Pharmacokinetics of dexloxiglumide after administration of single and repeat oral escalating doses in healthy young males

OBJECTIVE: To assess the pharmacokinetics, safety and tolerability of dexloxiglumide, a new CCK1 receptor antagonist currently under development for the treatment of the constipation-predominant irritable bowel syndrome. SUBJECTS AND METHODS: Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design. Plasma and urine were collected before drug administration and up to 72 h after dosing. Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard noncompartmental methods. In addition, dexloxiglumide safety and tolerability were evaluated throughout the study period by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence and severity of adverse events. RESULTS: After a single oral administration, dexloxiglumide was rapidly bioavailable with mean t(max) ranging from 0.9 - 1.6 h at all doses. The mean peak plasma concentrations (Cmax) were 1.7+/-0.6, 5.4+/-1.7, and 11.9+/-4.7 microg/ml, and the mean area under the plasma concentration-time curves (AUC) were 4.4+/-3.3, 8.6+/-3.6, and 18.3+/-5.9 microg x h/ml at the 3 doses, respectively. Apparent plasma clearance (CL/F) was 30.8+/-13.9, 27.2+/-10.6, and 21.1+/-8.6 l/h at the 3 doses, respectively. The apparent elimination half-life from plasma (t1/2) ranged from 2.6 - 3.3 h at the 3 doses. The excretion of unchanged dexloxiglumide in 0 - 72 h urine accounted for approximately 1% of the administered dose and this was true for all doses. Dexloxiglumide renal clearance (CLR) averaged 0.4+/-0.4, 0.4+/-0.2, and 0.3+/-0.3 l/h for the 3 doses, respectively. After the last dose of the repeated dosing period dexloxiglumide Cmax occurred at 1.1 - 1.6 h after drug administration and averaged 2.4+/-1.3, 7.1+/-2.9, and 15.3+/-2.7 microg/ml for the 3 doses, respectively. The AUC values averaged 5.9+/-3.0, 16.0+/-8.8, and 50.8+/-38.1 microg x h/ml, respectively. The area under the plasma concentration-time curve calculated at steady state within a dosing interval (AUCss) averaged 4.6+/-1.6, 11.3+/-3.6, and 28.4+/-8.2 microg x h/ml, whereas CL/F averaged 20.3+/-8.3, 16.3+/-9.0, and 10.3+/-5.0 l/h at the 3 doses, respectively. Dexloxiglumide t1/2 could not be accurately calculated due to the high inter-subject variability and to sustained dexloxiglumide plasma concentrations that precluded the identification ofthe terminal phase of the plasma concentration-time profiles. However, it appeared that dexloxiglumide t1/2 was considerably prolonged at the dose of 400 mg. CLR averaged 0.4+/-0.4, 0.3+/-0.3, and 0.3+/-0.1 l/h for the 3 doses, respectively. After a single dose, the plasma pharmacokinetics of dexloxiglumide were dose-independent in the dose range 100 - 400 mg. After repeated dose the pharmacokinetics of dexloxiglumide were virtually dose-independent in the dose range 100 - 200 mg. A slight deviation from linear pharmacokinetics was found with a dose of 400 mg. Dexloxiglumide plasma pharmacokinetics were also time-independent in the dose range 100 - 200 mg with a deviation from expectation based on the superimposition principle with a dose of 400 mg. Dexloxiglumide urinary excretion and renal clearance were both dose- and time-independent in the dose range 100 - 400 mg. The safety and tolerability of dexloxiglumide administered to healthy young males was good up to the maximum investigated dose of 400 mg both after single and after repeated doses. CONCLUSIONS: The safety and pharmacokinetic profile of dexloxiglumide when the drug is administered as single and repeated doses in the dose range 100 - 400 mg provides the rationale for the choice of the treatment schedule (200 mg t.i.d.) for the efficacy trials in patients with (constipation-predominant) irritable bowel syndrome.     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Steady-state pharmacokinetics of rufloxacin in elderly patients with lower respiratory tract infections.

