Effects of mimosine, a potential chemical defleecing agent, on wool growth and the skin of sheep.

Twenty-two Merino sheep were dosed with various amounts of L-mimosine, given either as an intravenous or an intraperitoneal injection, or as a continuous intravenous infusion for periods of 1-4 days. Single injections of mimosine (1-16 g) had no effect on the strength of wool, and wool growth rates were not appreciably altered by injections of small amounts (4 g or less). Injections of larger amounts slightly reduced both length growth rate and diameter of tibres during the 4 days after dosing. The effects of intravenous infusions of mimosine depended on the rate and the duration of administration. Small amounts (0.5 or 1 g/day given for 4 days) has no effects on the strength of wool or on wool growth rates. Infusions of a total of 8 g, either at the rate of 2 or 8 g/day, weakened the wool but not sufficiently to allow the sheep to be defleeced. Both these treatments caused a temporary reduction in length growth rate and in diameter of fibres, and transient degenerative changes were observed in wool follicles. A region of the fibres representing 1-2 days' growth was constricted to about half the pre-infusion diameter when 8 g was given for 1 day. Infusions of at least 8 g mimosine over a period of 1 1/2-2 days were effective for defleecing all sheep dosed. This corresponded to a daily rate of infusion of about 80 mg/kg. No toxic effects were observed with infusions given for periods of 2 days. Defleecing was judged to be possible by 6-7 days after the start of infusion, and was readily carried out by about 14 days. Defleecing was associated with follicle retrogression and an abrupt cessation of wool growth within 2 days of the start of the infusions. It was estimated that fibre growth stopped for about 10 dyas; regrowth was first observed 17-18 days from the beginning of dosing. Low rates of infusion of mimosine (up to 2 g/day) resulted in plasma levels below 0.1 mmol/l. Infusion at the rate of 4 g/day or above, which produced defleecing, quickly resulted in levels of mimosine in plasma above 0.1 mmol/l; after 2 days the concentration was steady at aboug 0.2 mmol/l. Injections of 8 or 16 g mimosine resulted in very large, but transient, rises of the level in plasma.     

Effects of intravenous infusion of mimosine on wool growth of Merino sheep.

Merino sheep were given continuous intravenous infusions of L-mimosine for periods of 1 1/2, 2 or 21 days; efficacy as a defleecing procedure and effects on subsequent wool growth were measured. In addition, the amino acids tyrosine, phenylalanine and cystine were investigates as antagonists to the effects of mimosine. Infusions for 1 1/2 or 2 days at the daily rate of 80-120 mg/kg caused a cessation of wool growth by 1 1/2-2 days from the start of infusion, and all sheep were subsequently defleeced. It was estimated that, on average, fibre growth stopped for 10 1/2-13 days in four sheep after a 2-day infusion, and for 5 1/2 and 9 1/2 days in two sheep after an infusion for 1 1/2 days. There was considerable variation in the time taken for new fibres to recommence growth. During the period 3-5 weeks after infusion of mimosine, length growth rate was consistently greater than the pretreatment rate. Likewise, fibre diameter was greater in three out of the four sheep. As a result, the volume growth rate of fibres was greater post-treatment than it was pretreatment. Infusion for 3 weeks at the daily rate of 21-24 mg/kg did not stop wool growth. However, both length growth rate and fibre diameter were considerably depressed, and after 12 days' infusion, fibre diameter and volume growth rate were reduced to less than half the pretreatment values, and wool fibres were very weak. After the mimosine infusion stopped, fibre diameter increased to above pretreatment values and remained ther for the period of 2-3 weeks studied. The concurrent infusion of tyrosine, phenylalanine or cystine with mimosine failed to prevent any of the effects of mimosine on wool growth.     

