Adjunctive topiramate enhances the risk of hypothermia associated with valproic acid therapy.

BACKGROUND: Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia. OBJECTIVE: We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia. METHODS: This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs. RESULTS: We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected. CONCLUSION: We have found hypothermia, defined as an unintentional drop in body core temperature to <35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.

Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management.

BACKGROUND AND OBJECTIVE: Older oncology patients with multiple comorbidities are at risk for adverse drug events associated with polypharmacy and drug-drug interactions due to patients' altered pharmacokinetic/pharmacodynamic status and the narrow therapeutic windows associated with anti-neoplastic agents. This study addresses the issue of polypharmacy and potential drug-drug interactions in outpatients in a community setting in the USA, and the prescribing behaviour of oncologists after being made aware of potential drug-drug interactions. METHODS: We performed a retrospective cohort study in patients with multiple comorbidities exposed to chemotherapy to profile the potential for adverse drug reactions and to define physicians' responses to risks arising from drug interactions. The medical records of 100 patients aged >or=70 years receiving chemotherapeutic agents at a community-based, university-affiliated medical practice were randomly selected and reviewed. Drug class usage was quantified, and potential drug-drug interactions were assessed and categorized. Treating oncologists were encouraged to modify their prescriptions on the basis of potential interactive drug evaluation reports. Physicians' responses were catalogued. RESULTS AND DISCUSSION: The mean age of the study population was 78 years (range, 70-90 years). Patients had an average of three comorbid conditions. Each patient received an average of 9 x 1 medications. Cardiovascular drugs were the most common medications that patients used to treat chronic conditions. Carboplatin and paclitaxel were the most frequently used chemotherapeutic agents. Inspite of the potential for drug-drug interactions, physicians made no adjustments to prescriptions. CONCLUSION: Given that polypharmacy and the chronic use of multiple drugs are a reality for older patients with cancer and polymorbidities, outcome data need to be generated and motivations/incentives provided for physicians to optimize safe and effective supportive oncologic therapeutics.

Ischemic colitis and sumatriptan use.

Sumatriptan succinate, a serotonin-1 (5-hydroxytryptamine-1) receptor agonist, is an antimigraine drug that is reported to act by selectively constricting intracranial arteries. Recently, vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic, pulmonary, and coronary circulations. Cases have been published of coronary vasospasm, myocardial ischemia, and myocardial infarction occurring after sumatriptan use. We report on the development of 8 serious cases of ischemic colitis in patients with migraine treated with sumatriptan.

Follicular growth and production of estrogen and progesterone after injection of gilts with human chorionic gonadotropin on day 12 of the estrous cycle.

Twenty cyclic gilts were injected im with either saline (control) or 1,000 IU of human chorionic gonadotropin (hCG) on d 12 of the estrous cycle to determine the effects of hCG on follicular development and steroidogenesis. Blood was collected when gilts were sacrificed on d 13 or 16. Follicles were classified as medium (3 to 6 mm in diameter) or large (greater than 6 mm diameter), dissected from the ovary, measured and weighed. Pieces of follicle wall were incubated 3 h in Krebs Ringer bicarbonate buffer (KRB) on ice in an atmosphere of air or at 37 C in an atmosphere of 95% O2:5% CO2. Unconjugated estrogen and progesterone in blood plasma, follicular fluid and 10,000 X g supernatants of incubated follicular tissue homogenates were quantified by radioimmunoassay. On d 13 follicles on ovaries of control or hCG-injected gilts were less than or equal to 6 mm in diameter. On d 16, one of five control gilts had some large follicles, while all five hCG-treated gilts had large as well as medium follicles. On d 16 follicular fluid of large follicles from hCG-injected gilts contained twofold more estrogen and 40-fold more progesterone than medium follicles on the same ovaries. Tissue from large follicles of hCG-injected gilts produced more progesterone in vitro than did tissue from medium follicles (P less than .05), but estrogen production did not differ. On d 16 medium follicles from control or hCG-injected gilts were larger, contained more estrogen and less progesterone than those recovered on d 13 (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of sex hormones on glucose-6-phosphate dehydrogenase in rat levator ani muscle.

We studied the influence of sex hormones using the hormone-sensitive levator ani muscle as a model tissue and glucose-6-phosphate dehydrogenase as an indicator of hormone action. Injection of testosterone or estradiol cause a 50% increase in the specific activity of glucose-6-phosphate dehydrogenase. The effect was dose-dependent, and was maximal at a dose of 2.5mg/100g body weight. Estradiol increased glucose-6-phosphate dehydrogenase as early as 8 h after injection, while testosterone required 12 h. Injection of estradiol on 2 successive days increased enzyme activity by 80%. The effect of estradiol was abolished by actinomycin D, suggesting enzyme induction. The results indicate a direct effect of estrogen on striated muscle.