The pharmacokinetics of rufloxacin, after repeated doses, was evaluated in 12 elderly patients with lower respiratory tract infections. Patients were given a single loading dose of 400 mg on the first day of treatment and single daily maintenance doses of 200 mg for the next 6-9 days. Serum concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at regular intervals during treatment and fitted to a one-compartment open model for repeated doses. The maximum serum concentration after the first dose was 6.46 +/- 1.06 (mean +/- SEM) micrograms/ml and was reached in 4.3 +/- 0.8 h after the first administration. The elimination half-life was 28.7 +/- 4.1 h. The area under the serum levels-time curve from 0 to 24 h was 103 +/- 14 micrograms/h/ml after the first dose. On the last day of observation it increased to 155 +/- 28 micrograms/h/ml, with a mean extent of accumulation of 2.3 +/- 0.3 times. The elimination half-life was comparable to those in other studies in healthy young subjects, while plasma levels were about 80% higher. These results suggest that in elderly patients elevated drug concentrations may be reached in the serum. Although no untoward reactions related either to the drug concentration in serum or the dose have been noted with rufloxacin, this patient population should nevertheless be monitored carefully for adverse effects.     

Clinical pharmacokinetics after repeated intrapleural bupivacaine administration

Patients (n = 14) who underwent thoracotomy during surgery of the oesophagus for cancer received an initial intrapleural dose of 10 ml bupivacaine hydrochloride 2.5 mg/ml followed by repeated administration every 8 hours from the first to the fourth postoperative day. The mean (+/- SD) peak plasma drug concentration (Cmax) [352 +/- 120 micrograms/L], time to peak (tmax) [0.83 +/- 0.51 h], and first-order absorption rate constant (ka) [5.46 +/- 4.95 h-1] after the twelfth dose were significantly different from the Cmax (206 +/- 81 micrograms/L), tmax (1.8 +/- 1.2h), and ka (1.8 +/- 1.47 h-1) determined after the first dose. Half-life (3.5 +/- 2.2h) and mean concentration (204 +/- 105 micrograms/L) were not significantly different on the fourth day from those on the first (4.1 +/- 2.6h and 142 +/- 71 micrograms/L, respectively). No sharp peak corresponding to systemic toxicity and no accumulation could be expected with these low doses, administered at short intervals and providing good pain relief in this surgical series.     

The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat

1. The comparative gastric toxicology and pharmacokinetics of two phenoxyisobutyrate derivatives have been evaluated in the Fischer rat. 2. After oral administration of single daily doses for 7 days, the plasma elimination half-life for bezafibrate was rapid (t1/2 of 4-5 h) in comparison to ciprofibrate (t1/2 of 76 h). 3. The area under the plasma drug concentration versus time curve (AUC) 0-24 (micrograms.h/ml +/- SD) for bezafibrate (dose 125 mg/kg per day) was 1553 +/- 334, which was less than half the value of 3748 +/- 358 achieved by ciprofibrate (10 mg/kg per day) after 7 days. 4. Oral administration of ciprofibrate at 10 mg/kg every 48 h produced similar sustained plasma concentrations to those achieved by bezafibrate 125 mg/kg dosed every 12 h. The AUC 0-48 values (micrograms.h/ml +/- SD) achieved were 5124 +/- 450 for bezafibrate compared to 4207 +/- 240 for ciprofibrate. 5. In chronic oral multidose studies with ciprofibrate and bezafibrate, similar gastric toxicity (neuroendocrine cell hyperplasia) occurred in the rat when dose regimens were adjusted to compensate for the pharmacokinetic differences between these two drugs.     

Plasma metronidazole concentrations after single and repeated vaginal pessary administration.