Pharmacokinetics of meloxicam in rabbits after single and repeat oral dosing

We evaluated the pharmacokinetic profile of meloxicam (0.3 and 1.5 mg/kg) given as single and repeated (once daily for 5 d) oral doses to female rabbits (n = 5/group) to define the optimal dose and dosing interval for clinical use. Clinical signs, body weight, and serum chemistry parameters (sodium, potassium, chloride, total protein, urea, creatinine, glucose, alkaline phosphatase, gamma glutamyl transferase, and alanine aminotransferase) were evaluated before and 5 d after dosing to monitor safety at the 2 dose levels in both studies. Plasma samples were collected serially, and concentrations were determined by high performance liquid chromatography. After single oral dosing at 0.3 or 1.5 mg/kg, maximal plasma concentrations of meloxicam were achieved at 6 to 8 h and were 0.14 and 0.3 microg/ml, respectively. Plasma drug levels decreased rapidly to near-undetectable levels by 24 h. There was moderate interindividual variability in plasma meloxicam concentrations with less than proportional increases in peak plasma concentration and area under the concentration curve values at the higher dose after the single and repeat dosing. The elimination half-life was approximately 8 h at both dose levels, suggesting that metabolism was not saturated. Oral clearance of meloxicam is high in rabbits, indicating rapid metabolism and elimination. There was no accumulation of meloxicam when given at 0.3 or 1.5 mg/kg for 5 d, and meloxicam was rapidly eliminated after discontinuation of dosing. Rabbits may require a dose exceeding 0.3 mg/kg given once daily to achieve optimal plasma levels of meloxicam over a 24-h interval.     

Species differences in the metabolism of norephedrine in man, rabbit and rat

1. (+/-)-2-Amino-1-phenyl[1-(14)C]propan-1-ol ([(14)C]norephedrine) was administered orally to man, rat and rabbit and the metabolites excreted in the urine were identified and measured. Pronounced species differences in the metabolism of the drug were found. 2. Three male human subjects, receiving 25mg each of [(14)C]norephedrine hydrochloride, excreted over 90% of the (14)C in the first day. The main metabolite was the unchanged drug (86% of the dose) and minor metabolites were hippuric acid and 4-hydroxynorephedrine. 3. In rats given 12mg of the drug/kg almost 80% of the (14)C administered was excreted in the first day. The major metabolites in the urine were the unchanged drug (48% of the dose), 4-hydroxynorephedrine (28%) and trace amounts of side-chain degradation products. 4. Rabbits given 12mg of the drug/kg excreted 85-95% of the dose of (14)C in the urine in the first 24h after dosing. The major metabolites in the urine were conjugates of 1,2-dihydroxy-1-phenylpropane (31% of the dose) and of 1-hydroxy-1-phenylpropan-2-one (27%) and hippuric acid (20%). The unchanged drug was excreted in relatively small amounts (8%).     

Pharmacokinetic profile of (+/-)-gossypol in male Sprague-Dawley rats following single intravenous and oral and subchronic oral administration

The pharmacokinetic profile of (+/-)-gossypol was determined in male Sprague-Dawley rats following a single intravenous or oral 10 mg/kg dose and after receiving a daily oral 10 mg/kg dose for 14 days. The intravenous plasma (+/-)-gossypol level data were fitted with a three-compartment, open-model system. The apparent half-life of elimination of (+/-)-gossypol following intravenous administration was 11.44 hr, corresponding to an elimination rate constant of 0.05 hr-1. The total plasma clearance (Cl), volume of distribution (Vd), and AUCplasma following a single intravenous administration were 0.16 liter/hr/kg, 0.05 liter/kg, and 63.09 mg.hr/liter, respectively. The bioavailability of a single oral dose of (+/-)-gossypol in rats was 60%. The change in plasma (+/-)-gossypol concentration after a single or after multiple doses showed a biphasic pattern. A single oral dose of (+/-)-gossypol, however, was eliminated five times faster than the daily administered chemical. Thus, a single oral dose of (+/-)-gossypol was eliminated at a rate constant of 0.01 hr-1, corresponding to half-life of 64.76 hr. Subchronic oral administration of (+/-)-gossypol showed an apparent half-life of 101.91 hr-1, corresponding to a rate constant of 0.007 hr-1. The results indicate that multiple oral dosing of (+/-)-gossypol resulted in its longer retention in body tissue than a single oral dose. This study suggests that pharmacokinetics of (+/-)-gossypol may play, at least in part, a role in the reproductive toxicity of subchronic but not single oral dosing.     

