Pharmacokinetics of fusidic acid in laboratory animals.

The ability of evaluate the efficacy of fusidic acid in animal models of infectious disease is limited by the absence of pharmacokinetic data for the agent in laboratory animals. In our study, aspects of fusidic acid pharmacokinetics were compared in rats (Rattus norwegicus), mice (Mus musculus), rabbits (Oryctolagus cuniculus), and guinea pigs (Cavia porcellus). Sodium fusidate was poorly absorbed after oral administration to rats, although limited absorption occurred in guinea pigs, mice, and rabbits. Subcutaneous injections of diethanolamine fusidate to laboratory rats, however, achieved a serum profile similar to that observed in humans. There was no evidence of drug accumulation in rats given repeated subcutaneous doses of diethanolamine fusidate during a 4-day period, but rabbits showed clear evidence of a cumulative effect.     

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.     

Hydrocephalus in the laboratory rat

The state of hydrocephalus is applied to all conditions in which the intracranial volume of cerebrospinal fluid is abnormally large in relation to the volume of the brain. Increase in volume of cerebrospinal fluid raises the pressure and results in brain tissue atrophy and enlargement of the cranial vault. The condition can be hereditary or acquired and commonly arises from congenital malformations, inflammatory processes or expanding lesions such as tumours. The laboratory rat has an incidence of hydrocephalus of about 0.3% but no satisfactory indication of hereditary linkage. A small breeding unit of laboratory rats consisting of 2 males and 3 females produced 32 offspring of which 13 exhibited varying degrees of hydrocephalus. Examination indicated that the hydrocephalus was congenital in type, that 11 of the 13 hydrocephalic rats were proven males, that the remaining 2 were likely to be male, that female young were unaffected and that the incidence of the condition was 40.62%. Craniofacial examination showed that the cranial vault enlarged due to intracranial pressure and that the facial and basal components were mainly unaffected. The olfactory aspect of the frontal bone bulged slightly outwards, medial walls of orbits were laterally displaced, parietal and interparietal showed distention and their related sagittal and coronal sutures unfused and open to 1 mm in places. The basioccipital width showed a significant increase to the normal state. It is postulated that this particular congenital hydrocephalus in the rat is a normal autosome mutation, sex limited to males and one in which both males and females could transmit the trait to male progeny.     

Salmonella ochiogu: experimental infection of laboratory mice and oxytetracycline therapy

The oral infection of laboratory mice with 10(8) colony-forming units of viable Salmonella ochiogu bacteria resulted in clinical salmonellosis and death in 10 out of 45 of the mice (22%). None of the mice treated with oxytetracycline died. Infection in susceptible mice was characterized by septicaemia, respiratory involvement and mild enteritis. The organism was shed in the faeces from the first day after infection until day 30, and cultures from viscera showed systemic dissemination. S. ochiogu was recovered from the faeces of mice treated with oxytetracycline between days 1 and 9 post infection.     

The discovery of long acting beta2-adrenoreceptor agonists

The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.     

Effect of two long acting injectable progestogens on lactation in the human.

The effects of Depoprovera and Deladroxone were studied in humans, on certain milk components as well as on the growth of the nursed infants. Both drugs caused reduction in milk yield. Both drugs caused an increase in the concentration of milk total proteins, however. Depoprovera caused an increase while Deladroxone caused a decrease in the total amount of milk proteins per feed. Depoprovera showed no effect while Deladroxone caused an increase in the concentration of milk lipids; however, both drugs caused reduction in the total amount of milk lipids per feed. Both drugs showed no effect on the concentration of milk lactose, but caused reduction in the total amount of milk lactose per feed. The percentage increase in weight of nursed infants was decreased by Depoprovera, but not affected by Deladroxone.     

