Pharmacokinetics and clinical effects of cefixime in pediatrics

Pharmacokinetics and clinical effects of cefixime (CFIX), a new oral cephalosporin antibiotic, in pediatric field were investigated. The result obtained were summarized as follows. CFIX (5% granules) was given to each of 5 children twice in a single dose of 1.5 or 3.0 mg/kg in a cross-over trial. The mean peak serum concentration of CFIX was 0.64 micrograms/ml at 4 hours after given the dose of 1.5 mg/kg and 1.15 micrograms/ml at 4 hours after the dose of 3.0 mg/kg. The mean half-life and the mean AUC values were 2.72 hours and 4.10 micrograms X hr/ml, respectively after the dose of 1.5 mg/kg, and 2.77 hours and 8.26 micrograms X hr/ml after the dose of 3.0 mg/kg. The urinary recovery was investigated in 5 children after the dose of CFIX of 1.5 mg/kg and in 4 children after the dose of 3.0 mg/kg. The mean peak urinary concentrations of CFIX and the mean 12-hour urinary recovery rates were 10.6-67.9 micrograms/ml at 2-10 hours and 15.7% after the dose of 1.5 mg/kg, and were and were 6.16-230 micrograms/ml at 2-8 hours and 18.9% after the dose of 3.0 mg/kg, respectively. CFIX was given to 6 children twice in a single dose of 50 mg either in the form of 5% granules or in capsules in a cross-over trial. The mean peak serum concentrations, half-life and AUC values were 1.26 micrograms/ml at 4 hours, 3.09 hours and 9.63 micrograms X hr/ml, respectively after the dose of 50 mg CFIX in 5% granules, and were 1.16 micrograms/ml at 4 hours, 2.87 hours, and 7.82 micrograms X hr/ml, respectively after the dose of 50 mg in capsules. The urinary recovery was investigated in 5 children. The mean peak urinary concentrations and the mean 12-hour urinary recovery rates were 19.1-114 micrograms/ml at 4-10 hours and 15.7%, respectively after the dose of 50 mg in 5% granules, and were 8.16-89.0 micrograms/ml at 4-10 hours and 11.3%, respectively after the dose of 50 mg in capsules. Clinical efficacy of CFIX was investigated in a total of 26 children including 2 with tonsillitis, 2 with acute bronchitis, 2 with scarlet fever and 20 with urinary tract infection. Each of children were given orally a dose of 2.6 mg/kg CFIX 2-3 times a day for 11 days in average.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiological disposition of CGS 16617 in rat, dog, and man

The disposition and metabolism of CGS 16617 (3-[(5-amino-1-carboxy-1S-pentyl)amino],2,3,4,5-tetrahydro-2-oxo-3S-1H-1 - benzazepine-1-acetic acid), and angiotensin l-converting enzyme inhibitor, were investigated in rats, dogs, and man. In rats, a single oral dose of 10 mg/kg 14C-CGS 16617 afforded peak plasma concentrations of drug between 0.5 and 6 hr of dosing. The AUC was on average 9.6% of that after iv administration of the same dose, indicating low oral absorption of the drug. The apparent volumes of distribution, V1 and Vdss, were 0.45 and 2.5 liters/kg, respectively. Disappearance of the drug from plasma after the iv dose was biphasic, with mean half-lives of 0.5 and 13 hr, respectively, for the lambda 1 and lambda 2 phases. After single iv doses (10 mg/kg) to dogs and rats, 14CGS 16617 was almost exclusively eliminated by the renal route, with urinary recoveries of greater than 90% of dose. The same dose administered orally gave urinary recoveries of less than 10% of the dose in rats and about 15% in the dog. The remainder of the dose was eliminated in the feces. Bile duct-cannulated rats excreted less than 3% of an oral 10 mg/kg dose in the bile, in 24 hr. In man (N = 4), a single oral dose of 100 mg 14C-CGS 16617 resulted in peak plasma concentrations of 0.02-0.07 microgram of drug eq/ml between 4 and 6 hr of dosing. The mean terminal half-life was estimated at 81 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of neuroleptics on pharmacokinetic parameters of amphetamine in rat after single and double injections

