Acute, Distribution, and Subchronic Toxicological Studies of Succinate Tartrates

The estimated single-dose oral toxicity (50% lethality) of succinatetartrates (ST) was 2–3 g/kg in rats. ST produced minimalto moderate dermal irritation but no evidence of systemic toxicityin a standard acute percutaneous toxicity test in rabbits. STwas not an eye irritant in a standard rabbit low-volume eyeirritation test ST was not genotoxic in a series of six genotoxicitytests. A 14-day oral gavage study in rats at a dose range of0.05–1.0 g ST/kg/day produced only gastric irritation.The no-observed-effect level (NOEL) for gastric irritation was0.1 g/kg for males and 0.05 g/kg for females. A 28-day percutaneoustoxicity study in rabbits produced minimal to moderate dermalirritation and no adverse systemic effects at a high dose of450 mg ST/kg/day. Single-dose absorption, distribution, andelimination (ADE) studies in male rats showed that 10–15%of an oral dose and 1–3% of a dermal dose were absorbed.Approximately 98% of the orally administered ST was eliminatedas ¹⁴C in urine, feces, or expired CO₂ after 72 hr. Approximately80% of the dermally absorbed ¹⁴C dose was eliminated in urine,feces, or expired CO₂ after 72 hr. In conclusion, no adverseeffects were noted in acute toxicity, genotoxicity, or subchronictoxicity studies conducted with ST.     

Developmental Toxicity of Dichloroacetonitrile: A By-Product of Drinking Water Disinfection

Developmental Toxicity of Dichloroacetonitrile: A By-productof Drinking Water Disinfection. SMITH, M. K., RANDALL, J. L.,STOBER, J. A., AND READ, E. J. (1989). Fundam. Appl. Toxicoi.12, 765–772. Dichloroacetonitrile (DCAN), a by-productof drinking water disinfection formed by reactlon of chlorinewith background organic materials, was evaluated for its developmentaleffects in pregnant Long-Evans rats. Animals were dosed by oralintubation on Gestation Days 6=18 (plug = 0) with 0, 5, 15,25, or 45 mg/kg/day. Tricaprylin was used as a vehicle. Thehighest dose tested (45 mg/kg) was lethal in 9% of the damsand caused resorption of the entire litter in 60% of the survivors.Embryolethality averaged 6% per litter at the low dose and 80%at the high dose and was statistically significant at 25 and45 mg/kg/day. The incidence of soft tissue malformations wasdose related and was statistically significant at doses toxicto the dam (45 mg/kg). These anomalies were principally in thecardiovascular (interventricular septal defect, levocardia,and abnormalities of the major vessels) and urogenital (hydronephrosis,rudimentary bladder and kidney, fused ureters, pelvic hernia,cryptorchidism) systems The frequency of skeletal malformations(fused and cemcal ribs) was also, dose related and significantlyincreased at 45 mg/kg. The no-observed-adverse-effect dose fortoxicity in pregnant Long-Evans rats was established by statisticalanalysis to be 15 mg/kg/day.     

Investigation of feline brain anatomy for the detection of cortical spreading depression with magnetic resonance imaging

Cortical spreading depression (CSD) and peri‐infarct depolarisation (PID) are related phenomena that have been associated with the human clinical syndromes of migraine (CSD), head injury and stroke (PID). Nevertheless the existence of CSD in man remains controversial, despite the detection of this phenomenon in the brains of most, if not all, other animal species investigated. This failure to unambiguously detect CSD clinically may be at least partly due to the anatomically complex, gyrencephalic structure of the human brain. This study was designed to establish conditions for the study of CSD in the brain of a gyrencephalic species using the noninvasive technique of magnetic resonance imaging (MRI). The 3‐dimensional (3D) gyrencephalic anatomy of the cat brain was examined to determine the imaging conditions necessary to detect CSD events. Orthogonal transverse, sagittal and horizontal T₁‐weighted image slices showed that the marginal and suprasylvian gyri were the most appropriate cortical structures to study CSD. This was in view of (1) their simple geometry: (2) their lengthy extent of grey matter orientated rostrocaudally in the cortex: (3) their separation by a sulcus across which CSD spread could be studied and (4) the discontinuity in the grey matter in these regions between the right and left hemispheres dorsal to the corpus callosum. The structure suggested by the T₁‐weighted images was corroborated by systematic diffusion tensor imaging to map the fractional anisotropy and diffusion trace. Thus a single horizontal image plane could visualise the neighbouring suprasylvian and marginal gyri of both cerebral hemispheres, whereas its complex shape and position ruled out the ectosylvian gyrus for CSD studies. With the horizontal imaging plane, CSD events were reproducibly detected by animating successive diffusion‐weighted MR images following local KCl stimulation of the cortical surface. In single image frames, CSD detection and characterisation required image subtraction or statistical mapping methods that, nevertheless, yielded concordant results. In repeat experiments, CSD events were qualitatively similar in appearance whether elicited by sustained or transient KCl applications. Our experimental approach thus successfully describes cat brain anatomy in vivo, and elucidates the necessary conditions for the application of MRI methods to detect CSD propagation.     