Absorption of cadmium after a long-term oral administration of cadmium to dogs

A long-term experiment using beagle dogs to investigate the absorption of cadmium was conducted. The dogs in the experimental groups were given a commercial diet and pelleted food containing 1, 3, 10, 50, and 100 mg of cadmium per day. The cadmium concentration in the blood increased continuously, gradually reaching a steady state following the administration of cadmium. The cadmium excreted daily in urine increased continuously. The cumulative excreted amount of cadmium in urine was calculated by using the trapezoidal rule based on the data of excretion of cadmium in urine. Then the absorbed fraction of administered cadmium was estimated on the basis of the relationship between the cumulative excreted amount of cadmium in urine and the cumulative administered dose of cadmium after the cadmium concentration in blood reached a steady state. The absorbed fraction of cadmium decreased with an increase in the administered dose of cadmium. A dose-dependent increase between the absorbed amount and the administered dose was observed.     

The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats.

Mice fed a diet containing 1% (w/w) 3-hydroxy-4(1H)-pyridone (DHP) developed goitre even with a diet high in iodine whereas mimosine (0.5% w/w) did not produce goitre even with a low-iodine diet. Thyroid enlargement was apparent (measured morphometrically) by the 7th week and was advanced by the 11th week. Histologically the goitre was hyperplastic in type. No marked histological changes were found in other organs of mice fed DHP or any organs of mice fed mimosine, except for some atrophy of hair follicles. A single intragastric dose of DHP inhibited the uptake of 125I by the thyroid in the rat but an equivalent dose of mimosine did not. Evidence is presented that the inhibition occurs at the iodine binding step, as with methyl thiouracil, rather than at the iodide trapping step, as with thiocyanate. Chronic treatment of mice with DHP, as with 6-methyl thiouracil, increased the avidity of the thyroid in taking up 125I. The major conjugated form of DHP in mammals, DHP-3-O-glucuronide, was almost as effective a goitrogen as the unconjugated compound when given by mouth but considerably less active than the free form in the blood stream. It was concluded that DHP is a potent antithyroid compound of the thiouracil type with low general toxicity, since mammals can tolerate a level of intake sufficient to produce goitre in spite of iodine supplementation.     

Critical Tests on Thiabendazole as an Anthelmintic in Sheep

The results of critical tests on thiabendazole given at three dose levels, 50 mg/kg, 80 mg/kg and 100 mg/kg, to groups of naturally parasitized lambs are reported. While the compound appeared to be efficient at all levels, the best results were obtained at 100 mg/kg. The total percentage removals of all worms present in the gut at these three dosage levels were 79.1 per cent at the 50 mg/kg level, 96.3 per cent at the 80 mg/kg level and 99.5 per cent at the 100 mg/kg level. No activity against T. ovis, Capillaria or Moniezia was observed. Useful activity in a limited number of lambs was observed against Dictyocaulus filaria especially at the 100 mg/kg level. This drug appeared to be completely effective at the 100 mg/kg level in removing tissue-phase parasites. Inhibitory activity against developing larvae in faecal cultures obtained 24 hours after dosing was also shown.At levels up to 500 mg/kg the drug appeared relatively non-toxic. The result at 800 mg/kg was complicated by the death of the treated animal 22 days after dosing from a septicaemia. Dosage at a level of 1.6 mg/kg proved rapidly fatal to a ewe. No effect on pregnant ewes or the lambs therefrom was observed at a dose level of 160 mg/kg. The most efficient level for routine treatment of sheep under Canadian conditions of management would appear to be 100 mg/kg of body weight. This compound appears to be the best anthelmintic to have been tried to date at this laboratory against the internal parasites of sheep.     