Metronidazole concentrations in plasma were measured by h.p.l.c. in 12 healthy female volunteers after single and repeated vaginal administration of 500 mg metronidazole pessaries. The area under the plasma concentration-time curve (AUC(0,12 h) was 8.4 +/- 3.9 micrograms ml-1 h (mean +/- s.d.) on day 1 and 20.6 +/- 7.1 micrograms ml-1 h (mean +/- s.d.) on day 5. The peak plasma drug concentration on day 1 was 1.2 +/- 0.6 micrograms ml-1 (mean +/- s.d.) and on day 5 it was 2.0 +/- 0.7 micrograms ml-1 (mean +/- s.d.). The plasma concentration of metronidazole at steady state was above the minimum inhibitory concentration (MIC) for anaerobic Streptococci and Clostridium tetani. These results demonstrate much lower systemic exposure than after oral administration.     

Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men

OBJECTIVES: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men. METHODS: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. CONCLUSIONS: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.     

Bioavailability of dihydroergotamine in man.

1 The pharmacokinetics of dihydroergotamine (DHE) in plasma were examined in six normotensive subjects after single acute doses of dihydroergotamine, 10 micrograms/kg i.v. and 10, 20 and 30 mg orally. 2 The mean apparent half-time of elimination was 2.37 +/- 0.29 h and plasma clearance of dHE was 1002 +/- 169 ml/min. 3 Mean apparent absorption of DHE determined from the 10 mg dose was 26.6 +/- 10% and ranged from 8.9 to 60.3%. The oral bioavailability after the 10, 20 and 30 mg doses averaged 0.47 +/- 0.07%, 0.59 +/- 0.13% and 0.52 +/- 0.14% respectively. Inter-patient variability in bioavailability was 6-fold. 4 The results indicate that pre-systemic 'first-pass' extraction of DHE is the main determinant of its oral bioavailability. Oral doses of the drug up to 30 mg do not saturate this extraction process resulting in apparently linear kinetics for the drug.     

Comparative oxycodone pharmacokinetics in humans after intravenous, oral, and rectal administration.

The pharmacokinetics of oxycodone have been determined after single-dose administration by the intravenous (4.6-7.3 mg), oral (tablets, 9.1 mg and syrup, 9.1 mg), and rectal (30 mg) routes, in 48 patients undergoing minor surgery. There were no significant differences in the mean elimination half-lives between the intravenous (5.45 +/- 1.43 h), oral tablets (5.65 +/- 1.13 h), oral syrup (4.80 +/- 1.13 h), and rectal suppository (5.40 +/- 1.19 h) formulations of oxycodone. After intravenous administration, the mean plasma clearance of oxycodone was 25.5 +/- 10.1 L/h and the mean volume of distribution at steady state was 2.5 +/- 0.8 L/kg. The mean normalized area under the curve (AUC/D) obtained after intravenous dosing (48.2 +/- 30.2 micrograms.h/L/mg) was more than twice the AUC/D values obtained after the administration of oxycodone tablets (19.8 +/- 3.5 micrograms.h/L/mg), oxycodone syrup (17.5 +/- 5.3 micrograms.h/L/mg), and rectal suppository (20.3 +/- 5.1 micrograms.h/L/mg), indicating that the amount of oxycodone reaching the systemic circulation after the extravascular routes of administration was < 50% of that obtained after intravenous dosing. The mean absorption lag times after oxycodone tablets (0.52 +/- 0.33 h), oxycodone syrup (0.48 +/- 0.40 h), and rectal suppository (0.76 +/- 0.47 h) were consistent with the onset of pharmacological effects reported by the patients.     

Pharmacokinetics of dihydroartemisinin in Artekin tablets for single and repeated dosing in Chinese healthy volunteers

