly alter antipyrine elimination.

Bioavailability of digoxin-hydroquinone complex: a new oral digoxin formulation.

A new oral digoxin formulation, a digoxin-hydroquinone complex (99% dissolution at 5 min), was evaluated in 12 healthy human volunteers with reference to bioavailability and extent and time of peak serum digoxin levels. This preparation was compared with a commercial digoxin tablet (26% dissolution at 5 min), digoxin elixir, and a parenteral digoxin solution. Bioavailability was assessed by the 24-hr area under the serum digoxin-time curve and 48-hr digoxin excretion in urine. The bioavailability of the complex was similar to that of the elixir but not statistically different from that of the tablet. The tablet was less bioavailable than the elixir. There was less interindividual variation in bioavailability with the complex than with the elixir. Peak serum digoxin levels were higher with the complex than the tablet and were achieved more quickly.

The interaction between halofenate and propranolol.

The effect of halofenate on beta adrenergic blockade by propranolol was studied in 4 subjects during chronic drug administration in a randomized, double-blind study. The plasma propranolol concentration was significantly lower during treatment with halofenate than with placebo. The reduction in propranolol levels correlated with a decrease in beta adrenergic blockade. The mechanism for the decrease in plasma concentration has not been determined.

Serum quinidine concentrations: comparison of fluorescence, gas-chromatographic, and gas-chromatographic/mass-spectrometric methods.

Serum quinidine concentrations were determined in patients on chronic therapeutic doses. Although results were higher by a protein precipitate-fluorescence method as compared to a specific extraction fluorescence method, there was substantial correlation between results by the two methods (r = 0.945, P less than 0.001). We established the specificity of the extraction method by a methylation gas-chromatographic method in which the base peak in the mass spectra of the methylated products of both quinidine and cinchonidine, the internal standard, was monitored. We conclude that the protein precipitate method should be discarded.

One-year trials with halofenate, clofibrate, and placebo.

The hypolipidemic as well as other laboratory and clinical effects of halofenate, clofibrate, and placebo were compared in 29 patients with type IV hyperlipoproteinemia in a double-blind, controlled, therapeutic trial of 1 yr duration. Plasma drug levels were obtained to monitor compliance. Clofibrate and halofenate lowered serum triglycerides to a similar extent. The hypotriglyceridemic effect of halofenate was significant only when data from noncompliant patients were discarded. Only clofibrate lowered baseline levels of plasma cholesterol. Very low density lipoproteins were decreased and low density lipoproteins were increased by clofibrate but not by halofenate. Halofenate had a marked hypouricemic effect that was greater than that of clofibrate. The hypouricemic effect of halofenate and clofibrate was paralleled by a concomitant decrease in serum bilirubin. Abnormal increases in serum creatine phosphokinase were observed with both drugs primarily in patients who had abnormal initial levels.

Clinical use of digitalis glycosides.

The pharmacology of digitalis compounds is reviewed, and the clinical use of the cardiac glycosides is discussed with particular attention to the selection of patients for digitalis therapy and to a study of the usefulness of various methods to monitor digitalis therapy. The discussion includes pharmacokinetics, clinical considerations, and digitalis toxicity and its treatment. It is concluded that the digitalis glycosides remain the most useful and reliable drugs for producing a long-term increase in myocardial contractility. However, in view of the high frequency of toxicity, it is important to consider the possibility that these drugs may have been overused.