Ten-year long monitoring of laboratory mouse and rat colonies in French facilities: a retrospective study

From 1988 to 1997, a total of 69 mouse colonies and 36 rat colonies were examined for the presence of antibodies to 14 indigenous viruses of mice and rats. Among mouse viruses, high positivity rates were observed with mouse hepatitis virus (MHV), Theiler's encephalomyelitis virus (THEMV), minute virus of mice (MVM), Sendai virus and pneumonia virus of mice (PVM); the prevalence rates were high in rats with Khilam's rat virus (KRV), THEMV, Toolan's H-1 virus, Sendai virus, Parker's rat coronavirus (RCV/SDA) and PVM. During the last decade, the prevalence of some agents such as MHV, Sendai virus, THEMV, PVM and MVM has apparently decreased although they were still present in 1997 (except for PVM). Another point is the constant increase of colonies found free of viruses through this decade, demonstrating the efforts of the French research community to increase the quality of hygiene in laboratory animals.     

Anorectic properties of a new long acting serotonin uptake inhibitor

RU 25591 (6, 7, 8, 9-tetrahydro N, N-dimethyl 5-[4-nitrophenyl] oxy 5H-benzocyclohepten 7-amine) cis, fumarate a potent, selective and long acting serotonin uptake inhibitor was examined for anorectic properties. It was found that RU 25591 reduced food intake in rats, dogs and pigs. Kinetics in single dosed animals showed that the duration of RU 25591 food intake depression was shorter than in vivo serotonin uptake inhibition. In repeated dosing treatment a progressive time- related decrease in the inhibition of food consumption was observed which was more evident in pigs than in dogs. The anorectic activity of RU 25591 does not depend exclusively on its ability to block 5HT uptake. However available biochemical results do not enable us to understand its possible mechanism of action which is not classical and remains to be clarified in further experiments.     

Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma

In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.     

Photoperiodic response in the male laboratory rat

Normally photoperiodic laboratory rats can be induced to respond reproductively to a change in the length of the day by various experimental manipulations. One such paradigm that results in significant gonadal regression involves the treatment of rats with exogenous testosterone during exposure to short days. Studies were undertaken to assess various aspects of this model system including 1) the testicular response of testosterone-treated rats exposed to various photoperiods, 2) the time course for testicular regression under a short photoperiod, and 3) the role of the pineal gland as a mediator of the effects of day length on the neuroendocrine-gonadal axis. Photoperiods ranging in length from 2 to 22 h/24 h had no effect on testicular size in untreated rats. In contrast, while near normal testicular weights were maintained in laboratory rats treated with testosterone and exposed to 10 or more h of light per day, testicular regression occurred in rats implanted with testosterone-filled capsules and exposed to photoperiods of 8 or fewer h of light per day. Maximal testicular regression was reached in about 9 wk in testosterone-treated rats exposed to 6L:18D. Removal of the pineal gland totally blocked the inhibitory effects of exposure to short day lengths in testosterone-treated rats. These studies define some of the characteristics of an extant, but dormant, system for photoperiodic time measurement in the common laboratory rat and implicate a role for the pineal gland in this system. These experiments offer evidence that neuroendocrine factors that regulate continuous vs. seasonal reproductive patterns are malleable. Such flexibility in the photoperiodic response may also contribute to the evolution of seasonal to non-seasonal species and vice versa.     

Detection of a long acting endogenous opioid in blood and small intestine.

The blood of guinea-pigs and certain other species was found to contain two substances with opiate-like activity. These two substances could be separated by thin layer chromatography in a variety of solvent systems, which enabled them to be categorised as either fast or slow moving material. Although both substances caused a naloxone-antagonisable inhibition of the twitch tension of the electrically-stimulated myenteric plexus-longitudinal muscle strip from the guinea-pig ileum, the fast moving material differed in that its effect could only be reversed by many repeated washings of the preparation. Both fast and slow moving material were found to be 30 times less potent on the isolated mouse vas deferens than on the guinea-pig ileum preparation. The inhibiting effects of these opioids were not altered by incubation with either trypsin or pronase. An opioid was also detected in the fluid bathing strips of the guinea-pig ileum preparation. This opioid had similar properties to the fast moving material isolated from blood. The release of this material from strips of the guinea-pig ileum was not enhanced by electrical stimulation of the preparation.     

