Antihistamines Block Radiation-Induced Increased Intestinal Blood Flow in Canines

Antihistamines Block Radiation-Induced Increased IntestinalBlood Flow in Canines. COCK-ERHAM, L. G., DOYLE, T. F., DONLON,M. A., AND GOSSETT-HAGERMAN, C. J. (1985). Fundam. Appl. Toxicol.5, 597–604. Radiation-induced systemic hypotension isaccompanied by increased intestinal blood flow (IBF) and anincreased hematocrit (HCT) in dogs. Histamine infusion leadsto increased IBF and intestinal edema with consequent secretionof fluid into the intestinal lumen. This study was performedto determine whether these effects could be diminished by prioradministration of H₁ and H₂ histamine blockers. Dogs were givenan iv infusion of mepyramine (0.5 mg/min) and cimetidine (0.25mg/min) for 1 hr before and for 1 hr after radiation (H₁ andH₂ blockers, respectively). Mean systemic arterial blood pressure(MBP), IBF, and HCT were monitored for 2 hr. Systemic plasmahistamine levels were determined simultaneously. Data obtainedindicated that the H₁ and H₂ blockers, given simultaneously,were successful in blocking the increased IBF and the increasedHCT seen after 100 Gy, whole-body, radiation. However, thepostradiation hypotension was only somewhat affected, with theMBP falling to a level 28% below the preradiation level. Plasmahistamine levels reached a sharp peak, as much as 20% abovebaseline, at 4 min postradiation. These findings implicate histaminein the radiation-induced increase in IBF and HCT but not forthe gradual decrease in postradiation blood pressure     

Effect of Chronic Aromatase Inhibition by Δ1 -Testolactone on Pituitary-Gonadal Function in Oligozoospermic Men

Aromatase inhibition by delta 1-testolactone (Teslac, 500 mg twice daily) for 6 months in 9 patients with idiopathic oligozoospermia lowered the levels of serum estradiol (E2) and thereby sex hormone binding globulin (SHBG) (rS = +0.40, p less than 0.025) to values -35 and -25%, respectively, below the pretreatment values (P less than 0.001 and less than 0.005). The E2 decrease was accompanied by a temporary increase (+50%) in the levels of follicle stimulating hormone (FSH), not of luteinizing hormone (LH), and of 17 alpha-hydroxyprogesterone (17 alpha-OHP), but less of testosterone (T) (+30%), which led to a transient rise in the 17 alpha-OHP/T ratio. The T/E2 ratio and "free T" index (T/SHBG) almost doubled until the end of the treatment period. During delta 1-testolactone treatment the mean sperm density gradually rose from 8.1 +/- 1.3 (SEM) before to 21.3 +/- 6.7 X 10(6)/ml after 6 months (P less than 0.01), whereas the total sperm count almost threefold increased (P less than 0.05). Sperm concentrations exceeding 20 X 10(6)/ml were achieved in 4 of the 9 patients. Two of these patients' wives became pregnant. Although the data point to a pivotal role of estrogens in the pathogenesis of the spermatogenic lesion in some patients with idiopathic oligozoospermia, the lack of a beneficial effect of estrogen lowering in others points to a multicausal nature of the disease entity.     

Human Soluble Antigens and Their Use in Sperm Antibody Testing*

ABSTRACT: Efforts were made to disrupt and solubilize human sperm cells and to evaluate the product for its content of infertility antibody-related antigens. In the procedure that was developed, a well-washed sperm sample is treated with 0.1 M dithiothreitol for 60 min, followed by trypsin at 0.1 mg/ml for 30 min, and then by soybean trypsin inhibitor. A mixture of DNAses I and II are added. After centrifuging, the resuspended pellet (RP) and the final supernatant (FS) show several degrees of cellular breakdown. Immunological evaluation was done with a strongly positive human serum containing sperm-head antibody. From the inhibition of sperm agglutination, we could conclude that the desired soluble antigen was obtained in the FS fraction.     

Aldicarb Immunotoxicity: Functional Analysis of Cell-Mediated Immunity and Quantitation of Lymphocyte Subpopulations

Aldicarb Immunotoxicity: Functional Analysis of Cell-MediatedImmunity and Quantitation of Lymphocyte Subpopulations. THOMAS,P., RATAJCZAK, H., DEMETRAL, D., HAGEN, K., AND BARON, R. (1990).Fundam. Appl. Toxicol. 15, 221–230. Adult female B6C3F1mice received distilled water only or water containing 1.0,10, or 100 ppb of aldicarb daily for 34 days. The target concentrationof aldicarb present in the 100 ppb dosing solution was analyticallyverified. To further develop an immune profile of this compound,following aldicarb exposure, the ability of splenic naturalkiller cells and specifically sensitized cytotoxic T-lymphocytesto lyse YAC-1 lymphoma and P815 tumor cells, respectively, wasevaluated. To supplement the functional assays, the impact ofaldicarb exposure on the percentages and absolute numbers oftotal T-cells, T-suppressor, T-helper, and B-cells was evaluated.The absence of statistically significant effects on any of theseparameters supports earlier reports that aldicarb does not resultin adverse effects on the immune system of mice.     