Sprague-Dawley rats (90–100 g) were injected i.p. with saline, iprindole (10 mg/kg), clozapine (10 mg/kg), pimozide (10 mg/kg), or molindone (10 mg/kg), and 30 min later with dextro-³H-amphetamine (5 mg/kg). For two dose studies, a second injection of ³H-amphetamine (5 mg/kg) was administered 3 hr after the first dose in saline or iprindole pretreated rats. In both studies, brain and hepatic levels of amphetamine paralleled the plasma levels, were highest at 1 hr in single dose and at 4 hr in two dose study, and thereafter, started declining. Iprindole markedly increased tissue amphetamine levels in single dose experiments and further raised and prolonged them up to 24 hr in two dose experiments. Both pimozide and molindone significantly enhanced amphetamine levels, and this effect lasted for 1 and 3 hr, respectively (single dose study); clozapine was ineffective. From the data, it appears that several chemically unrelated neuroleptics alter the distribution and elimination of amphetamine; such alterations need to be assessed in clinical situations, since neuroleptics are used in amphetamine intoxication.     

Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects

Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous plasma samples were obtained during the multiple-dose regimen, and appropriate equations were fitted to all the multiple-dose data. Diazepam absorption was satisfactorily described by a first-order process, with disposition characterized by a linear two-compartment open model. The harmonic mean absorption half-life was 32 min, and the harmonic mean terminal exponential half-life was 57hr. The mean apparent oral total drug plasma clearance was 22.7ml/hr/kg. Steady-state plasma levels of the primary metabolite, desmethyldiazepam, were reached after 5–8 days of dosing. Steady-state diazepam plasma concentration-time profiles suggested that once daily administration of the total daily dose at bedtime might be a satisfactory dosing regimen.     

Effects of intravenous azimilide on cardiac performance, fibrillation threshold, and hemodynamics in anesthetized dogs

The class III antiarrhythmic azimilide (E-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[4-(4-methyl-1- piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride; WHO No. 7299, CAS 149888-94-8), by slow infusion or stepwise bolus doses, was evaluated for effects on heart rate, blood pressure, and cardiac pump function, excitability, and refractoriness in anesthetized dogs. Infusion (0.6 mg/kg/min) in male beagles (n = 5) to a maximum dose of 54 mg/kg increased QTc more than 20 ms at 2.0 mg/kg. At a dose of 8.9 mg/kg i.v., QTc increased 34% above baseline and remained elevated throughout the subsequent infusion and for at least 60 min postinfusion. At this maximum class III dose, azimilide increased heart contractile force (HCF) 10% and +dP/dt 34% and decreased heart rate (HR) 12%, without significantly changing mean blood pressure (MBP), left ventricular end diastolic pressure, -dP/dt, stroke volume (SV), or cardiac output (CO). At the mean maximum 47 mg/kg i.v. dose, QTc remained elevated, but decreases were observed in HCF (-27%), +dP/dt (-24%), -dP/dt (-35%), SV (-16%), and CO (-52%). Cumulative intravenous bolus injections of azimilide (0.3, 1, 3, 10, and 30 mg/kg) in male mongrels (n = 5) increased effective refractory period (ERP) and +dP/dt (18% and 16%, respectively, at 10 mg/kg) as a function of dose and significantly decreased HR (-22% at 10 mg/kg). MBP decreased significantly (-23%) only at the highest dose. Ventricular fibrillation threshold (VFT) was unchanged at 30 mg/kg. Effects of dl- (n = 3) and d-sotalol (n = 4) on ERP and HR were similar to azimilide's, but both compounds caused a greater MBP depression and VFT elevation. These results suggest that azimilide is well tolerated by the cardiovascular system, providing an increase in contractility and a slight decrease in HR at intravenous doses that produced a large or maximum increase in cardiac refractoriness.     

