Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase inhibitor, in single and multiple dose escalation studies in healthy volunteers

OBJECTIVE: A novel sulfonamide derivative, S-3304, was discovered as a potent matrix metalloproteinase (MMP) inhibitor. It is a more specific inhibitor to MMP-2 and MMP-9 (in vitro) than to MMP-1, and may therefore lack the musculoskeletal side effects seen with non-specific inhibitors. The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of S-3304 when administered as single and multiple oral doses to healthy male volunteers. MATERIALS AND METHODS: 48 male volunteers received single oral doses ranging from 10 - 800 mg S-3304 or placebo under fasting conditions. At the 200 mg dose level, effects of high-fat diets were studied in a crossover design. In the multiple dose design, 24 male subjects were administered 200 mg, 400 mg or 800 mg S-3304 or placebo b.i.d. after meals for 10 - 17 days. Studies were conducted in a randomized double-blind fashion. Safety assessment was conducted based on blood chemistry, hematology, urinalysis, electrocardiogram and physical examination. Pharmacokinetic parameters were determined for S-3304 and its metabolites. All subjects were enrolled in the studies after obtaining informed consent. RESULTS: Adverse events reported after single dose administration of S-3304 or placebo were all of mild severity. Adverse events reported in the multiple dose treatment with S-3304 or placebo were mostly of mild severity, except for two episodes of moderate headache and two episodes of moderate myalgia. Most commonly reported adverse events in the multiple treatments with S-3304 were headache and somnolence. No clinically significant changes were observed in the clinical laboratory tests, except for reversible elevation of alanine aminotransferase of one subject at 800 mg S-3304 b.i.d. In the single dose administration, Cmax and mean AUC0-infinity linearly increased up to 63,167 ng/ml and 311,960 ng x h/ml at the 800 mg dose level, respectively; tmax and t1/2 ranged from 2 - 3 hours and from 9.5 - 15.5 hours, respectively. High-fat diets reduced Cmax from 21,565 ng/ml to 14,095 ng/ml but did not alter AUC0-infinity. Hydroxylated metabolites were detected in plasma in concentrations less than 1% of S-3304. Less than 1% S-3304 was excreted in urine. The AUC of one dosing interval and Cmax did not change after multiple doses but t1/2 increased from 9.5 - 10.0 hours to 12.5 - 13.5 hours. The 6beta-hydroxycortisol/ cortisol ratio was not changed after multiple doses suggesting no effect on CYP3A4 activity. CONCLUSION: S-3304 demonstrated a good safety profile and good systemic exposure when administered orally up to 800 mg b.i.d. during 10 - 17 days. At the highest dose level of 800 mg b.i.d., it was free of rheumatoid arthritis-like symptoms.     

Tolerance and pharmacokinetics of oral fendiline

Two studies with healthy volunteers were carried out to correlate safety with pharmacokinetics of the calcium antagonistic drug N-(3,3-diphenylpropyl)-(1-phenylethyl)-amine (fendiline, Sensit) after single and multiple oral doses. In the first study single doses of 200, 400, 600, 800, 1000, and 1200 mg of fendiline hydrochloride were administered to 6 subjects per dose level. 3 additional subjects per dose level received placebo. No significant objective or subjective effects were noted in the dose range studied. The pharmacokinetic analysis revealed that doses higher than 800 mg were absorbed incompletely. In the second study initially 400 mg twice daily was given to 9 subjects. 3 additional subjects received placebo. Due to subjective intolerability (trembling, dizziness) after 5 days, the dose was reduced stepwise to 2 X 200 mg and was then continued for another 19 days. The pharmacokinetic evaluation revealed manifold interindividual differences in plasma levels for maximal concentrations (9-170 ng/ml) as well as for minimal concentrations (4-96 ng/ml). The absorption profile in both studies has linear and nonlinear components. Maximal plasma levels were reached after about 4 h. Terminal elimination half-lives were about 20 h.     