A comparative study of hepatic DNA repair, DNA replication and hepatotoxicity in the CD-1 mouse following multiple administrations of dimethylnitrosamine

The objective of this study was to quantify hepatic DNA repair and DNA replication following multiple administrations of dimethylnitrosamine (DMN) and to determine if these events were correlated with hepatotoxicity. Male CD-1 mice, 50-100 days old, were dosed daily, p.o., with DMN in water at dose levels of 2, 4, 7 and 10 mg/kg for 2 weeks. After 2, 7 and 14 days of dosing, hepatocytes were isolated by an in situ perfusion procedure, incubated in the presence of [3H] thymidine, and fixed. Unscheduled as well as scheduled DNA synthesis were assessed by quantitative autoradiography. Unscheduled DNA synthesis (UDS) represents DNA repair while scheduled DNA synthesis (S phase) represents DNA replication. In addition, the animals' serum was examined for enzymes which indicate hepatic toxicity. After 1, 7 and 14 days of dosing, animals were orbital-bled and the serum was analyzed for serum glutamic pyruvic transaminase (SGPT), serum glutamic oxalacetic transaminase (SGOT), alkaline phosphatase (AP) and gamma-glutamyl transpeptidase (GGT). No morbidity or mortality was observed at dose levels of 2 and 4 mg/kg, but all animals receiving 7 and 10 mg/kg died after 4-6 days of dosing. GGT or AP were not elevated at any dose level or at any time point examined. At 4 mg/kg only a slight increase (less than or equal to 2 X) in the concentration of SGOT and SGPT was observed but a sharp increase (greater than 20 X) in replicative DNA synthesis was seen. The 2 mg/kg dose level of DMN did not increase replicative DNA synthesis and SGOT and SGPT were not elevated above control values at any time point following dosing at 2 mg/kg. A weakly positive DNA repair response was observed for dose levels of 4, 7 and 10 mg/kg DMN after two consecutive days of dosing. No DNA repair was observed after either 7 or 14 days of dosing at the 2 and 4 mg/kg/day levels. These results indicate that hepatic toxicity is associated with the induction of replicative DNA synthesis (S phase) but not with the induction of DNA repair. The results also confirm and extend a previous study (Doolittle et al., 1987b) indicating that a significant elevation in hepatic DNA replication is induced by hepatocarcinogens after multiple administrations of dose levels which do not alter hepatic DNA replication after a single administration. This finding indicates that the utility of the in vivo-in vitro hepatocyte assay may be enhanced by using a multi-dose protocol.     

Oral absorption and excretion of icaritin, an aglycone and also active metabolite of prenylflavonoids from the Chinese medicine Herba Epimedii in rats

Icaritin (ICT) is a main aglycone and also active intestinal metabolite of prenylflavonoids from the Chinese medicine Herba Epimedii. In the present study, the oral absorption and excretion of this compound was investigated using rats for exploring its fate in the body, so as to better understanding its in vivo pharmacological activities. The free (parent) and total (parent plus conjugated metabolites) ICT concentrations in rat plasma, urine and bile, after intravenous (i.v.) and oral administration both at 5mg/kg, were determined before and after enzymatic hydrolysis with β-glucuronidase/sulphatase, respectively, by a HPLC-UV method. The results showed that free ICT plasma concentration after i.v. dose was rapidly decreased with average t(1/2, λ) of 0.43h, while the total ICT concentration was decreased slowly with t(1/2, λ) of 6.86h. The area under the curve of ICT conjugated metabolites was about 11-fold higher than that of free ICT. The majority of ICT in the body was excreted from the bile with 68.05% of dose over 8h after i.v. dosing, in which only 0.15% was in parent form. While very little amount of ICT was excreted from the urine with 3.01% of dose over 24h, in which the parent form was 0.62%. After oral administration, very little amount of parent ICT was detected only in 0.5, 1 or 2h plasma samples with the concentration less than LOQ, however, its total plasma concentration after enzymatic hydrolysis treatment was at relative high level with average maximum concentration of 0.49μg/ml achieved at 1h post dose. The oral bioavailability of ICT was 35% of dose, estimated by its total plasma drug concentrations. It is concluded that ICT can be easily absorbed into the body, and then rapidly conversed to its conjugated metabolites, and finally removed from the body mainly by biliary excretion.     