Efficacy of immediate and subsequent therapies against soman-induced seizures and lethality in rats

The purpose of the present study was to examine the efficacy of a triple combination of drugs with adequate anticonvulsant effects and a dual combination with inadequate anticonvulsant effects followed by adjunct therapy. The results showed that combined intramuscular injections of HI-6 (42 mg/kg), atropine (14 mg/kg), and avizafone (3 mg/kg) administered 1, 16, and 31 min. after exposure to a soman dose of 4 x LD(50) completely terminated seizures with a moderate mortality rate (25%). When the soman dose was lowered to 3 x LD(50) the anticonvulsant effect was complete, and no rats died within 24 hr. Rats challenged with 5 x LD(50) of soman all died within 10 min. Without avizafone in the combination, seizures induced by 3 or 4 x LD(50) of soman could not be terminated unless an adjunct therapy consisting of procyclidine (6 mg/kg), diazepam (10 mg/kg), and pentobarbital (30 kg/kg) was given, and the mortality rate was comparatively high (78%). Administration of the adjunct therapy alone 6-16 min. after 4 x LD(50) of soman stopped the seizure activity, but all the rats died within 24 hr. Marked neuropathology was found in the piriform cortex and amygdala, whereas the hippocampal CA1 field was effectively protected when both the triple combination and the dual combination plus adjuncts had stopped seizures 35-55 min. after onset. It is concluded that termination of soman-induced seizures at an early stage (<20 min.) is crucial to avoid neuronal pathology.     

Disposition of RS-26306, a potent luteinizing hormone-releasing hormone antagonist, in monkeys and rats after single intravenous and subcutaneous administration.

The metabolic disposition of RS-26306, a new potent luteinizing hormone-releasing hormone antagonist, was studied in rats and monkeys after single i.v. and sc administration with the 3H-labeled compound. Plasma pharmacokinetics after iv administration were: CLs = 2.5 ml/min/kg, Vd beta = 0.29 liter/kg, t1/2 = 1.4 hr (rats), and CLs = 0.8 ml/min/kg, Vd beta = 0.32 liter/kg, t1/2 = 5.1 hr (monkeys). Cmax and Tmax in rats were 0.53 micrograms/ml and 4 hr after the 1 mg/kg sc dose, and were 1.07 micrograms/ml and 12 hr after the 10 mg/kg sc dose. AUC0-infinity after the 10 mg/kg sc dose in rats was seven times that after the 1 mg/kg sc dose. Apparent plasma disappearance t1/2 in rats were 3.6 and 15.2 hr, respectively, after the 1 and 10 mg/kg sc doses. An average of 12 and 4% of dose radioactivity remained at the injection site in rats 3 and 10 days, respectively, after a 10 mg/kg sc dose. In monkeys, Tmax after a 1 mg/kg sc dose was 0.5 hr for three animals but was 24 hr for the fourth animal, although plasma of this monkey contained substantial levels of RS-26306 between 15 min and 24 hr. Apparent plasma t1/2 in monkeys after a 1 mg/kg sc dose was at least 19 hr. Our data suggest depot formation after sc doses. In vitro plasma binding amounted to 82-84%. Excretion was mainly biliary: 12-25 and 55-84% of dose radioactivity was recovered in urine and feces, respectively, in both species. The biological samples contained only traces of 3H2O. Three metabolites, which were truncated peptides of the parent decapeptide, were identified in the rat bile. One of these was also present in the monkey plasma. The restricted enzymatic degradation of RS-26306, extensive plasma binding, and long circulating t1/2 of RS-26306 contribute to its prolonged activity in animal models and in humans.     

Anti-inflammatory activity of the steroid alkaloid glycoside, tomatine

1. Tomatine, isolated from extracts of crown gall-infected tomato plants or obtained commercially, was tested for anti-inflammatory activity using three different methods.2. Tomatine administered to intact rats intramuscularly in a dose range of 1-10 mg/kg or orally in doses of 15-30 mg/kg exerted a significant dose dependent inhibition of carrageenan induced paw oedema. The inhibitory effect of tomatine when given in a dose of 10 mg/kg intramuscularly to intact rats lasted more than 24 hr.3. In adrenalectomized rats significant dose-related inhibition of paw oedema was obtained with tomatine and the inhibition at each dose level (0.5-10 mg/kg) was found to be greater than that found in intact animals.4. Tomatine administered subcutaneously to intact rats daily for 7 days in doses of 5 or 10 mg/kg exerted a significant, dose dependent inhibition of granulation tissue formation induced by the subcutaneous implantation of carrageenan impregnated cotton pellets.5. Tomatine administered to intact mice in a dose of 10 mg/kg subcutaneously 1 hr before the intraperitoneal injection of acidified saline and intravenous pontamine sky blue significantly decreased the leakage of the protein bound dye into the peritoneal cavity.6. Tomatidine, the aglycone of tomatine, was not effective at dose levels of 10-20 mg/kg in any of the three tests.     

