Nonclinical Toxicology Studies with Zidovudine: Acute, Subacute, and Chronic Toxicity in Rodents, Dogs, and Monkeys

In single dose acute toxicity studies in CD-1 mice and CD rats,the median lethal dose (MLD) for zidovudlne (ZDV) was >750mg/kg after iv dosing and >3000 mg/kg after po administration(recommended human dose is 100 mg every 4 hr while awake). Becauseof the short half-life in rats (0.8 hr), dogs (1.0 hr), andmonkeys (0.8 hr), the daily dose of ZDV in most studies wasgiven in two equal portions approximately 6 hr apart. Intravenousadministration of ZDV was well tolerated in beagle dogs at doselevels up to 42.5 mg/kg bid for 2 weeks and in CD rats at doselevels up to 75 mg/kg bid for 4 weeks. In a 2-week dose range-findingstudy in beagle dogs, cytostatic effects were noted at po doselevels of 62.5 to 250 mg/kg bid in certain tissues with rapidcell replication rates. In contrast, in 3-to 12-month oral toxicitystudies in CD rats and cynomolgus monkeys, the principal toxicologicfinding was reversible macrocytic normochromic anemia whichoccurred at 225–250 mg/kg bid in rats and 17.5–150mg/kg bid in monkeys. In the 12-month rat study, RBC was decreasedat 25 and 75 mg/kg bid. In the 12-month monkey study WBC wasslightly decreased at 150 mg/kg bid.     

Bacterial and Human Cell Mutagenicity and Mouse Lung Tumorigenicity of the Oxygenated Polynuclear Aromatic Hydrocarbon Phenalenone

Phenalenone (perinaphthenone) is a major oxygenated polynucleararomatic hydrocarbon (oxy-PAH) atmospheric pollutant formedfrom the combustion of fossil fuels. Mutagenicity of phenalenonewas measured in quantitative forward mutation assays with Salmonellatyphimurium TM677 and metabolically competent human B-lymphoblastoidcell lines (MCL-5 and hlAlv2 cells), and its tumorigenicitywas also assessed in a newborn mouse assay. Phenalenone wasmutagenic in Salmonella in the presence of rat liver postmitochondrialsupernatant (PMS) at a minimum detectable mutagen concentration(MDMC) of 12 /µg/ml, but was not mutagenic in the absenceof PMS at concentrations up to 100 /µg/ ml. Phenalenonewas not significantly mutagenic in either human cell line after28 hr treatment, although mutant fractions were increased bynearly fivefold in hlAlv2 cells (at the tk locus) exposed at30 µg/ml. However, after 72 hr treatment, phenalenonewas mutagenic at the hprt locus in hlAlv2 cells with an MDMCof 3 µg/ml Phenalenone was also tumorigenic in male BLU:Hamice with a lung tumor incidence of 33% 6 months after injectionwith 4.2 mg phenalenone, the highest dose tested. Lung tumormultiplicity in this treatment group was 0.5 tumor/mouse. Noincrease in lung tumors in female mice was observed. Indicesof lung tumor incidence (ED₅₀) and multiplicity (TM_1.0) formale mice were 29.3 and 34.9 µxmol, respectively. Thesedata suggest that phenalenone does not contribute significantlyto the mutagenicity or carcinogenicity of combustion emissionextracts.     

Method for identification and classification of single motor unit potentials in diagnostic electromyography

It is important to have an objective method for recording jaw muscle capacity such as EMG before, during and after treatment of muscle dysfunction and also for oral rehabilitation with dentures, implants or other types of restorations. Because measurements of motor unit potentials (MUPs) are needed in several areas of EMG analysis, algorithms have been developed in our laboratory for use in a small computer-aided system for semi-automatic detection and pattern recognition of MUPs. Based upon the test recordings it is suggested that a characteristic 'maximal voltage increase per microsecond during the spike-phase' can be used as a supplement to the more generally used parameter 'rise-time'. Examples are given of how the programs can be useful in the study of the functional anatomy of jaw muscles by recording normative values for MUPs and their recruitment patterns.     

Influence of indomethacin on the haemodynamic effects of lipopolysaccharide in rats

Summary— This study was undertaken to evaluate the influence of the cyclooxygenase inhibitor indomethacin on the time course of the haemodynamic effects of lipopolysaccharide (LPS) intravenous infusion (10 mg·kg⁻¹·h⁻¹) in anaesthetized rats. LPS infusion produced a rapid (within 10 min) and prolonged (over the 90 min observation period) fall in mean arterial blood pressure (MABP) and a decrease in the pressor responses to noradrenaline (NA, 0.1, 0.3 and 1 μg·kg⁻¹, intravenously [iv]) elicited 60 and 90 min after the onset of LPS infusion. Indomethacin (7 mg·kg⁻¹ iv 30 min prior to the onset of saline or LPS infusion), which by itself did not affect basal MABP nor reactivity to NA in control rats, significantly attenuated the fall in MABP observed within 20 min after the onset of LPS infusion (but did not significantly modify the hypotension observed between 30 and 90 min). Indomethacin also completely prevented the hyporeactivity to NA observed 60 min after the onset of LPS infusion, but it did so only partially at 90 min. Aortic rings removed from LPS or LPS + indomethacin-treated rats showed an identical profile of contractile reactivity (hyporesponsiveness to NA, relaxation to L-arginine, and restoration of the contractile response by methylene blue). These results suggest that in this model, cyclooxygenase products are involved in the early haemodynamic effects of LPS. However, they do not seem to play an obligatory role in the onset of longer term haemodynamic changes.     

Red Cell Membrane Lipid Peroxidation and Hemolysis Secondary to Phototherapy

ABSTRACT. The exposure of red cells to phototherapy light in the presence of a sensitizer (bilirubin) resulted in oxidative injury to the red cell membrane as manifested by a significant increase in the concentration of the products of lipid peroxidation (TBA reactants and diene conjugation) in the membrane and hemolysis. To induce a photo-oxidized membrane injury, the sensitizer (bilirubin) has to be membrane bound. Thus, by altering the availability of free bilirubin in the red cell suspension through changes in the molar concentration ratio of bilirubin to albumin, one is able to regulate the occurrence and extent of the oxidative red cell membrane injury. The clinical implications of these findings are discussed.     

Polyurethane Sheath Disintegration Causing Impaction of Pacer Lead and Shock during Attempted Removal

Steady traction to remove a lead whose polyurethane sheath had disintegrated caused displacement of the heart and caused hypotension; the bared lead uncoiled and impacted in the wall of the subclavian vein. The tension on the intrathoracic lead was relieved via immediate anterior thoracotomy and compartmentalization of the superior vena cava.     

Electromyographic activity of human masticatory muscles in normal young people. Statistical evaluation of reference values for clinical applications

Electromyographic activity of anterior temporal and masseter muscles was measured in 92 young healthy men and women with sound dentitions during rest position, contact in centric occlusion and clench. Male and female mean potentials were similar except in clench, where males had higher electromyographic levels. Mean pooled electromyographic potentials were 1.9 μV (TA) and 1.4 μV (MM) during rest position, 6.5 μV (TA) and 2.8μV (MM) during contact in centric occlusion. Mean maximum voluntary clench potentials were 181.9μV (TA) and 216.2 μV (MM) in men, 161.7 μV (TA) and 156.8 μV (MM) in women. Examined muscles were more asymmetric at low electromyographic activity (rest and centric occlusion) with the temporal muscle less asymmetrical than the masseter. In females temporal muscle activity tended to dominate at every contraction level, while in males masseter activity was stronger in clench, and temporal activity in centric occlusion and in rest position.