Effect of parenterally injected benzimidazole compounds on Echinococcus multilocularis and Taenia crassiceps metacestodes in laboratory animals.

In mice infected with metacestodes of Taenia crassiceps, the following compounds were at least partially effective when injected intraperitoneally at the dosage indicated: cambendazole (500 mg/kg), mebendazole (6.25 mg/kg), oxibendazole (500 mg/kg), 5-benzamido-2(4-thiazolyl)benzimidazole (500 mg/kg), 2-carboethoxyamino benzimidazole (125 mg/kg), and 2-carbomethoxyamino benzimidazole (500 mg/kg). The following were inactive at the dosage indicated: parbendazole (500 mg/kg), thiabendazole (1,000 mg/kg), and fenbendazole (1,000 mg/kg). Mebendazole, which showed some activity at 6.25 mg/kg, was highly active as a single intraperitoneal dose at 25 mg/kg. When injected subcutaneously, mebendazole was much less active than when given intraperitoneally. In mice infected with metacestodes of Echinococcus multilocularis, intraperitoneal injection of mebendazole at 75 to 150 mg/kg, daily for 3 days, was highly effective (95 to 100% reduction in cyst mass). In contrast, oral administration at 1,000 mg/kg, daily for 3 days, was only partially effective. The drug was also effective when given intraperitoneally to infected cotton rats. A water-soluble benzimidazole, carboxymethyleneamino cambendazole, was approximately 50% effective in mice when injected daily for 3 days at a dosage of 75 or 150 mg/kg. The results suggest that, in metacestode infections of medical importance, it may be possible to kill the parasite by delivering a drug to its immediate vicinity, and so to reduce the required dosage with respect to the host.     

The metabolic fate of amphetamine in man and other species

1. The fate of [(14)C]amphetamine in man, rhesus monkey, greyhound, rat, rabbit, mouse and guinea pig has been studied. 2. In three men receiving orally 5mg each (about 0.07mg/kg), about 90% of the (14)C was excreted in the urine in 3-4 days. About 60-65% of the (14)C was excreted in 1 day, 30% as unchanged drug, 21% as total benzoic acid and 3% as 4-hydroxyamphetamine. 3. In two rhesus monkeys (dose 0.66mg/kg), the metabolites excreted in 24h were similar to those in man except that there was little 4-hydroxyamphetamine. 4. In greyhounds receiving 5mg/kg intraperitoneally the metabolites were similar in amount to those in man. 5. Rabbits receiving 10mg/kg orally differed from all other species. They excreted little unchanged amphetamine (4% of dose) and 4-hydroxyamphetamine (6%). They excreted in 24h mainly benzoic acid (total 25%), an acid-labile precursor of 1-phenylpropan-2-one (benzyl methyl ketone) (22%) and conjugated 1-phenylpropan-2-ol (benzylmethylcarbinol) (7%). 6. Rats receiving 10mg/kg orally also differed from other species. The main metabolite (60% of dose) was conjugated 4-hydroxyamphetamine. Minor metabolites were amphetamine (13%), N-acetylamphetamine (2%), norephedrine (0.3%) and 4-hydroxynorephedrine (0.3%). 7. The guinea pig receiving 5mg/kg excreted only benzoic acid and its conjugates (62%) and amphetamine (22%). 8. The mouse receiving 10mg/kg excreted amphetamine (33%), 4-hydroxyamphetamine (14%) and benzoic acid and its conjugates (31%). 9. Experiments on the precursor of 1-phenylpropan-2-one occurring in rabbit urine suggest that it might be the enol sulphate of the ketone. A very small amount of the ketone (1-3%) was also found in human and greyhound urine after acid hydrolysis.     