Aim. To study the pharmacokinetics of dihydroartemisinin (DHA) in Artekin (compound dihydroartemisinin) tablets in Chinese healthy volunteers. Methods. Eighteen healthy volunteers (9 males, 9 females) received Artekin tablets for oral administration. The plasma samples of DHA were analysed by liquid-liquid extraction and determined by HPLC/ESI/MS. Results. The plasma DHA concentration-time curves of single dose and repeated doses of DHA were fitted to a two-compartment open model. The mean pharmacokinetic parameters of DHA in a single dose were: t(1/2(beta))=1.245 +/- 0.495 h, C(max)=243.6 +/- 56.15 microg/l, AUC(0 --> infinity)=450 +/- 69 h x microg/l, V(d)=5.75 +/- 2.2 l/kg and Cl=3.245 +/- 0.38 l/h/kg, while in repeated doses they were: t(1/2(beta))=1.085 +/- 0.298 h, AUC(0 --> infinity)=444.35 +/- 80.43 h x ng/ml, V(d)=4.62 +/- 1.128 ml/kg, Cl=3.0125 +/- 0.875 ml/h/kg, respectively. Conclusion. The study showed that DHA in Artekin was rapidly absorbed, distributed and eliminated in the healthy subjects. The pharmacokinetic properties of DHA in Artekin were not affected by gender in a single dose. While in repeated doses accumulation of DHA did not appear after repeated doses.     

Pharmacokinetics of D(+)-usnic acid in rabbits after intravenous and oral administration.

The pharmacokinetics of D(+)-usnic acid--a lichen antitubercular, antitumor, and enzyme-inhibiting agent--was studied in rabbits following intravenous or oral administration of 5 and 20 mg/kg body weight doses, respectively. Plasma samples were collected at different time intervals, and usnic acid was determined by HPLC. Plasma usnic acid levels following intravenous administration showed a triexponential elimination with a mean +/- SD terminal half-life of 10.7 +/- 4.6 hr. The volume of distribution of the central compartment and systemic clearance were 43.9 +/- 21.3 ml/kg and 12.2 +/- 3.0 ml/hr/kg, respectively. Pharmacokinetic parameters obtained, based on compartmental and noncompartmental approaches, were comparable. Plasma concentration data obtained after oral administration were analyzed using a noncompartmental method. Peak plasma level (Cmax) of 32.5 +/- 6.8 micrograms/ml was achieved in 12.2 +/- 3.8 hr (tmax). Mean absolute bioavailability of usnic acid following oral administration was 77.8%.     

Steady-state serum pharmacokinetics and bioequivalence of 500 mg oral versus 200 mg intravenous ciprofloxacin

The pharmacokinetics of ciprofloxacin were examined after five days of treatment with 500 mg orally and 200 mg intravenously twice a day, in six healthy volunteers in an open, randomized crossover study. The ciprofloxacin concentrations were determined in serum by high performance liquid chromatography. The mean serum peak concentrations were obtained in 1 to 1.5 h by the oral route and the values reached were similar after the oral and intravenous dose (2.56 +/- 0.62 micrograms/ml and 2.6 +/- 0.67 micrograms/ml respectively). The terminal elimination half-life was about 4.5 h for oral form and 5 h for intravenous form. The absolute bioavailability of the oral ciprofloxacin was about 83%.     

Pharmacokinetics of canrenone after oral administration of spironolactone and intravenous injection of canrenoate-K in healthy man

Five healthy male volunteers received canrenoate-K 200 mg (Sincomen pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066 +/- 876 ng/ml was found after 29 +/- 15 min and thereafter the concentration declined with a half-life of 3.7 +/- 1.2 h. Total clearance was 4.2 +/- 1.7 ml/min . kg. After oral ingestion, the maximum concentration of 177 +/- 33 ng/ml was observed at 4.4 +/- 0.9 h. The absolute bioavailability of canrenone was 25 +/- 9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9 +/- 1.8 h (i.v.) and 3.9 +/- 1.2 h (p.o.).     

Flecainide pharmacokinetics after multiple dosing in patients with impaired renal function

Study objective: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. Design: Paired study of single followed by multiple oral doses. Setting: Patients enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. Patients: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end-stage renal disease receiving maintenance hemodialysis. Interventions: All patients received a single, oral, 200-mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single-dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (micrograms/L) were 330 +/- 104 micrograms/L (mean +/- SD) after the single dose and 687 +/- 505 micrograms/L after multiple doses. Time to peak occurred at 3.3 +/- 2.3 hours and 2.7 +/- 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 +/- 2.9 L/kg and 9.2 +/- 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half-life after the single dose (20.4 +/- 9.0 hours) was significantly shorter (P less than .001) than after multiple doses (37.8 +/- 39.7 hours), as was total body clearance: 391 +/- 154 mL/min versus 302 +/- 194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple-dose study.(ABSTRACT TRUNCATED AT 250 WORDS)     

The plasma pharmacokinetics of iophenoxic and iopanoic acids in goat.

