Studies on Reproduction in Rats with Meclofenamate Sodium, a Nonsteroidal Anti-inflammatory Agent

Studies on Reproduction in Rats with Meclofenamate Sodium, aNonsteroidal Anti-inflammatory Agent. PETRERE, J. A., HUMPHREY,R. R., ANDERSON, J. A., FITZGERALD, J. E., AND DE LA IGLESIA,F. A. (1985). Fundam. Appl. Toxicol. 5, 665–671. Reproductionand teratology studies were performed in rats given meclofenamatesodium, a nonsteroidal anti-inflammatory agent. Dosages of 0,3, 6, and 9 mg/kg were administered orally as dietary admixturesin the Fertility and Perinatal-Postnatal studies. In the Teratologystudy, dosages of 10, 12, 15, and 20 mg/kg were administeredby intragastric intubation. In the Male-Fertility study no adverseeffects on fertility or litter and offspring parameters wereobserved in two generations. In the Female-Fertility and Perinatal-Postnatalstudies, maternal toxicity (death associated with intestinalulceration and adhesions) was particularly evident during lactation.Prolonged gestation periods, decreased weanling weights, andincreased weanling mortality were evident at dosages of 6 and9 mg/kg. Increased postimplantation loss occurred at 6 and 9mg/kg in the Term Sacrifice subgroup of the Female-Fertilitystudy. Fertility rates were unaffected and all other litterand offspring parameters of the F₁ and F₂ generations appearednormal. In the Teratology study no adverse effects on embryonicor fetal development were evident at maternally toxic dosagesup to 20 mg/kg. © 1985 Society of Texicology.     

Corticosterone concentrations in mice during ethanol drinking and withdrawal

Consumption of an ethanol-containing diet by mice resulted in a significant increase in circulating concentrations of corticosterone which was maintained for 8 days. There were no changes in the concentrations of plasma corticosterone binding globulin. Ethanol withdrawal symptoms followed the removal of ethanol from the diet and circulating corticosterone concentrations were further increased. There was no correlation between blood ethanol and glucocorticoid concentrations during the chronic ethanol treatment. Stress related to ethanol consumption may be of greater importance than the circulating ethanol concentrations in producing the elevation in plasma glucocorticoids.     

A Digital Timing and Display Unit for Intraoperative Mapping of Cardiac Arrhythmias

An inexpensive display and timing unit incorporating a multichannel signal delay has been developed for mapping the heart during electrophysiological surgery. It provides a continuous digital readout of the time relationships between 3 introcardiac electrograms and the surface electrocordiogram. The electrograms are displayed on a storage oscilloscope with an automatic erase facility. This unit is used to locate accessory atriventricular connections in the Wolff-parkinson-White syndrome, to map ventricular tachycardias and to locate the bundle of His. The design has been refined during 5 years of use in over 200 operative procedures.     

Dofetilide for Atrial Arrhythmias in Congenital Heart Disease: A Multicenter Study

Background: Very little is known about use of the class III antiarrhythmic dofetilide in patients with congenital heart disease (CHD).
Methods: A multicenter retrospective review of experience with dofetilide in CHD patients was undertaken.
Results: Twenty adults with CHD and refractory atrial arrhythmias were treated with dofetilide at four institutions over a 7-year period. Three (15%) experienced adverse effects during in-hospital initiation of dofetilide (two with torsade de pointes, one with excessive QTc prolongation) and were not continued on this therapy. The remaining 17 were discharged taking dofetilide, with either resolved or improved arrhythmia. One was lost to follow-up. Five subsequently discontinued dofetilide due to waning effectiveness, manifest by recurrence of their arrhythmias. Eleven (55%) remained on dofetilide at most recent visit, with a median follow-up of nearly 1 year. Seven of these 11, or 35% of the CHD patients originally started on dofetilide, experienced a complete resolution of their arrhythmia. The remaining four had breakthrough episodes of atrial arrhythmia, but remained on dofetilide. No patient experienced torsade de pointes after the in-hospital initiation period.
Conclusions: Used appropriately, dofetilide appears to be a viable adjunct to catheter-based ablation and alternative pharmacological approaches for the treatment of atrial arrhythmias in adult patients with congenital heart disease.     