Aromatization of androgens to estrogens mediates increased activity of glucose 6-phosphate dehydrogenase in rat levator ani muscle.

Administration of testosterone propionate to immature male rats caused a 50% increase in the specific activity of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway, in the levator ani muscle. This effect appears to be mediated by conversion of testosterone to estradiol because of the following results: 1) the effect was not mimicked by the nonaromatizable androgens fluoxymesterone or 5 alpha-dihydrotestosterone; 2) it was mimicked by 17 beta-estradiol and diethylstilbestrol; 3) it was blocked by an estrogen antagonist but not by an androgen antagonist; 4) the inactive steroid 17 alpha-estradiol was without effect on glucose 6-phosphate dehydrogenase; and 5) the effect of testosterone was blocked by an inhibitor of androgen aromatase. These results demonstrate a direct effect of estrogen on striated muscle.

follicular fluid electrolytes and osmolality in cyclic pigs.

Sodium and osmolar concentrations of porcine folliclar fluid in the cyclic pig did not vary significantly during the oestrous cycle, and were similar to those in plasma. The K+ concentration was greater in small (Days 12-13) and medium-sized (Day 16) follicles than in plasma or large (Day 18-oestrus) follicles of cyclic sows. In contrast, follicular fluid obtained from slaughterhouse material had higher potassium and osmolality, and lower sodium values, which are assumed to be due to post-mortem changes.

Estrogen (EB) and EB + progesterone (P) induced changes in pituitary sodium, potassium adenosine triphosphatase activity (ATPase).

Estradiol-benzoate (EB) injected into previously ovariectomized (OVX) rats, increased pituitary ATPase activity 69% over controls, within one hour of treatment. Twelve hours after injection, ATPase activity was not significantly different from controls. Progesterone [(P): 5mg/100gBW] administered in conjunction with EB elicited an analogous response. AT at time of EB and EB+P induced increments in pituitary ATPase activity, plasma LH levels were dramatically reduced to normal, intact diestrous control levels. Post-castrational elevations in FSH were also suppressed after one hour of treatment with EB, but not following EB+P administration. The results suggest that the inhibitory actions of EB and EB+P on post-castrational LH levels may be related to modulation by these steroids of pituitary membrane ATPase activity.

Initiation of precocious sexual maturation in the immature rat treated with dehydroepiandrosterone.

Administration of dehydroepiandrosterone (DHA) to immature female rats on day 27 for 3 days resulted in an increase in uterine weight within 6 h of injection and a surge of FSH, LH and prolactin occurred on day 30 resulting in premature ovulation. Increase in ovarian weight and vaginal patency also occurred on day 30. Ovulations occurred at various times on day 30 and some as late as day 33 and these could be synchronized by the administration of pregnant mare serum gonadotropin (PMSG). The gonadotropin surge resulting in ovulation could be blocked by central nervous system blocking agents like phenobarbital and reserpine. The action of DHA in inducing precocious ovulation appeared to be mediated through conversion to estrogens because DHA and testosterone both of which can be aromatized to estrogens at appropriate dose elvels caused potentiation of the effect of PMSG on the secretion of gonadotropins. They also induced vaginal patency in the castrated immature rat. Dihydrotestosterone, an androgen not aromatized to estrogens did not induce precocious ovulation, vaginal patency or potentiation of the effect of PMSG in the release of gonadotropins. Furthermore, cyanoketone an inhibitor of 3beta-hydroxysteroid dehydrogenase and thus the conversion of DHA to estrogens, prevented vaginal patency and DHA-induced precocious ovulation.

Dehydroepiandrosterone-induced polycystic ovaries and acyclicity in the rat.

Administration of dehydroepiandrosterone (DHA) to the immature female rat resulted in one precocious ovulation followed by ovulatory failure. The animals exhibited either "constant-estrus" or "constant-diestrus" vaginal smears, and the ovaries were either polycystic or contained corpus luteum-like structures. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels showed an ovulatory type surge on day 30, at the time of the precocious ovulation. Thereafter, serum FSH levels were comparable to those of control rats, whereas the LH levels were very low. Serum prolactin was elevated significantly in DHA-treated animals. The ovaries of DHA-treated animals were responsive to gonadotropins and the pituitary was responsive to luteinizing hormone-releasing hormone. Withdrawal of androgen treatment resulted in restoration of cyclicity. This animal model demonstrates that an androgen insult can cause ovulatory failure and polycystic ovaries in spite of normal ovaries, adrenals, and hypothalamic-pituitary mechanisms. That such ovulatory failure is a result of the androgen administration is further substantiated by restoration of cyclicity after androgen withdrawal. This animal model in several ways is similar to the human polycystic ovary syndrome and has a potential application in the study of the mechanism of androgen-induced ovulatory failure.