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Pretreatment with a single moderate dose of morphine (e.g. 5.6-10 mg/kg) 4-24 hr prior to challenge with an opioid antagonist such as naloxone results in reliable expression of behaviors that resemble aversive or emotional consequences of withdrawal from chronic opioid exposure, including suppression of operant responding, elevations in brain reward thresholds, and conditioned place aversion. Repeated daily or weekly treatment with these same morphine doses results in a progressive increase in naloxone potency to elicit these withdrawal signs. The current study sought to determine whether increased anxiety-like behavior during withdrawal from chronic opioid dependence is also seen after acute morphine exposure, and progresses with repeated intermittent treatment. Male Wistar rats were handled and injected with either vehicle or morphine for 4 consecutive days. Three injection regimens were employed: Morphine Naive (4 vehicle injections), Acute Morphine (3 vehicle injections, 4th injection 5.6 or 10 mg/kg morphine), or Repeat Morphine (all 4 injections with 5.6 or 10 mg/kg morphine). Acute pretreatment with 5.6 mg/kg or 10 mg/kg morphine resulted in time-dependent increases in exploration of the open arms of the plus maze in naloxone-naive rats when tested at 2, 4 or 8 hr after the final pretreatment injection, with the effects at the higher dose appearing later (4 hr) than after the lower dose (2 hr). This pattern of results, in combination with a separate study which confirmed a significant anxiolytic-like effect of a low dose of morphine (0.56 mg/kg) administered 15 min prior to test, suggested that low residual morphine levels remaining in plasma at 2-4 hr after 5.6 and 10 mg/kg morphine may be sufficient to elicit anxiolytic-like effects. Repeat treatment with either dose of morphine resulted in a further increase in the magnitude and duration of this anxiolytic-like effect. These effects had dissipated by 8 hr post-morphine, and therefore precipitation of withdrawal by one of several doses of naloxone (0.10-3.3 mg/kg) was assessed in separate cohorts of rats 8 hr after the final pretreatment under Morphine Naïve, Acute Morphine, or Repeat Morphine conditions. Naloxone resulted in a significant dose-dependent expression of anxiety-like behavior with no effects on general activity after Acute Morphine pretreatment at either 5.6 or 10 mg/kg morphine. A further significant shift in naloxone potency was observed after Repeat Morphine pretreatment at the 10 mg/kg but not the 5.6 mg/kg dose. Thus, anxiety-like behavior is a prominent feature of the negative emotional consequences of naloxone-precipitated withdrawal from acute opioid dependence.     

Age-related changes in disposition and metabolism of benzene in male C57BL/6N mice.

Benzene disposition and metabolism were examined as a function of age in male C57BL/6N mice aged 3 and 18 months. Mice received a single oral dose of either 10 or 200 mg/kg 14C-benzene (approximately 25 microCi/kg). Excretion of 14C-derived benzene radioactivity (RA) was monitored in urine, feces, and as exhaled 14CO2 from 0 to 72 hr, and as exhaled unmetabolized benzene from 0 to 6 hr. At 10 mg/kg 14C-benzene, urinary elimination was the major route of excretion in both 3- and 18-month mice. Urinary excretion of 14C-derived benzene RA was significantly decreased in 18- vs. 3-month mice at 4, 6, 24, and 48 hr, while fecal excretion was significantly increased at 72 hr. Elimination of 14C-benzene as 14CO2 and unmetabolized 14C-benzene was also increased in 18- vs. 3-month mice at this dose. Hydroquinone glucuronide (HQG), phenylsulfate (PS), and muconic acid (MUC) were the major urinary metabolites at 10 mg/kg 14C-benzene in both 3- and 18-month mice, representing approximately 40, 28, and 15% of an administered dose of 14C-benzene. Smaller amounts of phenyl glucuronide (4.0%), pre-phenyl mercapturic acid (1.2%), and catechol glucuronide (0.5%) were also detected. No significant differences were found with age in the percentage of an administered dose of benzene excreted as the various metabolites at 10 mg/kg. At 200 mg/kg 14C-benzene, the total percentage of 14C-derived benzene RA eliminated in urine within 72 hr was not significantly different with age, but elimination at early time points (4, 6, and 8 hr) was significantly decreased in 18- vs. 3-month mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of MCI-2016 (bifemelane hydrochloride) on cerebral ischemia following ligation of both common carotid arteries in Mongolian gerbils

