Effect of furosemide on the pharmacokinetics of benzylpenicillin and its penetration through the hematoencephalic barrier in experimental and clinical meningococcic meningitis]

Pharmacokinetics of sodium benzylpenicillin after intramuscular administration in a dose of 250 000 gamma/kg and simultaneous intramuscular injection of furosemid (lazix) in doses of 0.5--1--2 mg/kg was studied in experiments on a model of meningococcal meningitis of rabbits and in clinics on patients with meningococcal meningitis. A pronounced effect of furosemid on pharmacokinetics of benzylpenicillin as dependent on a number of factors was found. Furosemid and meningococcal endotoxin had a synergic effect and decreased benzylpenicillin excretion with urine resulting in prolongation of the antibiotic effect in the blood. An increase in benzylpenicillin blood levels and inflammation of the soft brain membranes increased permeability of the hemato-encephalic barrier for the antibiotic.     

Pharmacokinetics of pralidoxime chloride in the rat

The pharmacokinetics of pralidoxime chloride (2-PAM) was studied in rats. Different groups of rats were given an intramuscular injection of 2-PAM at one of three doses (20, 40, or 80 mg/kg). This range of doses is used commonly in studies concerned with the efficacy of 2-PAM against poisoning by potent organophosphorus inhibitors of cholinesterase enzyme. Individual, sequential blood samples were collected during the course of the experiment. From these blood samples the plasma concentrations of 2-PAM were determined over time for each animal. Next the relationship of plasma concentration to time was expressed in terms of a standard pharmacokinetic model. Estimates of various pharmacokinetic parameters were calculated using an open, one-compartment model: volume of distribution (Vd), maximal plasma concentration (Cmax), elimination rate constant (k10), absorption rate constant (k01), area under the curve (AUC) and clearance (CL). Of the pharmacokinetic estimates, only Cmax and AUC were found to be statistically significant (p less than 0.0001) when compared across all the doses; these pharmacokinetic estimates were highly correlated with doses with r = 0.998 and r = 0.997, respectively. However, when AUC and Cmax were normalized by dividing through by dose, no significant differences were found in the transformed data. The results of this study in rat indicate that the pharmacokinetics of 2-PAM is linearly related to dose in a range employed in therapeutic studies of 2-PAM.     

Use of an experimental design method for studying the effect of proteolytic enzymes on the pharmacokinetics of antibiotics]

The effect of chemotripsin on the pharmacokinetics of ampicillin as dependent on the drug dose and the administration intervals was studied on rats using the method of the experiment design. With the use of the method it was found that intramuscular injections of chemotripsin to rats in doses of 3, 4.5, 6, 8 and 10 mg/kg, 0.5, 1, 1.5 and 2 hours before intramuscular administration of ampicillin in doses of 10, 20, 35, 75 and 100 mg/kg caused a simple effect inducing an increase in the antibiotic levels in the blood and organs, when the enzyme and antibiotic were present simultaneously in the animal organism for an hour. The increase in the antibiotic levels in the rat organs due to simultaneous presence of chemotripsin and ampicillin the animal organism for 2 hours was less pronounced     

Determination of vertilmicin in rat serum by high-performance liquid chromatography using 1-fluoro-2,4-dinitrobenzene derivatization

A procedure for the high-performance liquid chromatographic determination of vertilmicin in rat serum was described using pre-column derivatization. The serum proteins were precipitated with acetonitrile and vertilmicin in the supernatant was derivatized with 1-fluoro-2,4-dinitrobenzene. Etimicin was selected as the internal standard. The mobile phase consisted of methanol--20mM ammonium acetate (80:20, v/v), and flow-rate was 0.9 ml/min. Ultraviolet detection was set at 365 nm. The reaction products were chromatographed on a C(18) column kept at 40 degrees C. A good linearity was found in the range of 0.5-250 microg/ml. Both intra- and inter-day precisions of vertilmicin, expressed as the relative standard deviation, were less than 7.4%. Accuracy, expressed as the relative error, ranged from -0.1 to 3.6%. The mean absolute recovery of vertilmicin at three different concentrations was 92.5%. Serum volumes of 50 microl were sufficient for the determination of vertilmicin. The method was proved suitable for the pharmacokinetic study of vertilmicin in rats.     