Subchronic Oral Toxicity Study of Diisopropyl Methylphosphonate in Mink

Diisopropyl methylphosphonate (DIMP), produced during manufactureof the chemical agent GB (Sarin), is a groundwater contaminantat Rocky Mountain Arsenal, Colorado. DIMP was fed for 90 daysto dark brown "Ranch Wild" mink housed under controlled indoorconditions. One-year-old mink, 10 of each sex, were fed 0, 50,450, 2700, 5400, or 8000 ppm in standard ranch diet. ActualDIMP consumption was 0, 8, 73, 400, 827, and 1136 mg/kg bodywt/day, respectively. Two additional groups of 10 served as"pair-fed" controls. Body weight and food intake were recordedweekly. Complete blood count and 15 chemical analytes were measuredat Weeks 0, 3, 7, and 13. Necropsy and microscopic examinationwere performed on all mink. No clinical morbidity or deathsoccurred. Both sexes fed 8000 ppm ate approximately 20% lessand weighed approximately 20% less than the controls; 5400 ppmfemales had a 10% weight decrement. Plasma cholinesterase (ChE)decreased in the top three dose groups starting at Week 3. At13 weeks, decrements were approximately 50% but returned tonormal after 1 week without DIMP. Erythrocyte ChE was not reduced.Heinz bodies occurred in 10–15% of RBCs in 50% of 8000ppm mink at 13 weeks, and 0.1–2.0% of RBCs in 25% at 2700ppm. There were mild decreases in RBC count, hematocrit, andhemoglobin, and increases in reticulocyte count, at the 5400and 8000 ppm doses. All recovered within 3 weeks after DIMPwas with drawn. The 8000 ppm group had marginal splenic hematopoiesis,histologically. No other treatment-related changes were noted.The 450 ppm dose was a clear no-effect level (approximately73 mg DIMP/kg body wt/day). Compared to reports of similar studiesof DIMP in rats and dogs, these mink displayed no unique speciessusceptibility.     

Carisoprodol: Reproductive Assessment by Continuous Breeding in Swiss Mice

Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant,was evaluated for reproductive toxicity in Swiss CD-1 mice usingthe Reproductive Assessment by Continuous Breeding (RACB) protocol.Male and female mice were given CARI in corn oil suspensionby daily gavage at doses of 0, 300, 750, and 1200 mg/kg bodywt/day. Clinical signs of general toxicity in Fo animals includedsedation, primarily in the high-dose group during the firstweek of exposure, and reduced body weight in high-dose females.CARI administration for 14 weeks did not affect the abilityof the F₀ animals to produce litters. However, decreases inproportion of pups born alive (4%) and absolute (5%) and adjustedlive pup weight (7%) were observed at 1200 mg/kg CARI when comparedto controls. In a crossover mating trial to determine the affectedsex, there were no significant differences in the measured reproductiveparameters. CARI at the high dose increased the proportion oftime spent in proestrus and estrus, but cycle length was unaffected.At F₀ necropsy (Week 27 of treatment), all sperm parameterswere normal. Right epididymis and liver weights, relative tobody weight, were increased (12 and 23%, respectively) overthe control group for high-dose males. A mating trial to determinethe fertility and reproductive competence of the F₁ generationshowed no effect of CARI on indices of mating, pregnancy, orfertility, the proportion of F₂ pups born alive, the sex ratioof live F₂ pups, live F₂ pup weight, or gestation length. However,decreases in the number of F₂ pups per litter (22%) and adjustedlive F₂ pup weight (8%) were observed in the high-dose group.Indications of generalized toxicity in the F₁ generation includeddecreased survival through Postnatal Day 21 at 750 (5%) and1200 (9%) mg/kg CARI, and transiently decreased body weightsduring postnatal development and as adults for males and femalesat all dose levels. At necropsy, there was no effect of treatmenton the relative weight of any male or female reproductive organs;testicular spermatid concentration was reduced at all levelsof CARI. Relative liver weight was increased for females at300 mg/kg and for males and females at both 750 and 1200 mg/kg.In summary, CARI produced generalized toxicity and moderateeffects on the reproductive processes of F₀ and F₁ generationSwiss mice during chronic exposures of up to 1200 mg/kg/day.     

