ADX71943 and ADX71441, novel positive allosteric modulators of the GABA receptor with distinct central/peripheral profiles, show efficacy in the monosodium iodoacetate model of chronic osteoarthritis pain in the rat.

We tested novel positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABA), ADX71943 and ADX71441in the monosodium iodoacetate model of chronic osteoarthritis pain in rats with the objective to delineate the role of peripheral versus central GABA receptor populations in modulation of chronic pain. Anesthetized Sprague-Dawley rats received an injection of monosodium iodoacetate into the knee and were tested for hyperalgesia starting post-MIA day 14. Effects of compounds on ipsilateral joint compression threshold were evaluated on post-MIA day 14 (after acute treatment), as well as after repeated, daily treatment on days 21 and 28 (ADX71943 only) and were compared to those of celecoxib (30mg/kg, p.

The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring.

Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders.

There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy.

Overcoming the barriers to the uptake of nonclinical microsampling in regulatory safety studies.

Toxicokinetic analysis is an essential part of nonclinical drug development. Advances in bioanalytical techniques have opened up the potential to use smaller sample volumes (microsamples) to assess drug exposure in blood, plasma and/or serum. Microsampling can increase the amount of nonclinical safety information available, improve its validity by linking toxic effects to drug exposure in individual animals and represents the most significant opportunity to reduce animal use in toxicology studies in the short term.

The development and validation of an immunoassay for the measurement of anti-thymidine phosphorylase antibodies in mouse and dog sera.

Erythrocyte encapsulated thymidine phosphorylase (EE-TP) is under development as an enzyme replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a fatal metabolic disorder resulting from an inherited deficiency of the enzyme thymidine phosphorylase. We report here the development and validation of a sensitive electrochemiluminescent (ECL) bridging immunoassay to support Good Laboratory Practice (GLP)-compliant preclinical safety studies of EE-TP in the mouse and dog. Affinity-purified rabbit anti-E.

The pharmacokinetics and metabolism of sucralose in the rabbit.

The excretion and metabolism of (14)C-sucralose has been investigated in non-pregnant and pregnant rabbits after administration of single 10mg/kg oral doses. Means of 22% and 55% of the dose were excreted in urine and faeces, respectively, by non-pregnant animals during 5 days. Excretion was similar in pregnant animals with means of 22% and 65% of the dose in urine and faeces, respectively, during the same time.

The pharmacokinetics and metabolism of sucralose in the mouse.

The excretion and metabolism of (14)C-sucralose has been investigated in mice following intravenous and oral administration. A 20mg/kg intravenous dose was rapidly excreted mainly in the urine (80% in 5 days). After 100, 1500 and 3000mg/kg oral doses of (14)C-sucralose, means of 23%, 15% and 16% of the dose, respectively, were excreted in the urine during 5 days.

The pharmacokinetics and metabolism of sucralose in the dog.

The pharmacokinetics and metabolism of sucralose were investigated in dogs following intravenous or oral administration. Oral doses of (14)C-sucralose were rapidly absorbed, although there was some variation in the extent of absorption (range 18-48% of the dose). After intravenous or oral administration, radioactivity excreted in the urine was associated mainly with unchanged sucralose.

[Four-week intravenous toxicity study of montirelin hydrate (NS-3) in dogs followed by 4-week recovery test].

A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. The dogs were given the drug intravenously for 4 weeks at doses of 0 (control), 0.0002, 0.

Induction of rodent hepatic drug-metabolizing enzyme activities by the novel anticonvulsant remacemide hydrochloride.

Remacemide hydrochloride [FPL 12924AA; 2-amino-N-(1-methyl-1,2-diphenylethyl) acetamide hydrochloride] is being evaluated as a novel neuroprotective treatment for epilepsy and stroke. Preliminary safety evaluation studies in the rat have shown that repeated doses of the compound produce histological and biochemical changes consistent with hepatic enzyme induction. To examine this further, the levels and activities of the major drug metabolizing cytochrome P450 (CYP) subfamilies (CPY1, CYP2, and CYP3) were monitored in microsomal samples from male Sprague-Dawley rats dosed by gavage with FPL 12924AA (250 mg base.

Analgesic activity of the lysozyme peptide N-(N-L-threonyl-L-alpha-aspartyl)-L-tyrosine in the monkey and the dog.

N-(N-L-Threonyl-L-alpha-aspartyl)-L-tyrosine (CAS 115053-54-8, SPA-S-646) was originally derived from lysozyme. It has previously been found to have analgesic properties following oral and intravenous administration to laboratory rodents. In the rhesus monkey, intramuscular administration of SPA-S-646 caused a dose-related analgesia.

beta-Cyclodextrin: 52-week toxicity studies in the rat and dog.