Cerebral protective effect of MCI-2016 and influence of age on survival time in the cerebral ischemic model induced by bilateral-carotid-arterial ligation in male Mongolian gerbils were studied. Of all animals (6 to 40 weeks old), the mean survival time of the immature group (6 to 7 weeks) was long (3.6 hr), but variable, and that of the 10 to 40 weeks group was relatively stable (1.9-2.4 hr), but that of the older group (30-40 weeks) inclined to be reduced. Effects of drugs on this model were studied in 10 to 15 weeks old male Mongolian gerbils. The mean survival time in the control groups was 2.3-2.4 hr. After a single administration of MCI-2016 at doses of 25 mg/kg, i.p., and 100 mg/kg, p.o., the mean survival time were 8.1 and 6.4 hr, respectively. In these cases, some animals survived over 12 hr, while no animals surviving over 12 hr were observed in the control group. In this model, animals showed severe neurological symptoms. This, however, tended to be depressed by the administration of MCI-2016 at a dose of 25 mg/kg, i.p., which was observed early after ligation. A cerebral metabolic activator, Ca-hopantenate, slightly increased the survival time at a dose of 100 mg/kg, i.p., and a cerebral vasodilator, ifenprodil, was not effective. Subsequently, consecutive administration of MCI-2016 at a dose of 25 and 50 mg/kg, p.o., was more effective than a single administration of MCI-2016 at each dose. The mechanism for the cerebral protective effect of MCI-2016 was discussed.     

Pharmacokinetics of N-(4-hydroxyphenyl)-all-trans-retinamide in rats

The concentration of N-(4-hydroxyphenyl)-all-trans-retinamide (HPR) was determined in plasma and a variety of tissues from rats after an intravenous dose (5 mg/kg). The plasma concentration-time curve could be accurately described by a triexponential equation. The apparent volume of distribution of HPR was approximately 10-12 liter/kg and the terminal half-life was 12 hr. Metabolites of HPR were more abundant than intact drug in most tissues 24 hr after the iv dose. A 5-day excretion study with radiolabeled HPR revealed that less than 2% of a single iv dose (5 mg/kg) is excreted as unmetabolized HPR in urine and feces and that most of the radioactivity is eliminated in the feces. HPR was incompletely absorbed after an oral dose (10 mg/kg).     

Inhibition and induction of theophylline metabolism by 8-methoxypsoralen. In vivo study in rats and humans

The effects of 8-methoxypsoralen (8-MOP) on the metabolism of theophylline were studied in rats and humans. Rats were randomized into three groups and prepared with iv jugular catheters. Group I (N = 4) received a single ip injection of 27 mg/kg of 8-MOP, group II (N = 5) vehicle (corn oil), and group III (N = 4) 50 mg/kg/day of 8-MOP for 3 days. Rats were subsequently administered 15 mg/kg of theophylline iv, and timed blood samples (0.2 ml) were assayed for theophylline by HPLC. Theophylline clearance (ml/min/kg; mean +/- SD) was 1.7 +/- 0.3, 2.4 +/- 0.5, and 9.5 +/- 1.6 in groups I, II, and III, respectively. The half-life (harmonic mean) from 0.5 to 12 hr was 7.2, 3.6, and 0.8 hr. Urinary excretion of unchanged theophylline (mean +/- SD) from 0 to 24 hr was 60 +/- 10, 41 +/- 6, and 13 +/- 3% of the administered dose. In a crossover study, three healthy, male, nonsmokers received 600 mg of oral theophylline. Urine and plasma were collected for 48 hr. One week later, subjects received 1.2 mg/kg of oral 8-MOP followed in 1 hr by 600 mg of oral theophylline. Mean residence time of theophylline increased from 10.7, 17.2, and 12.2 hr in the control period, to 20.3, 19.0, and 18.4 hr after 8-MOP. The AUC (microgram.hr/ml) of theophylline increased from 204, 213, and 204, to 555, 364, and 432, while clearance (ml/min/kg) decreased from 0.74, 0.57 and 0.63, to 0.27, 0.33, and 0.30, respectively. Urinary excretion of unchanged theophylline from 0 to 48 hr increased from 14, 14, and 15, to 24, 21, and 20%. We conclude that 8-MOP administered acutely is a potent inhibitor of theophylline metabolism and chronically in the rat is a powerful inducer.     