Generation of thioarsenicals is dependent on the enterohepatic circulation in rats

Three minor sulfur-containing arsenic metabolites: monomethylmonothioarsonic acid (MMMTA(V)), dimethylmonothioarsinic acid (DMMTA(V)), and dimethyldithioarsinic acid (DMDTA(V)) were recently found in human and animal urine after exposure to inorganic arsenic. However, it remains unclear how the thioarsenicals are formed in the body and then excreted into the urine. It is hypothesized that the generation of thioarsenicals occurs during enterohepatic circulation. To address this hypothesis, male Sprague Dawley (SD) rats and Eisai hyperbilirubinuric (EHB) rats (with deficiency of multidrug resistance-associated protein 2) were orally administered a single dose of inorganic arsenite (iAs(III)) at 3.0 mg kg(-1) of body weight. Five hours after dosing, less than 1.0% of the dose was recovered in the bile of EHB rats, while more than 27% of the dose was recovered in the bile of SD rats, with the majority being monomethylarsinodiglutathione [MMA(SG)(2)] with a small amount of arsenic triglutathione [iAs(SG)(3)]. During the early time periods (3 h and 6 h) the arsenic levels in the liver, red blood cells (RBCs) and plasma of EHB rats were higher than those of SD rats, and approximately 76% and 87% of the dose was recovered in the RBCs of SD and EHB rats, respectively, at day 5 after dosing. However, there were no significant differences in arsenic concentration in urine between the two types of animal. Regarding the arsenic species in the urine of both types of rat, significant levels of thiolated arsenicals MMMTA(V) and DMMTA(V) were detected in SD rat urine, however in EHB rat urine only low levels of DMMTA(V) were detected. The present result of the metabolic balance and speciation study suggests that the formation of MMMTA(V) and DMMTA(V) in rats is dependent on enterohepatic circulation. In addition, in vitro experiments indicated that arsenicals excreted from bile may be transformed by gastrointestinal microbiota into MMMTA(V) and DMMTA(V), which are then absorbed into the bloodstream and finally excreted into the urine.     

洛伐他汀在巴马香猪体内的分布和排泄

目的研究洛伐他汀在巴马香猪体内的分布和排泄特点。方法以抗动脉粥样硬化药物洛伐他汀为模型药,选择健康6月龄雄性巴马香猪为实验对象,经灌胃途径给药(45 mg/kg或2.4 mg/kg),采用RP-HPLC方法测定各组织及体液中的药物浓度,并对其分布和排泄过程进行研究。血浆蛋白结合率通过透析法测定。结果给药后,洛伐他汀快速分布到贲门、胃、小肠、肝、大肠、胰、前列腺、肺、肾、心、肌肉、睾丸、肾上腺、膀胱、脑和脾。以胃、肠、肝组织中药物浓度较高。单次给药4h后,贲门、胃、小肠、肝、心、肾上腺、膀胱药物浓度同给药后1h相比略有下降,其余组织均高于1 h。血浆蛋白结合率为95%以上,同正常人血浆非常一致。96 h尿中累积排泄量为给药量的7.4%,原形药经胆汁及粪排泄量达到80%以上。结论洛伐他汀在巴马香猪体内同人的分布排泄和血浆蛋白结合率相似,均在组织中广泛分布,血浆结合率达到95%以上,主要经胆汁和粪排泄。     

Dose-dependent activity of albendazole against benzimidazole-resistant nematodes in sheep: relationship between pharmacokinetics and efficacy