Simultaneous determination of morphine and monoamine transmitters in a single mouse brain

A simple procedure for the simultaneous determination of morphine and monoamine transmitters was developed. The procedure consisted of (1) n-butanol extraction and (2) separation and quantitative determination by means of high-performance liquid chromatography combined with electrochemical detection. The maximum intracerebral concentration (210 ± 35 ng/g wet tissue) of morphine was detected 30 min after intramuscular injection (10 mg/kg), which agreed with previous research. Noradrenaline was significantly decreased by morphine injection, while dopamine and 5-hydroxytryptamine were unchanged. However, 3-methoxytyramine, a metabolite of dopamine, was increased, suggesting that the drug increased the turnover rate of dopamine. The procedure used revealed a direct correlation between pharmacokinetics (e.g., distribution of morphine) and pharmacodynamics (e.g. changes of monoamine concentrations) of the drug in vivo.     

Pharmacokinetics and pharmacodynamics of injectable testosterone undecanoate in castrated cynomolgus monkeys (Macaca fascicularis) are independent of different oil vehicles

Testosterone undecanoate (TU) dissolved in soybean oil was developed in China to improve the pharmacokinetics of this testosterone ester in comparison with TU in castor or tea seed oil. As a pre-clinical primate model, three groups of five castrated cynomolgus macaques received either a single intramuscular injection of 10 mg/kg body weight TU in soybean oil, in tea seed oil, or in castor oil (equals 6.3 mg pure T/kg body weight for all preparations). Testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone as well as prostate volume, body weight and ejaculate weight were evaluated. After injection supraphysiological testosterone levels were induced. There were no significant differences in the pharmacokinetics of the three TU preparations for testosterone and estradiol. The gonadotropin levels showed a high individual variation. Prostate volumes increased equally in all groups after administration and declined to castrate level afterwards. The results suggest that TU in soybean oil produces similar effects as TU in the other vehicles. This study in non-human primates provides no objection to testing of this new preparation in humans.     

Immobilization of sika deer with medetomidine and ketamine, and antagonism by atipamezole

Forty wild sika deer (Cervus nippon) were immobilized with medetomidine and ketamine and reversed by atipamezole in summer and fall captures from September 1994 to October 1995. For large yearling and older deer, mean +/- SD doses of 57.0+/-15.6 microg/kg medetomidine and 1.64+/-0.49 mg/kg (male) or 4.02+/-1.16 mg/kg (female) of ketamine were administered by intramuscular injection. For calves and small yearlings, 69.3+/-7.0 microg/kg medetomidine and 2.69+/-0.44 mg/kg ketamine were administered. While immobilized, deer were easy to handle, and muscles were well relaxed. After intramuscular administration of atipamezole (about 5 times the dose of medetomidine), deer recovered rapidly and smoothly.     

Pharmacokinetics of 19-nortestosterone esters in normal men

A reliable method for the isolation of 19-nortestosterone (NT), testosterone (T) and dihydrotestosterone (DHT) by high-performance liquid chromatography (HPLC) and quantitation of the individual steroids by radioimmunoassays is described. The method was used to measure serum concentrations of NT, T and DHT in a pharmacokinetic study and in a clinical trial for male fertility control. Following intramuscular injection of either 50 mg 19-nortestosterone-3-(p-hexoxyphenyl)-propionate (NP) or 50 mg 19-nortestosterone-decanoate (ND) serum NT increased rapidly to maximal concentrations of 4.6 +/- 3.2 and 2.0 +/- 1.3 nmol/l (+/-SD), respectively, in the 6 volunteers. The half-life time was 8 days for ND and 21 days for NP. Based on these findings a clinical trial with NP was performed. NP was given to 5 healthy men in doses of 100 mg/week for the first 3 weeks followed by 200 mg/week for 10 further weeks. Serum NT levels increased gradually and maximal concentrations were reached in the 13th treatment week (20.2 +/- 3.4 nmol/l). Measurable amounts of NT were detectable for 19 weeks after the last injection. The study shows that NT accumulates under this treatment regime and wider spacing of the injection intervals may be possible in future trials.     

Population pharmacokinetics of methotrexate in the guinea pig.

The population pharmacokinetics of an antitumoral and antiinflammatory agent, methotrexate (MTX), a folic acid antagonist, was studied in guinea pigs. Animals received an acute intraperitoneal injection of 0.25, 1 or 5 mg/kg MTX. Blood sampling was carried out for 12 hrs. after MTX administration and plasma drug concentrations were measured by fluorescence polarization immunoassay. The pharmacokinetic (PK) parameters were computed using the bayesian population model. MTX reached the level of detection at 3 hrs. for the animals injected with the lowest dose (0.25 mg/kg), at 3.5 hrs. for those animals which had the intermediate dose (1 mg/kg) and more than 6 hrs. for animals having received the highest dose (5 mg/kg). Each kinetic parameter (half life, total clearance - CLt, volume of distribution at steady state - VDSS, mean residence time - MRT - and area under curve - AUC) didn't show any significant difference between doses. MTX kinetic was linear for the first two doses (0.25 and 1 mg/kg MTX) and non-linear thereafter. MTX presented a one compartment distribution.     