Fundamental and clinical evaluations of ceftazidime in neonates and premature infants

Ceftazidime (CAZ) was administered to 24 neonates and premature infants aged 0-31 days in a dose of 10 mg/kg or 20 mg/kg by an intravenous bolus injection, and plasma concentration, urinary concentration and urinary recovery rate during the first 6 hours after the administration were determined. The CAZ was also administered to a total of 43 patients consisting of neonates, premature infants and infants at ages ranging from 0 day to 1 year 9 months (21 suffering or suspectedly suffering with various bacterial infections, and 22 treated for prophylaxis of infections), by intravenous bolus injections in a mean daily dose of 59.6 mg/kg in 2 to 4 divided doses for 9 days on the average. The clinical efficacy, prophylactic effects and bacteriological response were evaluated. Adverse effects of the drug were examined in 65 cases including 22 drop-out cases, and in some of them, abnormal laboratory findings were also examined. The results obtained are summarized as follows: Patients given 10 mg/kg of CAZ were divided into 5 groups on the basis of age: 0-3 days, 4-7 days, 8-14 days, 15-21 days, and 29 days and older, and mean peak plasma concentrations of CAZ were 40.7, 43.1, 37.1, 38.0 and 35.6 micrograms/ml, respectively, at 5 minutes after administration, with no significant difference. Mean AUC values were higher in younger-age groups, i.e. 189.9, 170.8, 159.1, 135.3 and 134.4 micrograms X hr/ml for the 5 different day-age groups, respectively, and mean half-lives of CAZ in plasma tended to be longer in younger-age groups, i.e. 3.16, 3.05, 2.84, 2.44 and 2.43 hours for the 5 groups, respectively. Patients given 20 mg/kg of CAZ were divided into 4 groups also on the basis of age: 0-3 days, 4-7 days, 8-14 days, and 15-21 days, and mean peak plasma concentrations for the 4 day-age groups were 72.9, 73.3, 70.0 and 78.4 micrograms/ml, respectively, at 5 minutes after administration, without any difference among these groups. Mean AUC values were 429.9, 327.3, 279.3 and 302.1 micrograms X hr/ml for the 4 groups, respectively, with the highest AUC in the youngest-age group. Dose response was observed in mean peak plasma concentrations and mean AUCs when 10 mg/kg and 20 mg/kg dose groups were compared for similar day-age patients. Mean half-lives of CAZ in plasma were 4.01, 3.51, 3.00 and 3.07 hours, the longest being in the youngest-age group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetics of o-nitroanisole in Fischer 344 rats

The pharmacokinetics and metabolism of o-nitroanisole (ONA) were studied in male Fischer 344 rats. Three dose levels of [14C]ONA (5.0, 50, or 500 mg/kg) were administered orally to rats and daily excreta were analyzed for 14C. Since the highest dose altered the urinary excretion rate of ONA, a dose of 25 mg/kg was used for subsequent pharmacokinetic studies. Following a single 25 mg/kg iv dose of [14C]ONA, blood, tissues, and excreta were collected at times ranging from 15 min to 7 days. Urinary excretion accounted for 82% of the dose by 24 hr and 86% by 7 days. Fecal excretion was 7.5% in 24 hr and 9.0% by 7 days. Fifteen min after ONA administration, most of the 14C content was found in muscle (20%), skin (10%), adipose tissue (6.8%), and blood (6.5%). All other tissues contained less than 5% of the dose. Within 8 hr, less than 1% of the dose was present in any tissue. The initial elimination t1/2 for 14C in all tissues was 1-2 hr and the terminal t1/2 was approximately 4 days. The elimination of parent ONA from blood followed first order biphasic elimination kinetics (initial t1/2 = 30 min; terminal t1/2 = 2.2 hr). Parent ONA was rapidly eliminated from all other tissues in a monophasic manner (t1/2 = 15 min to 2 hr). Skin and fat demonstrated an uptake phase prior to the elimination of parent. Only 0.5% of the dose was excreted as ONA in the urine. Urinary metabolites of ONA were predominantly conjugated compounds (63% as sulfates; 11% as glucuronides).     