Evaluation of the Immunotoxicity of Orally Administered 2-Methoxyacetic Acid in Fischer 344 Rats

Evaluation of the Immunotoxicity of Orally Administered 2-MethoxyaceticAcid in Fischer 344 Rats. SMIALOWICZ, R. J., RIDDLE, M. M.,ROGERS, R. R., COPELAND, C. B., LUEBKE, R. W., AND ANDREWS,D. L. (1991). Fundam. Appl. Toxicol. 17, 771–781. We previouslydemonstrated that the glycol ether 2-methoxyethanol (ME) isimmunotoxic in the rat. In this study, the immunotoxicity of2-methoxyacetic acid (MAA), the principal metabolite of ME,was evaluated in adult male Fischer 344 rats. Rats were dosedby gavage with MAA on 10 consecutive days at dosages rangingfrom 50 to 200 mg/kg/day. Thymic involution, in the absenceof body weight loss, was observed at 100 and 200 mg/kg/day MAA.Lymphoproliferative responses to the mitogens concanavalin A,phytohemagglutinin, and pokeweed mitogen were also reduced atthese dosages. The in vitro generated cytotoxic T lymphocyteresponse was reduced at 200 mg/kg/day MAA. The mixed lymphocytereaction and natural killer cell activity were unaffected byexposure to MAA. Enumeration of splenic lymphocyte populationsrevealed a reduction in the percentage of W3/25-positive cellsat 100 and 150 mg/kg/day and an increase in the percentage of0X39-positive cells at 200 mg/kg/day; however, no changes inthe absolute number of either of these subsets were observed.The plaque forming cell (PFC) response to trinitropheny-lipopolysaccharide(TNP-LPS) was suppressed at 50-200 mg/kg/day MAA, while thePFC response to sheep red blood cells (SRBQ was elevated at50 mg/kg/day. Immunization of rats with TNP-LPS or SRBC followedby oral exposure to MAA at 4 and 28 hr postimmunization resultedin the suppression of the PFC response to TNP-LPS and SRBC atdosages of 100 and 200 mg/kg and 200 and 400 mg/kg, respectively.Equal suppression of the PFC response to TNP-LPS was achievedat equimolar concentrations of ME and MAA. The effects of MAAon the immune system of the rat presented here are very similarto results reported from this lab for ME-induced immune alterations.These results, along with results of experiments in which ME-inducedsuppression of the PFC response to TNP-LPS was reversed by 4-methylpyrazole,an inhibitor of the oxidation of ME to MAA by alcohol dehydrogenase,indicate that MAA is the proximate immunotoxicant followingexposure to the glycol ether 2-methoxyethanol.     

Independent folding of autolytic fragments of thermolysin and their domain-like properties

High molecular weight autolysis products from thermolysin have been isolated and identified. The primary fragments correspond to residues 1 to 187–204 (21kD) and residues 187–204 to 316 (12kD), respectively. The fragments are both capable of independent refolding upon removal of denaturant. On the basis of these results, we suggest that the first step in the unfolding pathway of thermolysin involves unfolding of an interdomain region and domain separation. Bound calcium ions at sites 1, 2 and 4 play a major role in protecting the protein against both autolysis and unfolding, probably by stabilizing the interdomain region and enhancing domain-domain interactions.     

Coexisting Preexcitation Syndrome and Intermittent Heart Block Presenting as Neonatal Seizures

An infant presented with neonatal syncope and seizures. An ECG showed a preexcitation pattern, most compatible with Wolff-Parkinson-White (WPW) syndrome. Rhythm monitoring during an event demonstrated prolonged periods of complete AV block with no ventricular escape mechanism. We postulated that ventricular asystole was initiated by mechanical or autonomic influences on the accessory pathway and sustained by electrophysiologic interactions between the accessory pathway and the junctional escape focus. This is the first case report of a newborn having coexisting congenital AV block and WPW syndrome.