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor,omapatrilat in healthy subjects

AIMS: To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects. METHODS: The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. RESULTS: In the multiple-dose study, peak plasma concentrations (Cmax = 10-895 ng ml(-1); tmax = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, Cmax (1-1009 ng ml(-1)) and AUC(0,t) (0.4-1891 ng ml(-1) h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, Cmax but not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 +/- 4.1 (+/- SD) ng 24 h(-1) in the placebo group to 60.0 +/- 18.2 ng 24 h(-1) in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single- and multiple-dose studies. CONCLUSIONS: Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.     

Ranitidine upon meal-induced gastric secretion: oral pharmacokinetics and plasma concentration effect relationships.

1 Ranitidine oral kinetics and plasma concentration-effect relationships upon meal-induced gastric secretion were investigated in normal subjects. Four oral doses of ranitidine (50, 100, 150 or 200 mg) and placebo were tested. 2 Oral ranitidine showed a terminal half-life of about 2 h 25 min. Maximal plasma level was about 240 ng/ml for a 100 mg dose, and occurred about 1 h after dose. From the range of 50 to 200 mg dose, no indication of non-linearity was observed in the drug kinetics. 3 Ranitidine administration resulted in a dose-related reduction in meal-stimulated acid secretion reaching, 46, 70, 82 and 92%, respectively. Mean ranitidine plasma concentrations producing 50 and 80% inhibition of acid secretion were 73 and 180 ng/ml, respectively, with great inter-individual variability. 150 and 200 mg ranitidine oral doses maintained IC50 for at least 4.5 and 5.5 h, respectively. Upon oral administration, ranitidine exerted no effect on gastric emptying of the meal but slightly decreased the gastrin response to the meal.     

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men

AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.     

Pharmacokinetics of therapeutic doses of tropisetron in healthy volunteers

AIMS: To establish the bioavailability of tropisetron (5 mg) administered orally as capsule compared with 2 mg given intravenously. METHODS: Using a randomized crossover design, 18 healthy volunteers received a single oral dose of tropisetron (5 mg) and an intravenous bolus of tropisetron (2 mg) separated by a wash-out period of 1 week. Plasma concentrations of tropisetron were determined by h.p.l.c. and the pharmacokinetic parameters were estimated. RESULTS: The mean pharmacokinetic parameters for 5 mg tropisetron given orally were Cmax 3.46 ng ml(-1), t(max) 2.6 h, t(1/2) 5.7 h and AUC(0,infinity) 32.9 ng ml(-1) h. After intravenous administration initial plasma concentration was 15.1 ng ml(-1), t(1/2) 5.6 h, AUC(0,infinity) 20.7 ng ml(-1) h, V 678 l and CL 1800 ml min(-1). An inverse correlation was demonstrated between CYP2D6 activity, measured by the sparteine metabolic ratio, and the bioavailability (mean 0.60, range 0.27-0.99) of oral tropisetron. CONCLUSIONS: Tropisetron exhibits a wide range of oral bioavailability at therapeutic doses, which is mainly determined by CYP2D6 activity.     

The pharmacokinetics and pharmacodynamics of a new thromboxane synthetase inhibitor, 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904), in man after single oral administration

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex-vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP-1904 from gastro-intestinal tract was rapid. After oral doses of 10-800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean +/- s.e., n = 5) of 0.215 (+/- 0.041), 0.399 (+/- 0.037), 1.47 (+/- 0.22), 2.86 (+/- 0.22), 4.66 (+/- 0.58), 7.28 (+/- 0.72) and 16.9 (+/- 2.6) micrograms mL-1 were reached within 1 h. DP-1904 concentrations declined monophasically after Cmax with half lives of 30-40 min. These half lives were independent of the administered doses. The mean area under the concentration-time curves (AUCs) increased from 0.398 (+/- 0.038) to 30.0 (+/- 2.7) micrograms h mL-1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0.930 and 0.960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP-1904 proved to be linear in the dose range studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults

This study examines the plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) in young adults for up to 143 hours after drug administration. Seventeen female and male participants (black, white, and Hispanic) received placebo, low (1.0 mg/kg), and high (1.6 mg/kg) oral MDMA doses (comparable to recreational doses) in a double-blind, randomized, balanced, within-subject design while residing on a closed research unit. Doses were separated by 1 week or more. A fully validated two-dimensional gas chromatography/mass spectrometry method simultaneously quantified MDMA, HMMA, MDA, and HMA. Calibration curves were MDA, 1 to 100 ng/mL; HMA, 2.5 to 100 ng/mL; and MDMA and HMMA, 2.5 to 400 ng/mL. Mean +/- standard deviation maximum plasma concentrations (C(max)) of 162.9 +/- 39.8 and 171.9 +/- 79.5 ng/mL were observed for MDMA and HMMA, respectively, after low-dose MDMA. After the high dose, mean MDMA Cmax significantly increased to 291.8 +/- 76.5 ng/mL, whereas mean HMMA C(max) was unchanged at 173.5 +/- 66.3 ng/mL. High intersubject variability in C(max) was observed. Mean MDA C(max) were 8.4 +/- 2.1 (low) and 13.8 +/- 3.8 (high) ng/mL. HMA Cmax were 3.5 +/- 0.4 and 3.9 +/- 0.9 ng/mL after the low and high doses, respectively. AUC infinity displayed similar trends to C(max), demonstrating nonlinear pharmacokinetics. Times of last plasma detection were generally HMA < MDA < MDMA < HMMA. Mean half-lives (t1/2) of MDMA, MDA, and HMMA were approximately 7 to 8 hours, 10.5 to 12.5 hours, and 11.5 to 13.5 hours, respectively. HMA t1/2 showed high variability. Mean MDMA volume of distribution was constant for low and high doses; clearance was significantly higher after the low dose. This study presents MDMA plasma pharmacokinetic data for the first time from blacks and females as well as measurement of HMMA and HMA concentrations after low and high MDMA doses and more frequent and extended plasma sampling than in prior studies.     

Bioavailability investigation of two different oral formulations of methylprednisolone

Two different oral methylprednisolone (CAS 83-43-2) formulations (Methylprednisolon-ratiopharm 8 mg tables as test preparation (T) and tablets of a reference preparation (R)) were investigated in 16 healthy volunteers in order to prove bioequivalence between these preparations. A single 8 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of methylprednisolone plasma concentrations were collected at pre-defined time points up to 16 h following drug administration. A washout period of 3 days separated both treatment periods. Methylprednisolone plasma concentrations were determined by means of a validated HPLC method. Values of 342.53 ng.h/ml (test preparation) and 336.61 ng.h/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 66.58 ng/ml and 70.51 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 2.2 h for both preparations. Cmax and AUC0-infinity-values were tested parametrically by the two one-sided t-test procedure. Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80-125% for AUC0-infinity and 70-143% for Cmax. Based on the results obtained in this study, bioequivalence between Methylprednisolone ratiopharm and the reference preparation was demonstrated.     

Dose-proportionality of oral thioctic acid--coincidence of assessments via pooled plasma and individual data.

Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.     

Pharmacokinetics of alfuzosin after single oral administration to healthy volunteers, of three different doses.

The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2.5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2 beta) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1-5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2.5, and 5 mg were, respectively: tmax (h) 1.5 +/- 0.3, 1.1 +/- 0.2, 1.3 +/- 0.1; Cmax (ng ml-1) 2.6 +/- 0.3, 9.4 +/- 1.2, 13.5 +/- 1.0; AUC (ng ml-1 h) 17.7 +/- 2.9, 51.7 +/- 7.1, 99.0 +/- 14.1; t1/2 (h) 3.7 +/- 0.4, 3.9 +/- 0.2, 3.8 +/- 0.3. Cmax (corrected by the dose) obtained after 2.5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2.5 mg and 4 volunteers of 12 after 5 mg.     

A double-site absorption model fits to pharmacokinetic data of repaglinide in man.

The plasma concentrations of repaglinide in 16 male subjects were determined after an oral dose of 4 mg. Two-peak concentrations in plasma were observed. A type of one-compartment model with double sites of drug absorption was developed and successfully used to fit the data. A good agreement between observed and predicted data was found in all subjects with correlation index r2 > 0.97. The corresponding pharmacokinetic parameters were estimated as follows: Tmax1 0.61 +/- 0.14 h, Tmax2 1.45 +/- 0.43 h, Cmax1 40.60 +/- 20.57 ng/ml, Cmax2 42.70 +/- 17.54 ng/ml, T1 0.12 +/- 0.07 h, T2 0.67 +/- 0.30 h and T3 1.03 +/- 0.35 h.     

A double-blind, placebo controlled, cross-over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser-induced pain.

1. The analgesic efficacy of single oral doses (400 mg, 800 mg) of ibuprofen on argon laser-induced pain was studied in a double-blind, placebo controlled, three way cross-over comparison. Ten healthy volunteers participated. 2. Pain thresholds and plasma concentrations of the S- and R-enantiomers of ibuprofen were measured every hour up to 8 h after medication. 3. Ibuprofen (400 mg) produced an analgesic effect significantly superior (P less than 0.05) to placebo 1-4 h after medication. Ibuprofen (800 mg) was significantly superior to placebo 2-4 h after administration. No differences were found between 400 mg and 800 mg, when hourly threshold differences were compared. 4. Comparing total analgesic effect (area under effect curve), both active medications were superior to placebo (P less than 0.01-0.05), and 400 mg was superior to 800 mg (P less than 0.05). 5. Peak plasma concentrations of S- and R-ibuprofen occurred between 1.2 and 1.5 h. Concentrations after the 800 mg dose were higher than those after the 400 mg dose at all times.     

Pharmacokinetic profile of alniditan nasal spray during and outside migraine attacks

AIMS: To compare the pharmacokinetic profile of intranasal alniditan during and outside migraine attacks, and to investigate the relationship between initial rise of alniditan plasma concentration, and headache improvement. METHODS: Twenty-seven migraine patients (age: 18-65 years) were randomized to receive alniditan 2 mg or 4 mg, and investigated both during and outside a migraine attack. Maximal plasma concentrations (Cmax), time to Cmax (tmax), and the area under the curve over 2 h (AUC(0,2 h)), were calculated from the individual plasma concentration-time profile, obtained from 10 blood samples in each patient, during each of the two administrations. RESULTS: Alniditan was rapidly absorbed into the systemic circulation (tmax=11 min). All investigated pharmacokinetic parameters (Cmax, tmax, AUC(0,2 h)) were similar during and outside migraine attacks, both in the 2 mg (n = 13) and the 4 mg group (n = 14). In the 4 mg group, during attacks, mean plasma alniditan concentration at 5 min after administration (Ct=5) in responders (21+/-16 ng ml(-1); n=10) was significantly higher than the Ct=5 in nonresponders (3+/-3 ng ml(-1); P=0.01; n=4). However, the Cmax and AUC(0,2 h) in responders (33+/-18 ng ml(-1) and 12+/-6 ng ml(-1) h) were also significantly higher than the Cmax and AUC(0,2 h) in nonresponders (13+/-9 ng ml(-1); P=0.048 and 5+/-3 ng ml(-1) h; P=0.03). CONCLUSIONS: Absorption of alniditan nasal spray was not affected by migraine attacks, although 95% confidence intervals were wide. Early rise of plasma concentrations and the amount of drug in the circulation were related to headache improvement in the higher dose group.     