Melatonin protects against mercury(II)-induced oxidative tissue damage in rats

Mercury exerts a variety of toxic effects in the body. Lipid peroxidation, DNA damage and depletion of reduced glutathione by Hg(II) suggest an oxidative stress-like mechanism for Hg(II) toxicity. Melatonin, the main secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. N-Acetylcysteine, a precursor of reduced glutathione and an antioxidant, is used in the therapy of acute heavy metal poisoning. In this study the protective effects of melatonin in comparison to that of N-acetylcysteine against Hg-induced oxidative damage in the kidney, liver, lung and brain tissues were investigated. Wistar albino rats of either sex (200-250 g) were divided into six groups, each consisting of 8 animals. Rats were intraperitoneally injected with 1) 0.9% NaCl, control (C) group; 2) a single dose of 5 mg/kg mercuric chloride (HgCl2), Hg group; 3) melatonin in a dose of 10 mg/kg, 1 hr after HgCl2 injection, Hg-melatonin group; 4) melatonin in a dose of 10 mg/kg one day before and 1 hr after HgCl2 injection, melatonin-Hg-melatonin group; 5) N-acetylcysteine in a dose of 150 mg/kg, 1 hr after HgCl2 injection, Hg-N-acetylcysteine group, and 6) N-acetylcysteine in a dose of 150 mg/kg one day before and 1 hr after HgCl2 injection, N-acetylcysteine-Hg-N-acetylcysteine group. Animals were killed by decapitation 24 hr after the injection of HgCl2. Tissue samples were taken for determination of malondialdehyde, an end-product of lipid peroxidation; glutathione (GSH), a key antioxidant, and myeloperoxidase activity, an index of neutrophil infiltration. The results revealed that HgCl2 induced oxidative tissue damage, as evidenced by increases in malondialdehyde levels. Myeloperoxidase activity was also increased, and GSH levels were decreased in the liver, kidney and the lungs. All of these effects were reversed by melatonin or N-acetylcysteine treatment. Since melatonin or N-acetylcysteine administration reversed these responses, it seems likely that melatonin or N-acetylcysteine can protect all these tissues against HgCl2-induced oxidative damage.     

Behavioral effects of propentofylline (HWA 285) on ambulatory activity, discrete avoidance response and passive avoidance response in mice

Behavioral effects of propentofylline (HWA 285) were investigated by means of ambulatory activity, discrete lever-press avoidance and step-through type passive avoidance response in mice. Single administration of HWA 285 produced no marked change in the bodily condition and also produced no changes in ambulatory activity at 1.25-20 mg/kg, s.c.; the discrete avoidance response at 2.5-40 mg/kg, s.c.; and the passive avoidance response at 10-30 mg/kg, s.c. However, 5-20 mg/kg of HWA 285 attenuated the ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) and scopolamine (0.5 mg/kg, s.c.). HWA 285 tended to attenuate the avoidance-suppressing effect of chlorpromazine (2 mg/kg, s.c.) and physostigmine (0.1 mg/kg, s.c.) at 2.5 mg/kg, while it enhanced the effect of chlorpromazine at 10-40 mg/kg. The mice treated with HWA 285 (10-30 mg/kg) at 30 min before or immediately after the acquisition trial did not show a marked change in the passive avoidance response when the retention trial was done 24 hr after the acquisition trial. The treatment with scopolamine (2 mg/kg, s.c.) at 30 min before the acquisition trial suppressed the passive avoidance response, eliciting a marked shortening of the step-through latency and decrease in % of mice to the 300 sec criterion of latency. The effect of scopolamine was attenuated by combined administration of HWA 285 (30 mg/kg) and treatment with HWA 285 (30 mg/kg) after the end of the acquisition trial. The present results suggest that HWA 285 demonstrates complex behavioral effects which vary dependently on the doses and types of behaviors.     