The relationship between the pharmacokinetic behaviour and the anthelmintic efficacy of albendazole (ABZ) against benzimidazole (BZD)-resistant nematodes was studied in sheep. A micronized ABZ suspension was orally administered at two different dose levels to sheep naturally infected with BZD-resistant gastrointestinal (GI) nematodes. The experimental animals were allocated into the following groups (n = 8): (a) untreated control; (b) orally treated with ABZ at 3.8 mg/kg b.w.; and (c) orally treated with ABZ at 7.5 mg/kg b.w. Plasma samples were obtained serially over 72 h post-treatment from both treated groups and analysed by HPLC to measure the concentrations of ABZ and its sulphoxide (ABZSO) and sulphone (ABZSO(2)) metabolites. Faecal egg counts were performed prior to treatment and at the necropsy day. All experimental animals were sacrificed 10 days after treatment to perform GI worm counts. While ABZ parent drug was not recovered in the bloodstream, ABZSO and ABZSO(2) were the molecules found in plasma. ABZSO was the metabolite measured at the highest concentrations in the bloodstream for up to 36 (treatment at 3.8 mg/kg) or 60 h (treatment at 7.5 mg/kg) post-administration. There was a proportional relationship between the administered ABZ dose and the measured plasma concentrations of both ABZ metabolites. Over a 100% increment on the plasma AUC values for the anthelmintically active ABZSO metabolite was observed at the 7.5 mg/kg compared to the 3.8 mg/kg treatment. The low efficacy patterns (< 24%) observed against the GI nematodes investigated indicate a high level of resistance to ABZ given at 3.8 mg/kg an efficacious therapeutic dose rate recommended in some countries. However, the higher and prolonged plasma drug concentration measured after the 7.5 mg/kg treatment resulted in an improved efficacy pattern (estimated by both faecal egg and adult worm counts) against most of the GI nematodes studied compared to that obtained at the lower dose rate. A direct relationship between drug pharmacokinetic behaviour and anthelmintic efficacy against BZD-resistant nematodes in sheep was shown in the current work, although individual variation precluded the observation of statistically significant differences in worm counts.     

Studies on the chemoprophylaxis of subperiodic Brugia malayi infection in the leaf monkey (Presbytis melalophos) with diethylcarbamazine citrate

The chemoprophylactic use of diethylcarbamazine citrate at total oral doses of 15--180 mg/kg body weight was tested against subperiodic Brugia malayi infection in the leaf monkey (Presbytis melalophos). A total dose of 45 mg/kg body weight given over 9 days killed all developing infective larvae. Similarly, a total dose of 35 mg/kg body weight given over 7 days killed all fourth stage larvae. The minimum effective dose that prevents infection would be 5 mg/kg body weight daily for 7 days every month.     

Can urine lamivudine be used to monitor antiretroviral treatment adherence?

Patient adherence to treatment is an important factor in the effectiveness of antiretroviral regimens. Adherence to treatment could be monitored by estimation of antiretroviral drugs in biological fluids. We aimed to obtain information on the quantity and duration of excretion of lamivudine in urine following oral administration of a single dose of 300 mg and to assess its suitability for adherence monitoring purposes. Spot urine samples were collected before dosing and at 4, 8, 12, 24, 28, 32, 48, 72, and 96 hours post dosing from 10 healthy subjects, and lamivudine was estimated by high-pressure liquid chromatography (HPLC). Lamivudine values were expressed as a ratio of urine creatinine. About 91% of the ingested drug was excreted by 24 hours, and the concentration thereafter in urine was very negligible. A lamivudine value of 0.035 mg/mg creatinine or less at 48 hours is suggestive of a missed dose in the last 24 hours. The study findings showed that estimation of urine lamivudine in spot specimens could be useful in monitoring patient adherence to antiretroviral treatment. However, this needs to be confirmed on a larger sample size and among patients on once-daily and twice-daily treatment regimens.     