Absorption, Metabolism, and Excretion of N,N-Diethyl-m-toluamide Following Dermal Application to Human Volunteers

The absorption, metabolism, and excretion of N,N-diethyl-m-toluamide(DEET) in male human volunteers following dermal applicationof |¹⁴C|DEET was studied. DEET was applied to two groups ofsix volunteers either as the undiluted technical grade materialor as a 15% solution in ethanol. The material was applied overa 4 x 6-cm area on the volar surface of the forearm and wasleft in contact with the skin for 8 hr, then rinsed off theskin. Application sites also were tape stripped at 1, 23, and45 hr after rinsing. Serial blood samples and all urine andfeces were collected for 5 days after application. Aliquotsof these materials were analyzed for total radioactivity inorder to define absorption and excretion patterns. Urine samplesalso were analyzed by HPLC to characterize the metabolic profileand/or to identify metabolites. Absorption of DEET as evidencedby plasma radioactivity occurred within 2 hr after dose application.Elimination of radioactivity from plasma was rapid and quantifiablelevels of radioactivity were observed in plasma for only 4 hrafter the end of the 8-hr exposure period. Urine was the principalroute of excretion of radioactivity and accounted for an averageof 5.61 and 8.33/ of the applied dose in the undiluted DEETand 15/ DEET in ethanol groups, respectively. Excretion of radioactivityin the feces was less than 0.08/ of the applied dose in bothgroups. DEET did not accumulate in the superficial layers ofthe skin as evidenced by low amounts of radioactivity in thetape strippings. The major fraction of the applied radioactivitywas recovered in the skin rinses. Absorbed DEET was completelymetabolized and six major metabolites were observed in urine.Two major urinary metabolites tenta tively were identified.Based upon the percentage of applied dose recovered in the excreta,dermal absorption of DEET ranged from 3 to 8% with a mean of5.6/ in the volunteers applied undiluted technical grade DEET.The corresponding values for the volunteers applied 15/ DEETin ethanol were 4 to 14/ and 8.4/, respectively.     

The Myocardial Lesions Produced by the Potassium Channel Opener Aprikalim in Monkeys and Rats Are Prevented by Blockade of Cardiac {beta}-Adrenoceptors

Aprikalim is a potent, specific, and selective opener of ATP-sensitiveK⁺ (K_ATP) channels. By virtue of this pharmacological property,aprikalim affords cardioprotection in experimental models ofischemia/reperfusion injury, and, at higher doses, also causesperipheral or coronary vasodilatation. Direct-acting peripheralvasodilators can cause myocardial lesions, particularly in ratsand dogs. However, unexpectedly, aprikalim produced this effectalso in monkeys. Thus, the primary aim of this investigationwas to assess whether in monkeys these myocardial lesions werethe direct or indirect consequence of the vascular effects ofaprikalim. Cyno-mologus monkeys were given the ß-adrenoceptorantagonist nado-lol (2 mg/kg po, twice daily) for 4 consecutivedays. On the third and fourth day of the experiment, they receivedaprikalim (1 mg/kg po). In another series, two monkeys carryingtelemetry transmitters for blood pressure and heart rate measurementswere also given aprikalim or its vehicle. Finally, aprikalim(1 mg/kg po for 2 days) or its vehicle was administered to ratswhich were concurrently treated with the ß-adrenoceptorantagonist atenolol (5 mg/ kg sc) or its vehicle. In cynomologusmonkeys, aprikalim produced focal and multifocal myocardialnecrosis of minimal to moderate intensity in or near the papillarymuscles of the left ventricle. These effects were abrogatedby nadolol. Similarly, necrotic lesions were caused by aprikalimonly in those rats which had not been pretreated with atenolol.In monkeys, aprikalim produced a marked and long-lasting decreasein aortic blood pressure, accompanied by an even more prolongedtachycardia. These results demonstrate that aprikalim can producemyocardial necrosis not only in rats but also in monkeys. Toour knowledge, this is the first time that such adverse effectsare reported for a vasodilator in monkeys. More importantly,these effects were prevented by blocking cardiac ß-adrenoceptors.Thus, the myocardial lesions produced by aprikalim may be attributedto its profound and prolonged hemodynamic effects.     

Dapsone in the treatment of lupus erythematosus

Dapsone yielded excellent therapeutic results in certain forms of lupus erythematosus (LE), whereas discoid lesions and the maculo-papular rash of the systemic and disseminated chronic forms of discoid LE remained uninfluenced by the drug. On the basis of these observations, we suggest the following indications for dapsone treatment in LE:

• 1 Vasculitic urticaria
• 2 Oral ulceratino
• 3 Non-scarring form of chronic LE
• 4 Chloroquine intolerance.