1. The comparative plasma pharmacokinetics of two organic iodine-containing compounds were evaluated in the goat for their suitability as markers in wildlife studies. 2. After oral administration of a single dose, the plasma elimination half-life for iopanoic acid was considerably more rapid (t1/2 of 1-2 days) than that of iophenoxic acid (t1/2 of 81 days). 3. Similar peak plasma concentrations were obtained after administration of iophenoxic acid (1.5 mg/kg) and iopanoic acid (25 mg/kg); however, the AUC0----infinity for iopanoic acid at doses of 25, 50, and 100 mg/kg were 201 +/- 39, 604 +/- 225, and 1292 +/- 721 (micrograms h/ml +/- SD), respectively, which were less than the value of 36,600 +/- 6387 for the oral administration of iophenoxic acid at 1.5 mg/kg. 4. Iophenoxic acid was chosen as a suitable marker because of its persistence at detectable concentrations in the plasma for 5 months.     

Effects of enzyme induction, renal and cardiac function on ketamine plasma kinetics in patients with ketamine long-term analgosedation

Steady-state plasma levels of ketamine and its metabolites norketamine and dehydronorketamine were determined in 4 different groups of a total of 27 patients with ketamine long-term analgosedation (1.1 - 1.3 mg/kg/h). In 9 of the patients who had normal liver and kidney function (group 1), steady-state levels after 3 days of continuous infusion were 1.2 +/- 0.3 micrograms/ml ketamine, 1.0 +/- 0.6 micrograms/ml norketamine, and 2.6 +/- 1.0 micrograms/ml dehydronorketamine. The measured ketamine levels in group 1 were in agreement with the expected value, which may be calculated from published pharmacokinetic data after bolus injection. In 8 patients with acute renal failure (group 2), a tendency to about 20% higher ketamine steady-state plasma levels compared to group 1 was observed, but this difference was not significant. However, dehydronorketamine plasma levels were significantly higher in this group. Only a minor fraction of the ketamine dose (10% and 4%) was eliminated during hemodialysis or hemofiltration treatment, respectively. Steady-state plasma levels in 5 patients with cardiogenic shock (group 3) did not differ significantly from those of group 1. In 5 patients with long-term use of barbiturates (group 4), steady-state plasma levels of ketamine were significantly lower compared to groups 1 and 3, most likely due to barbiturate-induced enzyme induction. Hyperdynamic circulatory reactions were not observed in any of the patients. Psychomimetic effects could be excluded in 16 of the patients and were unlikely in 6 patients. In 5 further patients, psychomimetic effects could not definitely be excluded due to difficulties in non-verbal communication.     

Pharmacokinetics and the antiarrhythmic effect of mexiletine in patients with chronic ventricular arrhythmias

A new antiarrhythmic agent, 1-(2,6- dimethylphenoxy )-2-aminopropane (mexiletine), was investigated in 10 patients with chronic premature ventricular contractions (PVCs) to evaluate the antiarrhythmic efficacy and the pharmacokinetics after single intravenous, single oral and repeated oral dosings of mexiletine 150 mg. Mexiletine was well absorbed from the intestinal tract. The relative bioavailability was 83.2 +/- 8.9% (mean +/- S.E.). The time-concentration curve of mexiletine fitted in well with two-compartment open model. Elimination half-life, volume of distribution and plasma clearance were 10.54 +/- 0.26 h, 2.10 +/- 0.49 l/kg, 6.01 +/- 0.63 ml/min/kg, respectively. The computer-simulated time-concentration curves of multiple oral dosings , which were based on the kinetic parameters from single oral dosing, conformed well with measured concentrations. This might be applied to predict the plasma level of mexiletine. The steady state of plasma mexiletine level was reached 4-5 days after 450 mg/day dosings and ranged 0.75-2.18 micrograms/ml. In 6 of 10 patients, the frequency of PVCs was suppressed more than 75% as compared with the pre-medication value. Mexiletine was well tolerated at a dose of 450 mg/day. However, of 4 patients with the dose increased to 600 mg/day, the administration was ceased in three patients due to gastrointestinal symptoms and tremor. All of these adverse reactions disappeared when the administration was stopped. These results suggest that mexiletine is effective against ventricular arrhythmias and the dosage should be carefully adjusted. The prediction of plasma level would be applied to the dosage regimen of mexiletine.     