A 52-wk toxicity study by dietary administration was performed in Sprague-Dawley rats and in pure-bred beagle dogs with beta-cyclodextrin, a starch derivative that acts as a molecular inclusion agent. Doses of 0 (control), 12,500, 25,000 and 50,000 ppm were selected for the rat study, and 0 (control), 6200, 12,500 and 50,000 ppm were selected for the dog study. The liver and kidney were identified at the histopathological examination as target organs for toxicity in the rat at doses of 50,000 and 25,000 ppm, with the hepatic changes associated with increased plasma liver enzyme and reduced plasma triglyceride concentrations.

General pharmacology of [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3- dihydro-1H-pyrrolizine-5-yl]-acetic acid in experimental animals.

[2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]-acetic acid (ML 3000) is a newly synthesized compound with analgesic, antipyretic and anti-inflammatory activity. The general pharmacological effects of ML 3000 following oral administration were investigated in experimental animals. The results showed that with regard to the CNS, ML 3000 did not affect behaviour in the Irwin test, locomotor activity or hexobarbital-induced sleep at doses of 30, 100 and 300 mg/kg.

Genotoxicity testing of pidotimod in vitro and in vivo.

The mutagenic potential of pidotimod ((R)-3-[(S)-(5-oxo-2- pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was assessed in a series of five assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays.

Mast cell distribution in mice.

A survey on the distribution of mast cells in mice was carried out. Mast cells were present in abundance in tongue and to a lesser extent in sciatic nerve. Fewer numbers of mast cells were seen in lymph nodes, e.

Mast cell distribution in rats.

A survey on the distribution of mast cells in healthy rats was carried out. Mast cells were present in abundance in mesenteric lymph nodes and tongue and to a lesser extent in sciatic nerve. Fewer numbers of mast cells were seen in other lymph nodes, heart, salivary gland, thymus, pancreas, cervix, vagina, uterus, epididymis, liver, skeletal muscle, ovaries, prostate, seminal vesicles, harderian glands, parathyroid, thyroid, mammary gland, skin, adipose tissue, preputial gland, tail and bone marrow.

Effect of the cephalosporin cefepime on hepatic drug metabolising enzyme activity in rats.

Oral doses of the new cephalosporin cefepime administered to rats for 14 days (40 mg/kg/day) did not affect the activities of the hepatic drug metabolising enzymes measured. By contrast there were highly statistically significant increases in all measured parameters in rats treated with phenobarbitone (80 mg/kg/day), the positive control. Control activities in male rats exceeded those in females by about 2-3 fold.

Antitussive effects of levodropropizine in the dog.

The antitussive activity of levodropropizine (S(-)3-(4-phenyl-piperazine-1-yl)-propane-1,2-diol, DF 526, CAS 99291-25-5) was evaluated after oral administration to the conscious dog. Levodropropizine had a good antitussive activity, comparable with, but having a longer duration of action than dropropizine, the racemate from which it is derived. The antitussive activity of levodropropizine in the dog was approximately 1/20 of that of codeine phosphate.

Fifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in dogs.

A 52-week toxicity study by oral administration (capsule) was performed in beagle dogs with nefiracetam (N-(2,6-dimethylphenyl)-2-(2- oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, as a part of a safety evaluation program. Dosages of 0 (control), 10, 30 and 90 mg/kg/d were selected for this study. Treatment-related findings were confined to the 90 mg/kg/d level and indicated the kidney and the testis as the main target organs for toxicity.

Fifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in rats.

A 52-week toxicity study by oral gavage administration was performed in Sprague-Dawley rats with nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, as a part of a safety evaluation program. Dosages of 0 (control), 10, 30, 100 and 300 mg/kg/d were selected for this study. Treatment-related findings were confined to the 300 mg/kg/d level and, to a lesser extent, the 100 and 30 mg/kg/d levels, with the investigations indicating the kidney as the main target organ for toxicity.

Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration.

1. The metabolic fate of N,N-dimethylcarbamoylmethyl 4-(4-guanidino[14C]benzoyloxy)phenylacetate methanesulphonate (14C-camostat mesylate) was investigated after i.v.

Evaluation of the mutagenicity of a-dihydroergocryptine in vitro and in vivo.

The mutagenic potential of the ergot alkaloid a-dihydroergocryptine (a-DEC, CAS 14271-05-7) was assessed in a series of 5 assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays.