Setting a local research agenda for women's health: The National Centers of Excellence in Women's Health.

Although women's health research expanded greatly in the past 10 years, significant gaps in knowledge remain. Prioritization and promotion of research will help assure continuing progress in closing such gaps and improving the health of women. Although a comprehensive agenda for the new millennium has been developed at the national level, the process for establishing a local research agenda is not well defined. The purpose of this study was to describe criteria for and barriers to establishing a local research agenda in women's health. A secondary aim was to describe mechanisms for identifying women's health researchers and for facilitating multidisciplinary research. Directors of Research at National Centers of Excellence in Women's Health (CoEs) (n = 18) were surveyed by mail for this information. The results indicate that the local research agenda should emphasize health issues that are prevalent in women, research that is likely to establish treatment, psychosocial/cultural factors, and quality of life issues. The process of setting a research agenda should include input from the communities served as well as from scientists. Critical evaluation of scientific strengths and weaknesses is an essential preliminary step in prioritizing research opportunities in order to implement and evaluate a research agenda in women's health.

Hormone replacement therapy in a postmenopausal woman with epilepsy.

OBJECTIVE: To prospectively evaluate the effects of hormone replacement therapy (HRT) on seizure activity in a postmenopausal woman with epilepsy. BACKGROUND: Postmenopausal women are at an increased risk for cardiovascular disease and osteoporosis secondary to a lack of estrogen's protective effects. As a result, women without known contraindications often take HRT to counteract this risk. Postmenopausal women with epilepsy are at a greater risk for osteoporosis because of the negative effects that certain antiepileptic drugs have on bone density. Clinical studies and experience have shown that hormonal variances across a woman's lifetime play a significant role in seizure activity, but the effects of HRT in postmenopausal women with epilepsy are unknown. CASE SUMMARY: We report the case of a 51-year-old postmenopausal white woman with epilepsy who presented with frequent vasomotor flushing. To determine individual effects of HRT on seizure activity, therapy was initiated in two three-month phases, with monthly evaluation. A weekly transdermal patch of estradiol 0.1 mg/d was initiated for the first three months. During the second three months, the regimen was expanded to include oral medroxyprogesterone acetate 2.5 mg once daily. Antiepileptic medications and their dosages remained constant. HRT was associated with a decreased incidence of seizures, cessation of vasomotor flushing, improved sleep, and a positive impact on the lipid profile. CONCLUSIONS: This case report describing the prospective addition of HRT in a postmenopausal woman with epilepsy suggests that HRT can be initiated in certain women to achieve therapeutic benefits without adversely affecting seizure activity.

Referral characteristics of primary care physicians for seizure patients.

PURPOSE: To investigate primary care physicians' behavior with respect to referral patterns, antiepileptic drug (AED) initiation, and level of comfort in managing seizure patients. METHODS: A cross-sectional descriptive study design was used for collecting and analyzing data. A 20-item survey was developed and mailed to 8,195 primary care physicians including family practitioners, internal medicine physicians, and obstetrics-gynecologists throughout the state of Ohio; 504 primary care physicians that interact regularly with epilepsy patients responded to the survey. RESULTS: Two patterns of referral emerged. Data showed that the majority (n = 382) of physicians refer >/=50% of their patients, but a minority of physicians (n = 122) refer <50% of their patients. Differences between the two groups existed in three of the four research questions asked: who initiates AED therapy, comfort level, and percentage of patients referred to a neurologist. Influence of managed care on decision making was not different between the two groups. CONCLUSIONS: A minority of primary care physicians rate themselves very comfortable with seizure patients. These same physicians refer a minority of their patients to a neurologist. As a whole, however, primary care physicians refer a majority of their seizure patients to a neurologist. Neurologists evaluate most seizure patients because most primary care physicians claim not to be extremely comfortable with evaluation and treatment of seizures. We conclude that neurologists play an essential role in the treatment of most seizure patients.

Alternative medicine use by patients with epilepsy.

Purpose. The objectives of this study were, first, to determine the prevalence, characteristics, and demographic patterns of alternative medicine (AM) use in patients with epilepsy, and second, to ascertain the extent to which these patients inform the neurologist of AM use. Methods. Surveys were distributed randomly to patients attending a tertiary care epilepsy clinic. The survey assessed use of specific herbal medicine/dietary supplements, along with other forms of AM. Results. Of 150 surveys distributed, 92 were used for analysis. Twenty-two patients with epilepsy (24%) used AM, and only 31% of AM users reported such to their neurologists. Massage and herbs/supplements were used the most, and only two patients used AM specifically for treatment related to epilepsy. Conclusions. A sizable minority of patients with epilepsy who visit our tertiary care clinic use AM. Health professionals should actively monitor therapies to ensure safety and effectiveness with combined traditional medicine and AM use.

Characterization and health risk assessment of postmenopausal women with epilepsy.

Postmenopausal women with epilepsy represent an understudied patient population. The objectives of this cross-sectional study were to characterize the impact of menopause on seizure activity and to conduct a health risk assessment. We conducted telephone interviews of 40 postmenopausal women with epilepsy concerning the effect of menopause on seizure frequency. We surveyed use of hormone replacement therapy, postmenopausal bone fractures, use of vitamins, and frequency of exercise. The average age and mean seizure duration were 55.8 and 27.6 years, respectively. Twenty-six women had onset of seizure activity before menopause. Of these 26, 3 reported fewer seizures after menopause, 7 reported more seizures, 11 reported no change, and 5 were unsure whether menopause affected their seizures. Only 30% of the 40 women were currently taking hormone replacement therapy. The impact of menopause on seizure activity was variable. Osteoporotic and cardiovascular preventive measures are underutilized. Patient education on these protective measures should be part of the comprehensive treatment approach in this "at-risk" patient population.

Assessing the needs of pharmacists and physicians in caring for patients with epilepsy.

OBJECTIVE: To obtain primary care physicians' and community pharmacists' opinions of the Pharmacist Note, a model epilepsy patient profile maintained by the pharmacist and transmitted to the physician as needed, and the information it contains. DESIGN: A cross-sectional descriptive study design was used for collecting and analyzing data. Separate surveys were developed and mailed to physicians and pharmacists. PARTICIPANTS: 554 primary care physicians and 114 community pharmacists in Ohio who interact regularly with epilepsy patients. MAIN OUTCOME MEASURES: Pharmacist and physician opinions on the Pharmacist Note program. RESULTS: Physicians ranked seizure frequency as their most useful piece of information, followed by medication compliance and drug interaction screening. For medication profile and drug interaction screening, most physicians currently use themselves as their primary source of information, although a significant number would prefer to use pharmacists as information sources in these areas (p < .05). A majority (62%) would like to have pharmacists more involved in the care of their patients. Pharmacists identified lack of time and lack of appointments with patients, inadequate pharmacy staff, and insufficient reimbursement as barriers to implementing the Pharmacist Note program. CONCLUSION: Physicians desire pharmacist involvement in specific areas of care for patients with epilepsy, and the feasibility of implementing the Pharmacist Note and similar programs appears promising. However, pharmacists identified barriers to implementation, and these barriers need to be addressed if this type of program is to be successful.

Influence of endogenous progesterone on alprazolam pharmacodynamics.

The results of a recently completed study demonstrated that postmenopausal women were more sensitive to triazolam-induced psychomotor performance impairment when progesterone was administered concomitantly. That clinical evidence agrees with the emerging in vitro information regarding the rapid membrane effects of a progesterone metabolite that positively modulates the gamma-aminobutyric acid-A-benzodiazepine receptor complex. The objective of this study in premenopausal women was to determine whether the response to a benzodiazepine is altered when endogenous progesterone concentrations are high (luteal phases of a menstrual cycle) compared with when progesterone concentrations are low (follicular phases of a menstrual cycle). The pharmacokinetics and pharmacodynamics of oral alprazolam were evaluated in twelve healthy, normally menstruating women who were not receiving oral contraceptive agents. On two separate occasions, once during each phase of the menstrual cycle, the women randomly received an oral alprazolam 2-mg dose. Blood samples were collected, and psychomotor performance tests were conducted at selected times before and after dosing. These data show that fluctuations of endogenous progesterone across the menstrual cycle do not influence alprazolam pharmacodynamics. Despite endogenous progesterone concentrations being significantly higher during the midluteal than during the midfollicular drug administrations, no differences were observed in either the digit-symbol substitution test, card sorting by suit, or sedation scores on these two occasions. No pharmacokinetic differences were observed between the two menstrual cycle-phase drug administrations. In conclusion, the lack of changes during the menstrual cycle in demonstrable cognitive impairment and pharmacokinetics after alprazolam administration is reassuring. This implies that a dose adjustment made on the basis of menstrual timing is not required.

Pharmacotherapeutic issues for women of childbearing age with epilepsy.

OBJECTIVE: To provide an overview of key pharmacotherapeutic issues in epilepsy for the woman of childbearing potential. DATA SOURCES: A MEDLINE search (1966-1997) was done to identify pertinent literature. Chapters in epilepsy textbooks, pregnancy registries, and their respective bibliographies were also evaluated. STUDY SELECTION AND DATA EXTRACTION: All identifiable sources written in English were evaluated. DATA SYNTHESIS: Epilepsy is a common neurologic disorder. It is estimated that nearly 1 million American women of childbearing age have epilepsy. There are many women's health issues in epilepsy. These include menstrual cycle influences on seizure activity, contraceptive-antiepileptic drug interactions, pharmacokinetic changes during pregnancy, teratogenicity of antiepileptic drugs, breast-feeding, and quality of life. These issues challenge both the woman with epilepsy and the many healthcare providers involved in her care. This article reviews these issues and makes recommendations. It addresses both the first-generation antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, valproic acid) and the newer or second-generation agents (felbamate, gabapentin, lamotrigine, topiramate, tiagabine). CONCLUSIONS/RECOMMENDATIONS: Drug interactions between enzyme-inducing antiepileptic drugs and contraceptives are well documented. Higher doses of oral contraceptives or a second contraceptive method are suggested if epileptic women use an enzyme-inducing antiepileptic drug. Planned pregnancy is highly recommended and counseling before conception is crucial. Prepregnancy counseling should include, but is not limited to, folic acid supplementation, optimal control of seizure activity, monotherapy with the lowest effective antiepileptic drug dose, and medication adherence. Patient information should be provided about the risk of teratogenicity and the importance of prenatal care. Antiepileptic drug dosage adjustments may be necessary and should be based on clinical symptoms, not solely on serum drug concentrations. While the future holds promise for many aforementioned women's issues in epilepsy, many questions remain to be answered.

Progesterone: does it affect response to drug?

This article presents an overview of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex (GBRC) and its in vitro modulation by THP, a metabolite of progesterone, as well as the results of a single-dose study of progesterone and triazolam in 16 post-menopausal women. The study results indicate that a 300 mg oral dose of progesterone administered 2.5 hours prior to a challenge dose of triazolam significantly increases sensitivity to triazolam: concentration values required for 50 percent of maximum effect (EC50) decreased by 20 to 32 percent after pre-treatment with progesterone. These data support the In vitro findings that THP enhances binding of benzodiazepines to the GBRC. The full clinical implications of these data, including extensions to other steroids, need to be explored.

Epilepsy: a review of seizure types, etiologies, diagnosis, treatment, and nursing implications.

Critical care nurses must be able to adequately identify and document seizure activity, perform appropriate interventions, and recognize signs of AED toxicity. Critical care nurses not only share the responsibility of taking care of epilepsy patients, but also must help in valuable patient and family education as it relates to long-term management. Becoming better informed of the plan of care for epilepsy patients helps optimize expected outcomes and enables patients and families to manage this illness better.

Oral administration of micronized progesterone: a review and more experience.

Historically, oral progesterone has been regarded clinically ineffective because of its poor absorption and rapid clearance. Recent evidence suggests that an oral micronized form of natural progesterone is readily absorbed, produces luteal phase serum concentrations, provokes an end-organ response, and has no detrimental effect on the lipoprotein profile. Thus it is considered by many to be an attractive alternative to synthetic progestin. We evaluated the effects of a single oral dose of micronized progesterone 300 mg in eight healthy postmenopausal women. The maximum serum concentration ranged from 15.72-625.98 ng/ml. The extent of absorption increased with increasing age. The reviewed literature and our data indicate considerable intersubject variability in the extent of progesterone absorbed after administration of oral micronized progesterone.

Triazolam pharmacokinetics after intravenous, oral, and sublingual administration.

This study was designed to evaluate the relative and absolute bioavailability of triazolam, 0.25 mg, after the administration of the marketed oral tablet and a sublingual prototype wafer; an intravenous dose was used as a reference. Twelve men were evaluated in a three-way crossover study; study days were separated by 1 week. A single dose was administered to each subject at approximately 8 a.m.; serial blood samples were obtained for the determination of triazolam concentration. The fraction absorbed relative to intravenous was 20% higher in the sublingual than in the oral treatment (p = 0.0128); the difference between treatments was greatest in the first 2 hours as indicated by the area under the curve from 0 to 2 hours (p < 0.05). The extraction ratio ranged from 0.05 to 0.25, and the predicted availability after oral administration was 86% with a range of 75 to 95%. In contrast, the observed mean absolute availability was 44% (oral) and 53% (sublingual). A potential explanation for this discrepancy between predicted and observed bioavailability is that after oral administration, a fraction of triazolam may be metabolized by cytochrome P450IIIA4 in the gut wall, with a separate fraction subject to first-pass metabolism in the liver. Although this study was not designed to identify sites of triazolam metabolism, the proposed explanation is consistent with the occurrence of P450IIIA4 in the stomach, small intestine, and liver. Doses administered sublingually avoid first-pass metabolism, producing earlier and higher peak concentrations than do doses administered orally.

Time-dependent sensitization to triazolam? An observation in three studies.

Evidence of time-dependent sensitization (TDS) to triazolam was observed in three separate clinical studies. Study 1 was conducted in 12 normal-weight and 12 obese men; an intravenous bolus dose of triazolam, 0.5 mg, was administered on two occasions. Study 2 was a balanced crossover of three 0.25-mg oral doses and one 0.20-mg oral dose of triazolam in 11 men. Study 3 was a balanced crossover of one placebo, one 0.5-mg, and two 0.4-mg oral doses of triazolam. In all three studies, treatments were separated by 6 days and included serial blood sampling for characterization of pharmacokinetics. Psychomotor response was assessed with the Digit Symbol Substitution Test and the Continuous Performance Test (CPT). Sedation was rated by an observer. For each measure, an effect ratio was calculated as the area under the effect curve divided by the area under the triazolam concentration curve; this parameter relates the extent of response relative to drug concentration in plasma. Effect ratios increased progressively by week for CPT; the percentage increase ranged from 31.9% in the study 1 normal subjects (week 1 to week 2; p = 0.08) to 631% in study 2 (week 1 to week 4; p = 0.0013). Similar increases were observed for other responses. Overall, the effect ratio data demonstrate increasing responsiveness per unit of triazolam concentration when triazolam was administered as a single dose at 1-week intervals. This observation was incidental to the original objectives of the studies. However, the data suggest that definitive studies to verify the occurrence of this phenomenon need to be conducted.(ABSTRACT TRUNCATED AT 250 WORDS)

Orally administered progesterone enhances sensitivity to triazolam in postmenopausal women.

An endogenously formed metabolite of progesterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP) modulates the gamma-aminobutyric acid receptor complex and plays a physiologic role in brain excitability regulation. On the basis of in vitro observations of 3 alpha-OH-5 alpha-DHP-enhanced [3H]flunitrazepam binding, we investigated the potential clinical effect of coadministering oral progesterone and triazolam. Sixteen postmenopausal women were randomly assigned to receive either intravenous triazolam plus oral progesterone 300 mg (TRZPROG) or intravenous triazolam plus oral placebo (TRZ). Triazolam was infused until 0.5 mg was given or until a predetermined maximal response was attained. Pharmacodynamic evaluation included DSST, continuous performance test, hand-eye coordination, short-term memory, and sedation. Effect ratios were calculated as the ratio of area under the effect-time curve to area under the curve (AUC). Variants of the sigmoid Emax model were fit to the data from the three psychomotor performance tests. A triazolam dose of less than 0.5 mg was administered to seven of eight subjects in the TRZPROG and five of eight subjects in the TRZ group, resulting in lower triazolam AUC values for the TRZPROG than for the TRZ group (p = 0.0275). There was clear evidence for a pharmacodynamic interaction. Mean effect ratios for all tests were greater in the TRZPROG group than in the TRZ group (DSST, p = 0.0097; continuous performance test, p = 0.0338; hand-eye coordination, p = 0.0041). The TRZPROG group had lower EC50 values than the TRZ group (DSST, p = 0.0435; continuous performance test, p = 0.0381; hand-eye coordination, p = 0.0154).(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents.

Progesterone is metabolized by ring-A reduction with subsequent oxidoreduction to 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP), a naturally occurring metabolite that has been shown to enhance [3H]flunitrazepam ([3H]FNZ) binding. Medroxyprogesterone acetate (MPA), a commonly prescribed progestational agent, is a synthetic progesterone derivative that has a metabolic profile similar to that of progesterone. In this study, the effects of MPA and its ring-A reduced metabolites DHMPA and THMPA on [3H]FNZ binding were investigated. While known modulators of specific [3H]FNZ binding demonstrated expected effects in frozen and fresh rat cortical tissue, 3 alpha-OH-5 alpha-DHP enhanced [3H]FNZ binding only in fresh, not frozen, tissue. Neither DHMPA nor THMPA affected binding, while MPA partially inhibited [3H]FNZ binding by 40%. In addition, five test drugs were used to assess the effect of gender and hormonal status on [3H]FNZ binding. Neither gender nor hormonal status influenced binding. Thus, ring-A reduced metabolites of progesterone but not of MPA enhance [3H]FNZ binding. The clinical implications of these in vitro results are currently under investigation.

Exaggerated warfarin sensitivity: a case report.

A 64-y-old male was hospitalized because of significant bleeding and a prolonged prothrombin time (PT) (greater than 200 sec) following an inadvertent doubling of his anticoagulant dose. He was previously well controlled on 2.5 mg warfarin every fourth day. Treatment included vitamin K, fresh frozen plasma, and packed red blood cells. Warfarin plasma concentrations, clotting factor analysis (CFA) and PTs were analyzed to evaluate this patient. Following hospitalization, the patient was followed by the Anticoagulation Clinic and his dose was stabilized at 0.5 mg daily. He experienced no further bleeding episodes and his PT ratio was maintained at 1.5 times control. The response to a dose of warfarin varies greatly from patient to patient. Previous reports of abnormal responses to warfarin can be categorized as either warfarin "resistant" or "sensitive." The preponderance of reports are compliance or hereditary warfarin resistance. This patient represents a case of exaggerated warfarin sensitivity that cannot be easily explained. There was no evidence of a drug interaction, warfarin concentrations were not excessive, and CFA was reflective of a moderate warfarin effect. Extreme tissue sensitivity to warfarin is a plausible explanation for this abnormal response.

Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing.

Previous studies have suggested that elderly men eliminate alprazolam more slowly than young adults. This study in the elderly was designed to determine whether a change in pharmacokinetics influences the response to alprazolam during multiple dose regimens. In addition, the study was designed to determine alprazolam pharmacokinetics and the degree to which its hydroxymetabolites accumulate, the degree of psychomotor impairment, and whether tolerance to impairment and sedation develops during three different multiple dose regimens. Twenty-six subjects completed this study. The subjects were randomized into one of three treatment groups: 0.25 mg q8h, 0.5 mg q8h, and 2 mg q12h. Subjects remained in the clinic for 8 days (day -2-day 5). Day 0 was used as a drug free testing day to establish baseline scores for sedation, digit symbol substitution (DSS), card sorting (CS) tasks, and two computer tests. Subjects received the drug according to schedule on days 1 through 4, with day 5 as the washout day. Blood samples were assayed for alprazolam, alpha-hydroxyalprazolam and 4-hydroxyalprazolam. Alpha-hydroxyalprazolam concentrations were below assay detection limits in all subjects in the 0.25 and 0.5 mg q8h groups and less than or equal to 2.6 ng/ml in the 2 mg q12h group. When detectable, 4-hydroxyalprazolam concentrations were less than 10% of the corresponding alprazolam concentration. Mean alprazolam oral clearance values in the three treatment groups ranged between 0.54 and 0.62 ml/min/kg and half-lives were in excess of 21 h. Degree of sedation and impairment was dose related. Sedation and impairment was not higher on day 4 despite concentrations 2-3 times as great as on day 1, indicating development of tolerance. Subjects were not, however, back to baseline level of performance on day 4.