Interaction between aflatoxin B1 and oxytetracycline in isolated rat hepatocytes

Isolated rat hepatocytes were used as an in vitro model to investigate A possible interaction between oxytetracycline (OXT) and aflatoxin B₁ (AFB₁). LDH leakage, RNA and protein synthesis and glycogen accumulation were measured in the presence of both drugs, either separately or in combination. The evolution of LDH leakage during the incubation was identical in untreated and treated cells. AFB₁ inhibited RNA and protein synthesis at a concentration of 10^–7 M and 10^–6 M, respectively, and higher, whereas OXT did not influence RNA synthesis but inhibited protein synthesis at the highest tested concentration, 10^–3 M. As far as glycogen is concerned, rats were injected with glucagon before sacrifice in order to obtain a constant synthesis rate in isolated hepatocytes. AFB₁ inhibited the accumulation of glycogen from 10^–6 M upward. This effect was never observed before 90 min of incubation. OXT had no effect on glycogen synthesis. In the presence of both drugs, no interaction was demonstrated as far as RNA and protein synthesis were concerned, but OXT opposed the inhibition induced by AFB₁ on glycogen accumulation. If the in vivo protection, provided by OXT against AFBI-induced toxicity, is due to a direct interference in the toxic mechanisms of the mycotoxin, these results show that OXT does not influence the AFB₁-inhibition of RNA and protein synthesis. The latter are early and sensitive parameters inhibited by AFB₁. On the contrary, taking into consideration the results on glycogen accumulation, it seems more interesting to investigate further this metabolism.Abbreviations AFB₁ Aflatoxin B₁ - OXT Oxytetracycline - DMEM Dulbecco's Modified Eagle's Medium - LDH Lactate Dehydrogenase - DMSO Dimethyl Sulfoxide - BSA Bovine Serum Albumin     

Coprophagy in young laboratory rat

Coprophagy (ingestion of maternal faeces) was found in young laboratory rats between the ages of 16 and 28 days. The degree of this activity during the given period was not constant; a multiple increase on about the 25th day was followed by an abrupt drop and complete cessation coincided with the time of spontaneous weaning. Coprophagy did not appear in prematurely weaned young (at 16 days) which were given faeces and was protracted in undernourished young whose weaning time was prolonged. Young weaned rats without having ingested maternal faeces displayed relative hyperphagy for solid food. This early hyperphagy had later consequences for the feeding behaviour of adult males, which looked for food and consumed it more intensively in a new environment and also hoarded it. Defensive behaviour was not affected.     

Divergent effects of long acting cyclic nucleotides and lysine vasopressin on the release of matrix sulfated proteoglycans into the medium of fetal rat chondrocytes in monolayer culture

Release of sulfated proteoglycans into the medium of fetal rat chondrocytes in monolayer culture was studied by contrasting the effects of 10% calf serum, long-acting cyclic nucleotides (8 Br-cAMP or DBcAMP), and lysine vasopressin (LVP). Eight hours after initiation of the experiment, the monolayer was pulsed for 2 hours with Na2[35SO4=], the radioactivity was chased, and the monolayer was reincubated for 6 hours with conditioned medium from replicate cultures. Immediately after labelling, the amount of newly synthesized sulfated proteglycans was invariably higher in the insoluble matrix than in the medium compartment. Both additives selectively enhanced sulfate incorporation into chondroitin sulfate of the matrix when compared to serum controls, but only LVP stimulation caused increases in the medium. Remodeling (loss of cell layer and release into the medium at 6 hours) was suppressed by cAMP analogues and increased by LVP. This process was more active in cultures of lower cell density. Utilizing calibrated gel columns, no size difference of the glycosaminoglycans was found between the medium and cell layer compartments of the three treatment groups at the two time points. Because the cAMP analogues inhibit, while LVP stimulates cell division, our observations imply that the rate of degradation of the constraining matrix is increased when replication is favored, even when chondriotin sulfate synthesis is selectively stimulated.