Single dose pharmacokinetics of tiaprofenic acid. Effects of food and severe renal insufficiency

The single oral dose pharmacokinetics of tiaprofenic acid (Surgam) has been investigated in fasting and non-fasting healthy volunteers (200 and 300 mg) and in fasting patients with severe renal insufficiency (200 mg). A dose independent pharmacokinetics of tiaprofenic acid was shown in fasting healthy volunteers and the following parameters were calculated after administration of 200 mg: tl = 0.53 +/- 0.15 h, tm = 1.28 +/- 0.19 h, cm = 27.1 micrograms/ml, ka = 2.79 +/- 0.93 h-1, lambda 2 = 1.06 +/- 0.14 h-1, t1/2 = 3.0 +/- 0.2 h, AUCl-infinity = 80 +/- 7 mg X h/l, Clt = 43.8 +/- 3.7 ml/min and V beta = 11.1 +/- 0.8 l. A small, but significant positive deviation from linearity was observed with increasing dose for cm and AUCl-infinity in non-fasting healthy volunteers, probably due to a slightly higher bioavailability of the 300 mg formulation in the non-fasting state as compared with the 200 mg formulation. Intake of food decreased cm significantly at both dosage levels from 27.1 to 19.1 micrograms/ml and from 47.9 to 39.1 micrograms/ml for 200 and 300 mg, respectively. The absorption kinetics of tiaprofenic acid was not significantly different in fasting healthy volunteers and in fasting patients with severe renal insufficiency. However, a significant increase in t1/2 and AUCl-infinity to 5.8 +/- 0.9 h and 173 +/- 34 mg X h/l, respectively, and a significant decrease in total body clearance to 25.5 +/- 5.3 ml/min were observed in this category of patients. No correlation was found between creatinine clearance and tiaprofenic acid clearance.     

Pharmacokinetic and clinical studies of clarithromycin in the pediatric field

Pharmacokinetic and clinical studies on clarithromycin (TE-031, A-56268), a new macrolide antibiotic, were performed in the pediatric field. 1. Pharmacokinetic investigation We studied serum concentrations and urinary excretions after single oral administration of TE-031 granules and tablets. Doses were 1, 5, 10 and 15 mg/kg body weight in case of granules (10% TE-031) and 150 mg/kg body weight in case of tablets (50 mg TE-031, 3 tablets). As results, Tmax's were 1-2 hours after administration in case of both granules and tablets. Cmax's in cases of granules were 0.29 +/- 0.15 micrograms/ml in 1 mg/kg administration, 2.53 +/- 0.71 micrograms/ml in 5 mg/kg, 4.11 +/- 1.37 micrograms/ml in 10 mg/kg, 6.28 +/- 1.48 micrograms/ml in 15 mg/kg showing a dose dependency. T 1/2's were 1.8-6.5 hours in cases of 1, 5, 10, 15 mg/kg of granules and tablets. T 1/2's became longer with increased doses. Urinary recoveries were 9.4 +/- 2.4% to 31.6 +/- 19.0% in 6 hours after administration. 2. Clinical investigation Clinical study was carried out in 24 patients of respiratory infections. Clinical efficacies were excellent in 11 patients, good in 12 patients and fair in 1 patient. The clinical efficacy rate was 95.8%. No side effects were observed. The above results suggest that TE-031 is a useful oral antibiotic for treating pediatric respiratory infections, especially those due to Mycoplasma pneumoniae.