Intramuscular loading dose of quinine for falciparum malaria: pharmacokinetics and toxicity.

In a study of intramuscular injection of quinine eight adults with moderately severe falciparum malaria resistant to chloroquine were treated with quinine dihydrochloride, being given a loading dose of 20 mg salt (16.7 mg base)/kg followed by three or four eight hourly maintenance doses of 10 mg salt (8.3 mg base)/kg injected into the anterior thigh. All patients responded to treatment. Fever and parasite clearance times (mean (SD) 60 (23) h and 53 (22) h respectively) were comparable with those obtained with intravenous quinine. The mean peak plasma quinine concentration of 11.0 mg/l (34.4 mu mol/l) [corrected] was reached a median of five hours after administration of the loading dose. In all patients plasma quinine concentrations exceeded the high minimum inhibitory concentration for Plasmodium falciparum malaria prevalent in Thailand within four hours of the start of treatment but did not cause toxicity other than mild cinchonism. When intravenous infusion is not possible an intramuscular quinine loading dose is an effective means of starting treatment in patients with moderately severe falciparum malaria who cannot swallow tablets.     

Chronopharmacokinetics of imipenem in the rat

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10:00, 16:00, 22:00, or 04:00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C_max, T_max, elimination half-life (t_1/2), area under the concentration-versus-time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C_max (49%), T_max (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra-individual variability.     

The use of meperidine hydrochloride for chemical restraint in certain cetaceans and pinnipeds

Meperidine HCl was administered intramuscularly by hand-syringe to a number of individuals representing several species of cetaceans (n = 95) and pinnipeds (n = 36). Dosage administered was 0.11 mg/kg, 0.23 mg/kg or 0.45 mg/kg, with the majority of animals receiving the middle dosage. Meperidine HCl provided moderate restraint in cetaceans without obvious deleterious effects. Restraint was achieved rapidly, with maximum effect occurring 20 min after intramuscular injection and lasting for 2 to 3 hr. Analgesia appeared to last as long as 4 hr and was sometimes accompanied by a restoration of appetite in animals suffering from physical discomfort. Higher doses produced increased sedation and analgesia without noticeably depressing respiration. Meperidine HCl provided moderate restraint for phocids and walrus (Odobenus rosmarus) without apparent detriment. California sea lions (Zalophus californianus) showed little restraint, but demonstrated profound respiratory depression.     

Thermoregulatory, motor, behavioural, and nociceptive responses of rats to 3 long-acting neuroleptics

We investigated physiological effects of intramuscular injections of the following 3 long-acting neuroleptics commonly used in wildlife management: haloperidol (0.05, 0.1, and 0.5 mg/kg body mass), zuclopenthixol acetate (0.5, 1, and 5 mg/kg), and perphenazine enanthate (1, 3, and 10 mg/kg), in a rat model. Body temperature and cage activity were measured by intra-abdominal telemeters. Nociceptive responses were assessed by challenges to noxious heat and pressure. Haloperidol (0.5 mg/kg) produced a significant nocturnal hypothermia (p < 0.05) and decreased nighttime cage activity and food intake. Zuclopenthixol (5 mg/kg) significantly decreased nighttime body temperature and cage activity and, at 1 mg/kg and 5 mg/kg, significantly decreased food intake 5-17 h after injection (p < 0.05). Perphenazine (10 mg/kg) significantly decreased nighttime body temperature and cage activity and, at all doses, significantly decreased food intake 5-17 h after injection (p < 0.05). Significant analgesic activity was evident in rats given 5 mg/kg zuclopenthixol up to 40 h after injection, and 10 mg/kg perphenazine from 48 to 96 h after injection (p < 0.0001). Zuclopenthixol (5 mg/kg) and perphenazine (10 mg/kg) had significant antihyperalgesic activities at 16 h postinjection and 24-48 h postinjection, respectively (p < 0.0001). Haloperidol had no significant antinociceptive activity at doses tested. Motor function was impaired in rats given 0.5 mg/kg haloperidol, 5 mg/kg zuclopenthixol and 10 mg/kg perphenazine. Effects of long-acting neuroleptics on body temperature, feeding, and activity were short-lasted and should not preclude their use in wildlife. Antinociceptive actions were longer-lasting, but were nonspecific, and we recommend additional analgesics for painful procedures during wildlife management.     