Tγδ Cells and their Subsets in Blood and Synovial Tissue from Rheumatoid Arthritis Patients

We have examined the frequencies of T gamma delta cells in blood, synovial fluids, and synovial membranes of patients with rheumatoid arthritis (RA) and in blood from age-matched controls. Immunocytochemical and immunohistochemical techniques were used with monoclonal antibodies BB3 and A13 to define a major and minor blood subset of T gamma delta cells respectively. Together, these antibodies identify the majority (if not all) of the peripheral blood T gamma delta cells. Significantly lower levels of T gamma delta cells were found in the blood of RA patients compared with controls, whilst higher but not significant numbers were found in the synovial fluids of paired samples. Scattered T gamma delta cells were found only in some synovial membranes with a distribution similar to the T alpha beta cells. Analysis of the two different T gamma delta-cell subsets indicated a ratio of BB3 to A13 of about 5:1 in control and RA blood. However, this ratio was less than 1:1 in the RA synovial fluids and membranes. The migratory nature of the A13+ cells could account for their predominance in these sites. The possible pathological significance of these cells in the rheumatoid synovial fluid and synovial membranes is discussed.     

DIFFERING EFFECTS OF CARBOHYDRATE, FAT AND PROTEIN ON THE RATE OF ETHANOL METABOLISM

The rate of metabolism of ethanol in humans has been assessedby intravenous infusion of ethanol/saline under feedback controlto maintain a constant blood alcohol concentration. After equilibration,meals consisting predominantly of carbohydrate, fat or proteinwere eaten and changes in ethanol metabolic rate were found.Carbohydrate caused a significant increase in this rate andfat or protein caused small but non-significant decreases. Infusionof ethanol/saline resulted in a temporary fall in plasma freefatty acid levels and a steady rise in plasma triglycerides.The changes in alcohol metabolism following carbohydrate cannotbe accounted for by changes in insulin, free fatty acid or lactate/pyruvatelevels.     

PHARMACOKINETICS OF SINGLE-DOSE I.V.MORPHINE IN NORMAL VOLUNTEERS AND PATIENTS WITH END-STAGE RENAL FAILURE

Morphine 0.125 mgkg^–1 was administered i.v. to 11 normalsubjects and nine patients with chronic renal failure requiringregular haemodialysis. Plasma morphine concentrations were measuredusing high pressure liquid chromatography (HPLC). Although therewas considerable individual variation in both groups, mean plasmaconcentrations of morphine were significantly higher in thepatients with renal failure for 15 min after administration.The decay of plasma concentration fitted a three-compartmentmamillary pharmacokinetic model in all subjects. Derived values(mean $ SEM) of T^x, volume of distribution of the second compartment(V₂), total volume of distribution at steady state ( V^ss1) andtransfer rate constant from the first to the second compartment(k₁₂) were significantly different between groups. Mean valuesof terminal elimination half-life (T⁷) and total body clearancewere similar in the two groups. It was concluded that eliminationof unchanged morphine is not impaired significantly in patientswith chronic renal failure, although accumulation of morphine-3-glucuronideprobably occurs. Although the pharmacological effect of morphineis not related temporally to plasma morphine concentrations,the higher values in patients with renal failure may be implicatedin their increased sensitivity to the drug     

Effects of cholinesterase inhibitors on the neuromuscular blocking action of suxamethonium

Prolonged neuromuscular block occurs when suxamethonium is givenafter neostigmine or pyridostigmine; however, studies of edrophoniumand suxamethonium have yielded conflicting results. We havestudied, therefore, interactions between suxamethonium and allthree anticholinesterases in rats anaesthetized with pentobarbitone.After recovery from an initial bolus of suxamethonium, saline,edrophonium, pyridostigmine or neostigmine was administeredand a second dose of suxamethonium was then given. All threeanticholinesterases prolonged the duration of neuromuscularblock (90% suppression to 50% twitch recovery) to 127(SEM 9)%,127(10)% and 138 (11)% of baseline for edrophonium, pyridostigmineand neostigmine, respectively. Recovery index (25% to 75% twitchrecovery) was increased also to 125 (9)%; 149 (10%) and 185(15)% of baseline, respectively for the three drugs. Presented in part at the 1992 annual meetings of the AmericanSociety of Anesthesiologists and the California Society of Anesthesiologists.