A Novel Tertiary Pyridostigmine Derivative [3-N,N-Dimethylcarbamyloxy)-1-Methyl-{Delta}3-Tetrahydropyridine]: Anticholinesterase Properties and Efficacy against Soman

In an effort to develop an effective centrally acting pretreatmentcompound against organophosphorus poisons, the tertiary pyridostigmine(Pyr) derivative 3-(N,N-dimethyI-carbamyloxy)-l-methyl-³-tetrahydropyridine(THP) was synthesized and studied for its anticholinesteraseproperties, as well as its efficacy against soman intoxicationin guinea pigs. Injection of THP (262 µg/kg, im) intoadult male guinea pigs caused inhibition of Wood (30%) and brain(25%) acetylcholinesterase (AChE), showing that THP penetratesthe blood-brain barrier. Pyr (131 µg/kg, im) caused AChEinhibition in the Hood (59%), but not in the brain. The inhibitorypotencies of THP and Pyr were compared by determining theirIC50 values for in vitroinhibition of both AChE (brain, erythrocyte)and pseudo-cholinesterase (plasma) in three mammalian species(guinea pig, rat, rabbit). THP, although effective in inhibitingboth types of cholinesterase, was in general less potent thanPyr. Pretreatment of guinea pigs with THP (262 µg/kg,im) plus Pyr (131 µg/kg, im). 30 min prior to subcutaneoussoman challenge, with no antimuscarink or oxime treatment, protected60% of the animals against 2 ? LD50 of soman. Neither THP norPyr alone was effective. The protective pretreatment regimendid not prevent convulsions, but shortened the recovery timein surviving animals (median recovery time 1.6 hr, comparedto 24 hr in control and other groups of animals pretreated withTHP or Pyr alone). A combination of THP and Pyr thus appearsto provide a means of evaluating the relative importance ofselective peripheral plus central vs peripheral AChE protectionagainst soman.     

Use of Bromoergocryptine in the Validation of Protocols for the Assessment of Mechanisms of Early Pregnancy Loss in the Rat

Use of Bromoergocryptine in the Validation of Protocols forthe Assessment of Mechanisms of Early Pregnancy Loss in theRat. CUMMINGS, A. M., PERREAULT, S. D., AND HARRIS, S. T. (1991).Fundam. Appl. Toxicol 17, 563–574. Validated protocolsfor evaluating maternally mediated mechanisms of early pregnancyfailure in rodents are needed for use in the risk assessmentprocess. To supplement previous efforts in the validation ofa panel of protocols assembled for this purpose, bromoergocryptine(BEC) was used as a model compound because it is known to inhibitpituitary prolactin secretion. BEC was tested using the earlypregnancy protocol (EPP), the decidual cell response technique(DCR), the pre- vs postimplantation protocol (PPP), and embryotransport rate analysis (ETRA). These protocols evaluate theeffects of chemicals on multiple endpoints following exposureduring (a) the first 8 days of pregnancy, (b) early pseudopregnancyaccompanied by decidual induction, (c) the pre- and postimplantationintervals of early pregnancy, or (d) the period of embryo transport.In the EPP, dosing with BEC during Days 1–8 of pregnancyreduced the number of implantation sites found on Day 9 as wellas serum progesterone. The DCR technique revealed a dose-dependentinhibition of decidual growth concomitant with decreased serumprogesterone as a result of BEC treatment. A modified DCR techniqueusing hormone-supplemented ovariectomized rats demonstratedthat BEC did not impair decidual growth in the presence of adequateprogestogenic support. Pie- vs postimplantation dosing indicatedthat implantation is vulnerable to BEC effects at least throughDay 4. BEC had no effect on embryo transport rate. Data fromthese protocols identified BEC as having adverse maternal effectsduring early pregnancy. While the pituitary was not identifiedby these protocols as the site of BECs's primary action, theprotocols did identify a reduction in serum progesterone andimpaired uterine function as toxicological mechanisms mediatingthe reduced fertility seen following BEC exposure.     

MORTALITY OF JAMAICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

A retrospective study of all patients with systemic lupus erythematosus(SLE) who died at the University Hospital of the West Indiesover a 14-year period is presented. The major cause of deathwas infection followed by renal failure. Gram-negative organismswere the major microbiological agents causing infections. Side-effectsof therapy were common, in particular bone marrow depressionand haemorrhage related to anticoagulants. It appears that controllingsevere lupus activity without increasing the risk of life-threateningcomplications remains an important goal in the treatment ofSLE. KEY WORDS: Systemic lupus erythematosus, Mortality, Infection, Anticoagulants, Jamaica     

PROGNOSTIC VALUE OF ANGIOGENESIS IN OPERABLE NON-SMALL CELL LUNG CANCER

Tumour angiogenesis is an important factor for tumour growth and metastasis. Although some recent reports suggest that microvessel counts in non-small cell lung cancer are related to a poor disease outcome, the results were not conclusive and were not compared with other molecular prognostic markers. In the present study, the vascular grade was assessed in 107 (T1,2–N0,1) operable non-small cell lung carcinomas, using the JC70 monoclonal antibody to CD31. Three vascular grades were defined with appraisal by eye and by Chalkley counting: high (Chalkley score 7–12), medium (5–6), and low (2–4). There was a significant correlation between eye appraisal and Chalkley counting ( P <0·0001). Vascular grade was not related to histology, grade, proliferation index (Ki67), or EGFR or p53 expression. Tumours from younger patients had a higher grade of angiogenesis ( P =0·05). Apart from the vascular grade, none of the other factors examined was statistically related to lymph node metastasis ( P <0·0001). A univariate analysis of survival showed that vascular grade was the most significant prognostic factor ( P =0·0004), followed by N-stage ( P =0·001). In a multivariate analysis, N-stage and vascular grade were not found to be independent prognostic factors, since they were strongly related to each other. Excluding N-stage, vascular grade was the only independent prognostic factor ( P =0·007). Kaplan–Meier survival curves showed a statistically significant worse prognosis for patients with high vascular grade, but no difference was observed between low and medium vascular grade. These data suggest that angiogenesis in operable non-small cell lung cancer is a major prognostic factor for survival and, among the parameters tested, is the only factor related to cancer cell migration to lymph nodes. The integration of vascular grading in clinical trials on adjuvant chemotherapy and/or radiotherapy could substantially contribute in defining groups of operable patients who might benefit from cytotoxic treatment.