Pharmacokinetics of fluocortolone in long term therapy of patients with rheumatic and hematologic diseases

The pharmacokinetics of fluocortolone (Ultralan oral) and its effect on plasma cortisol levels were investigated during long-term treatment of patients with rheumatic and haematological diseases with different doses of fluocortolone. Fluocortolone was administered in the morning and plasma levels of fluocortolone and cortisol were measured in samples obtained 1.5, 3, 4, and 5 h p. adm. by means of specific radioimmunoassays. Maximum concentrations of fluocortolone in plasma (Cmax) and areas under the fluocortolone plasma level curves (AUC) increased linearly with the dose. The peak time (tmax = 2.04 +/- 0.85 h) and the plasma half-life (t1/2 = 1.53 +/- 0.52 h) were independent of the dose administered. Cortisol suppression as indicated by morning cortisol levels below 50 ng/ml plasma was not observed with doses below 10 mg/d.     

Toxicokinetics of lambda-cyhalothrin in rats

The toxicokinetics of lambda-cyhalothrin after single 20 mg kg(-1) oral and 3 mg kg(-1) intravenous doses were studied in rats. Serial blood samples were obtained after oral and intravenous administration. Liver, brain, spinal cord, sciatic nerve, vas deferens, anococcygeus and myenteric plexus tissue samples were also collected. Plasma, liver, hypothalamus, cerebellum, medulla oblongata, frontal cortex, striatum, hippocampus, midbrain, spinal cord, vas deferens, anococcygeus, myenteric plexus and sciatic nerve concentrations of lambda-cyhalothrin were determined by HPLC. The plasma and tissue concentration-time data for lambda-cyhalothrin were found to fit a two-compartment open model. For lambda-cyhalothrin, the elimination half-life (T1/2beta) and the mean residence time from plasma were 7.55 and 8.55 h after i.v. and 10.27 and 14.43 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.060l h(-1)kg(-1). After i.v. administration, the apparent volume of distribution and at steady state were 0.68 and 0.53l kg(-1), suggesting a diffusion of the pyrethroid into tissue. After oral administration, lambda-cyhalothrin was extensively but slowly absorbed (Tmax, 2.69 h). The oral bioavailability was found to be 67.37%. Significant differences in the kinetic parameters between nervous tissues and plasma was observed. The maximum concentrations in hypothalamus (Cmax, 24.12 microg g(-1)) and myenteric plexus (Cmax, 25.12 microg g(-1)) were about 1.5 times higher than in plasma (Cmax, 15.65 microg ml(-1)) and 1.3 times higher than in liver (Cmax, 18.42 microg ml(-1)). Nervous tissue accumulation of lambda-cyhalothrin was also reflected by the area under the concentration curve ratios of tissue/plasma (liver). The T1/2beta for lambda-cyhalothrin was significantly greater for the nerve tissues, including neuromuscular fibres, (range 12-26 and 15-34 h, after i.v. and oral doses) than for plasma (7.55 and 10.27 h, respectively).     

Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations

Oral administration of AG3340, a novel metalloprotease (MMP) inhibitor, suppresses the growth of human colon adenocarcinoma (COLO-320DM) tumors in vivo (Proc Am Assoc Cancer Res 39: 2059, 1998). In this report, we tested the hypothesis that the growth inhibition of these tumors is associated with maintaining minimum effective plasma concentrations of AG3340. Nude mice were given a total oral daily dose of 25 or 200 mg/kg; 6.25 mg/kg was given four times per day (QID) (25 mg/kg/day), and 100 mg/kg was given in two daily doses (BID) (200 mg/kg/day). Peak plasma concentrations (Cmax) of 83 +/- 43 (mean +/- SD) and 1998 +/- 642 ng/ml were detected 30 min after a single dose with 6.25 mg/kg and 100 mg/kg AG3340, respectively. AUC(0-24 h) values estimated from dosing with 25 and 200 mg/kg/day AG3340 were 672 and 10882 ng*h/ml, respectively. Importantly, both regimen inhibited tumor growth equivalently (74 to 82%). Efficacy was also compared at a total daily dose of 25 mg/kg by giving AG3340: QID (6.25 mg/kg per dose), BID (12.5 mg/kg per dose), and once daily (25 mg/kg per dose). The Cmax of these regimens was 83 +/- 43, 287 +/- 175 and 462 +/- 495 ng/ml, respectively. AG3340 did not inhibit tumor growth with the latter two regimens. The efficacy of 6.25 mg/kg QID (25 mg/kg/day) was superior to the efficacy of 25 mg/kg BID (50 mg/kg/day), substantiating the independence of efficacy from the total daily dose and Cmax. Expectedly, peak to trough fluctuations were significantly smaller with the QID regimen than with BID and QD dosing. After 24 h, the trough was greater than 1 ng/ml with QID dosing but was less than 1 ng/ml after QD and BID dosing. These results suggest that the antitumor efficacy of AG3340 was associated with maintaining minimum effective plasma concentrations of AG3340 and demonstrate that the antitumor efficacy of AG3340 was independent of the total daily dose, peak plasma concentration, and drug exposure in this tumor model.     

Double-blind, placebo-controlled study of INN 00835 (netamiftide) in the treatment of outpatients with major depression.

This study was designed to determine the safety, efficacy and pharmacokinetics of the antidepressant netamiftide (previously designated name: INN 00835) after 5 or 10 daily doses administered to patients diagnosed with major depression. Netamiftide was administered subcutaneously at a fixed dose of 18 mg/patient per day. Of the 55 enrolled patients, 22 were dosed for 10 days with drug, 11 for 5 days with drug followed by 5 days with placebo and 22 for 10 days with placebo only. The effect of treatment with netamiftide was evaluated by the following psychometric tests: Hamilton Depression Rating, Montgomery-Asberg Depression Rating Scale, Carroll Self-Rating Depression and Clinical Global Impression scales. None of the patients experienced significant adverse effects. A pharmacodynamic correlation (P < 0.05) was found between plasma drug concentrations and response to treatment. Highest plasma concentrations (Cmax) of netamiftide averaging 45.7 ng/ml were observed at 0.25 h after dosing. There were 89% responders in the group with Cmax > or = 45.7 ng/ml (minimum therapeutic concentration) versus 40% in the group with Cmax < 45.7 ng/ml. Onset of action was observed within 48 h after treatment, peak effect was observed at approximately 1 week after treatment and efficacy lasted during a 4-week follow-up period. Netamiftide is a promising antidepressant with rapid onset of action and with an excellent safety profile.     

Pharmacokinetics of CGP 6140 (amocarzine) after oral administration of single 100-1600 mg doses to patients with onchocerciasis.

The concentrations of CGP 6140 [4-nitro-4'-(N-methyl-piperazinylthiocarbonylamido)-diphenylamine] and of its N-oxide metabolite, CGP 13,231, were measured in plasma and urine after single oral dose of 100-1600 mg of CGP 6140 to 41 fasted Ghanaian patients with Onchocerca volvulus infections. The absorption of CGP 6140 was rapid and its terminal elimination half-life was about 3 h. The plasma concentrations of CGP 6140 were essentially proportional to the dose. A greater variability in plasma concentrations was apparent after the 800 and 1600 mg doses indicating a poor bioavailability of the drug administered in fasting conditions to several patients. In plasma, the concentrations of CGP 13,231 were similar to those of CGP 6140. The amount of CGP 13,231 excreted in urine was 25-40% of the dose of CGP 6140 whereas only 1.5% was excreted as unchanged drug. If a single dose of drug is used for the treatment, the plasma concentration would be maintained for 3-4 h at a high level. At 8 h, the concentration falls to about 10% of the Cmax. If sustained plasma concentrations of the drug are needed for efficacy, twice daily administration would maintain the minimum concentration at about 10% of the Cmax.