Pharmacokinetics and metabolism of formestane in breast cancer patients

Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.     

Pharmacokinetics and pharmacodynamics of terguride following intramuscular administration in cows and goats

The pharmacokinetics of intramuscular terguride (transdihydrolisuride) was evaluated in a single-dose study in cows (doses 100, 62 and 31 micrograms/kg b.w.) and goats (dose 100 micrograms/kg b.w.). A radioreceptor assay was used to quantitative plasma terguride concentrations. The peak plasma concentrations of terguride were attained within 0.6 h of the drug administration and then decreased monoexponentially with half-life of 1.3 h (cows) and 2 h (goats). The pharmacokinetics of terguride in cows is nearly linear. Pharmacodynamics of terguride was expressed as reduction in plasma prolactin levels. Maximal decline in prolactin was observed 3-4 h following terguride administration and the effect lasted for about 24 h.     

Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT.     

Evaluation of medetomidine/ketamine for short-term immobilization of variable flying foxes (Pteropus hypomelanus)

Four medetomidine/ketamine (M/K) doses (30 microg/kg/3 mg/kg; 40/4; 50/5; 60/6), administered by intramuscular injection, were evaluated for short-term immobilization of adult male variable flying foxes (Pteropus hypomelanus). The highest dose (60 microg/kg/6 mg/kg) produced a significantly faster induction (31 +/- 46 sec) than the lowest dose (30/3) (125 +/- 62 sec). The highest dose levels (50/5, 60/6) produced significantly longer immobilization times (52.5 +/- 25.7 min and 60.6 +/- 20.8 min, respectively) than did the lower doses (30/3, 40/4) (18.8 +/- 8.7 min and 31.0 +/- 14.3 min, respectively). The dose at which 50% of the bats were immobilized for > or = 30 min (ED(50)) was approximately 40 microg/kg/4 mg/kg. This dose produced a mean immobilization time of 31 +/- 14 min, bradypnea and bradycardia. In conclusion, a M/K dose of 50 microg/kg/5 mg/kg is recommended for greater than 30 min of relaxed immobilization in free-living variable flying foxes and is sufficient for safe collection of samples.     

Effect of mucin on the pharmacokinetics of antibiotics in the rat

The intramuscular pharmacokinetics of ticarcillin and amikacin in rats receiving 1 ml of 5% mucin suspension (equivalent to 250 mg/kg) administered intraperitoneally were not altered compared with the control animals. However, it is important to investigate the effect of mucin on the pharmacokinetics of antimicrobial agents in animals which are used to evaluate the efficacy of the agents.     

Chronopharmacokinetics of Imipenem in the Rat

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10∶00, 16∶00, 22∶00, or 04∶00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C_max, T_max, elimination half‐life (t_1/2), area under the concentration‐versus‐time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C_max (49%), T_max (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra‐individual variability.     

Relationship between doses of prostaglandin F2alpha and stages of the breeding season for synchronization of estrus and ovulation in ewes

Two experiments were conducted to compare estrous response to three doses (8, 16 and 24 mg) of prostaglandin F(2alpha) (PGF(2alpha)) administered by intramuscular injection to ewes between day 6 and 12 of the estrous cycle (Experiment I) and to ewes on unknown days of the estrous cycle during four different stages of the breeding season (Experiment II). In experiment I, a total of 41 ewes were treated with PGF(2alpha). The injection of 24 mg PGF(2alpha) resulted in a higher proportion of ewes exhibiting estrus (13 14 , 92.9%) within 5 days after treatment as compared to the other two doses (2 12 and 10 15 , for 8 and 16 mg PGF(2alpha), respectively). However, there was no significant difference for the proportion between 16 mg and 24 mg PGF(2alpha). In experiment II, PGF(2alpha) was given to ewes on the 3rd of February (early breeding season), the 28th of February (mid-early breeding season), the 10th of April (mid breeding season) and the 27th of May (late breeding season). These was a significant difference for the proportion of ewes exhibiting estrus between the early breeding season and the other three seasons (P < 0.05) but not for ewes ovulating. Throughout the breeding season, 16 mg PGF(2alpha) appeared to be slightly better than the other two doses (8 and 24 mg) although there was no overall difference in the estrous responses to treatment among the three doses. However, a significant difference in the proportion of ewes ovulating was found among the three doses of PGF(2alpha) (P < 0.05). Especially, 16 mg PGF(2alpha) was significantly superior to 8 mg (P < 0.01) and 24 mg (P < 0.05). It was considered that there was a complicated relationship between the doses of PGF(2alpha) and the stages of the breeding season for induction of estrus and ovulation in the ewe.