Disposition of flavodilol in laboratory animals

The disposition of flavodilol, a novel antihypertensive agent, was investigated in rats, rabbits, and dogs following iv or oral administration of 14C-flavodilol or unlabeled drug. Peak, plasma levels occurred within 6 hours of an oral dose in all three species. Following an iv dose, plasma elimination half-lives of flavodilol in rats, rabbits, and dogs were 3.0, 3.0, and 4.0 hr, respectively. Total body clearances were 0.71 liter/hr/kg for the rat, 1.89 liters/hr/kg for the rabbit, and 3.07 liters/hr/kg for the dog. Renal clearances were a small fraction of total clearance at 0.042, and 0.114 liter/hr/kg for the rat and dog, respectively, suggesting extensive nonrenal clearance. The volumes of distribution of 3.04 for the rat, 8.10 for rabbit, and 18.13 liters/kg for dog are large, suggesting significant extravascular distribution of flavodilol. Following 10 and 50 mg/kg po doses of 14C-flavodilol in rats, recovery of total radioactivity after 79 hr was 100.7% and 88.4% of the dose, respectively, most of which was recovered in the feces (77.5% and 66.6%, respectively). Tissue distribution studies of 14C in rats at 1.5, 5, 24, and 48 hr after a single po dose of 10 mg/kg 14C-flavodilol showed that the majority of the radioactivity was in the gastrointestinal tract and organs of elimination at all time points. Less than 1% of the dose remained in the body at 48 hr. 14C-Flavodilol was administered to rats iv at 1 mg/kg and orally at 10 mg/kg to assess comparative (label vs. nonlabel) absorption and distribution characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of diminazene in sheep

The pharmacokinetic behavior of diminazene in plasma after administration of 2 mg/kg i.v. and 3.5 mg/kg i.m. was studied in four healthy Dala x Ryggja rams. Following i.v. injection, the data were satisfactorily described by a tri-exponential equation; the apparent volume of distribution at the steady-state was 0.56 +/- 0.04 L/Kg (mean +/- SD; n = 4); total body clearance averaged 1.1 +/- 0.09 ml/kg/min and elimination half-life was 9.30 +/- 1.40 hr. After intramuscular administration peak plasma levels of 6.30-7.57 micrograms/ml were reached in 20 to 45 min and the mean absorption time averaged 5.83 +/- 1.61 hr. Systemic availability relative to the intravenous dose was 95.10 +/- 23.21% and mean residence time averaged 14.16 +/- 1.55 hr. The partition of diminazene between erythrocytes and plasma averaged 0.64 +/- 0.10; plasma protein binding was high (65-85%) and concentration-dependent. Based on the experimental data obtained, an initial i.m. dose of 2.5 mg/kg followed by 2 mg/kg 24 hr later should be safe and effective in cases of babesiosis and trypanosomiasis sensitive to diminazene. A preslaughter withdrawal period of 14-26 days was estimated.     

Centrally administered cycloheximide in rats: behavioural concomitants and modulation of amnesic effects by biogenic amines

The behavioural consequences of centrally administered cycloheximide (400 μg, intraventricularly) were examined at various times after the injection and compared with the degree of protein synthesis inhibition. Operant behaviour (FR3 responding for water reward) was significantly depressed at 1, 2, 4, 6, 8, 10 and 12 hr after the injection but not at 24 hr, while general locomotor activity was significantly depressed at all time points except 1 and 24 hr. Amnesia for a passive avoidance response was observed when the cycloheximide was administered 1, 3, 5, 7, and 9 hr before the training trial but not at 11 or 17 hr. Protein synthesis was found to be maximally inhibited (80%) at 1 and 2 hr, moderately inhibited (60%) at 4, 6, and 8 hr, less but still significantly inhibited (40%) at 12 hr and slightly elevated (15%) at 24 hr after the central injection of cycloheximide. Posttraining administration of 1-tryptophan (100 mg/kg) or corticosterone (5 mg/kg) significantly reversed the amnesia produced by a central injection of cycloheximide given 5 hr before training, while imipramine (5 mg/kg), d-amphetamine (5 mg/kg) and hydrocortisone (5 mg/kg) were without significant effect. These results suggest that the disruption of passive avoidance memory by centrally administered cycloheximide may not be related to the inhibition of synthesis of memory-specific protein, but rather to a depression of central levels of biogenic amines, particularly serotonin.