Pharmacokinetics/Pharmacodynamics of Y‐700, A Novel Xanthine Oxidase Inhibitor,in Rats and Man

The pharmacokinetics and pharmacodynamics of a novel xanthine oxidase (XO) inhibitor, Y‐700, were evaluated in rats and healthy male volunteers. In a rat model of hyperuricemia, oral Y‐700 (0.3–10 mg/kg) showed a more potent and a longer‐lasting hypouricemic action than allopurinol. A single oral dosing of Y‐700 (5, 20 or 80 mg) to volunteers caused a dose‐dependent reduction of serum uric acid levels indicating close relationship to plasma concentrations of the compound. In addition, Y‐700 was hardly excreted in urine but mainly excreted in feces in rats and volunteers. These results suggested that Y‐700 is a new effective inhibitor of XO in rats and humans with high oral bioavailability being predominantly eliminated via the liver unlikely to allopurinol.     

Extrahpetic distribution of sulfobromophthalein.

Plasma clearance of sulfobromophthalein (BSP) is widely used as a measure of hepatic function. Its validity depends upon its exclusive elimination from the body via bile. For example, in the present study, when BSP was administered intravenously (i.v.) to rats at four different doses (18.75, 37.5, 75, and 150 mg/kg), less than 0.5% of each dose was excreted into the urine and between 70 and 85% was excreted into the bile within 6 h after administration. It has been assumed that the distribution of BSP is limited to the blood and liver witith very little appearing in other tissues. When we measured the amount of BSP in the plasma, liver, and the bile 10 min after the i.v. administration of either a high (150 mg/kg) or a low (18.75 mg/kg) dose of BSP, only 60% of the dose was accounted for. The concentration of BSP and 12-I-labelled albumin (RISA) was measured in various tissue samples 10 min after administration of 17.5 or 150 mg of BSP or RISA per kilogram. More BSP was found in all tissues than was contained in the plasma entrapped therein. Thus, the distribution of BSP is not limited to the liver and plasma. During excretion BSP leaves other tissue (kidney, spleen, lung, etc.) and is ultimately excreted into the bile.     

The metabolites of cyclohexylamine in man and certain animals

1. [1-(14)C]Cyclohexylamine hydrochloride was synthesized and given orally or intraperitoneally to rats, rabbits and guinea pigs (dose 50-500mg/kg) and orally to humans (dose 25 or 200mg/person). The (14)C is excreted mainly in the urine, most of the excretion occurring in the first day after dosing. Only small amounts (1-7%) are found in the faeces. 2. In the rat, guinea pig and man, the amine is largely excreted unchanged, only 4-5% of the dose being metabolized in 24h in the rat and guinea pig and 1-2% in man. In the rabbit about two-thirds of the dose is excreted unchanged and about 30% is metabolized. 3. In the rat, five minor metabolites were found, namely cyclohexanol (0.05%), trans-3- (2.2%), cis-4- (1.7%), trans-4- (0.5%) and cis-3-aminocyclohexanol (0.1% of the dose in 24h). 4. In the rabbit, eight metabolites were identified, namely cyclohexanol (9.3%), trans-cyclohexane-1,2-diol (4.7%), cyclohexanone (0.2%), cyclohexylhydroxylamine (0.2%) and trans-3- (11.3%), cis-3- (0.6%), trans-4- (0.4%) and cis-4-aminocyclohexanol (0.2%). 5. In the guinea pig, six minor metabolites were found, namely cyclohexanol (0.5%), trans-cyclohexane-1,2-diol (2.5%) and trans-3- (1.2%), cis-3- (0.2%), trans-4- (0.2%) and cis-4-aminocyclohexanol (0.2%). 6. In man only two metabolites were definitely identified, namely cyclohexanol (0.2%) and trans-cyclohexane-1,2-diol (1.4% of the dose), but man had been given a smaller dose (3mg/kg) than the other species (50mg/kg). 7. The hydroxylated metabolites of cyclohexylamine were excreted in the urine in both free and conjugated forms. 8. Although cyclohexylamine is metabolized to only a minor extent, in rats the metabolism was mainly through hydroxylation of the cyclohexane ring, in man by deamination and in guinea pigs and rabbits by ring hydroxylation and deamination.