Sex hormones in stroke, chorea, and anticonvulsant therapy

US and British studies have shown significantly higher incidence of strokes due to thromboembolism, subarachnoid hemorrhage, and cerebral venous thrombosis in users of oral contraceptives, particularly high estrogen formulations. Estrogen increases plasma levels of fibrinogen and the clotting factors VII, VIII, IX, X, and XII; enhances platelet aggregation; and suppresses antithrombin III and the fibrinolytic system. Estrogen may also cause immune-mediated vasculitis. The risk of strokes increases for women over 35 and smokers. Estrogen-induced chorea, including chorea of pregnancy, may be due to direct dopaminergic action of estrogens or to an accumulation of dopamine in the brain caused by competitive binding to the dopamine-degrading enzyme catechol-o-methyltransferase. Epileptics taking anticonvulsants and oral contraceptives have 25 times the risk of pill failure as normally expected, due to metabolism of anticonvulsants, such as phenytoin, phenobarbital, primidone, carbamazepine, and ethosuximide, by the hepatic microsomal enzyme system, resulting in a dramatic decrease of circulating ethinyl estradiol. Available options are to increase the estrogen dose to as much as 100 mg, to substitute valproic acid for other anticonvulsants, or to augment ethinyl estradiol levels by oral administration of ascorbic acid, which increases the bioavailability of the steroid. During pregnancy, on the other hand, serum levels of anticonvulsants decrease by 30-40%.     

Tension headache--a review

Tension headache (TH) is an ill-defined headache syndrome, characterized by bilateral, daily headaches with fronto-occipital localisation. TH is often accompanied by a migraine and an abuse of analgesics and/or ergotamine. In the etiology of TH vascular, muscular and psychogenic factors are assumed. Floating transitions to common migraine are discussed. The increased muscle tension is not specific for TH, but more probably a consequence of TH. In addition a decrease of the pain threshold with a deficiency of the antinociceptive system is supposed. The efficacy of tricyclic antidepressives in TH is based on potentiation of serotonergic and noradrenergic mechanisms and - besides their analgetic potencies - upon an increase of the pain threshold. TH prophylaxis is indicated if patients suffer from TH more than ten times per month. Medication are tricyclic antidepressives of the amitriptyline-type. Prophylaxis of TH can only be successful if a simultaneous abuse of analgesics and/or ergotamine is discontinued. In addition, EMG-biofeedback, as well as relaxation - and vasoconstriction training might be helpful in specific cases.     

Minimal effect of estrogens on endothelial cell growth and production of prostacyclin

The effects of natural and synthetic sex hormones (10(-8)M) have been studied on human umbilical endothelial cell proliferation and prostacyclin production. 17 B estradiol and progesterone had no effect on cell multiplication. Ethinyl-estradiol increased proliferation when the initial plating density was 40,000 cells/cm2. However, the production of 6-keto PGF1 alpha induced by the Ca++ ionophore A 23187 was not different between control, 17 B estradiol-or ethinyl estradiol-treated cultures. These results demonstrate an in vitro effect of synthetic estrogen, ethinyl estradiol on endothelial cell proliferation. At the present time it is however difficult to correlate these results with the clinical observation of an increase in thromboembolic complications in women under oral contraceptives.     

A Double-Blind, Placebo-Controlled Study on the Effect of Vigabatrin on In Vivo Parameters of Hepatic Microsomal Enzyme Induction and on the Kinetics of Steroid Oral Contraceptives in Healthy Female Volunteers

Summary: Purpose: This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects. Methods: Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of ≤= 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-β-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum γ-glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 μg ethinyl estradiol and 150 μg levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays. Results: VGB treatment had no influence on antipyrine clearance (28 ± 5.6 vs. 30 ± 4.5 ml/h/kg on placebo), antipyrine half-life (15.5 ± 3.5 vs. 14.1 ± 2.1 h), urinary 6–β-hydroxycortisol excretion (488 ± 164 vs. 470 ± 228 nmol/day), 6-β-hydroxycortisol-to-cortisol concentration ratio (6.8 ± 3.1 vs. 6.1 ± 3.1) and serum γ-glutamyltransferase activity (12 ± 3 vs. 11 ± 3 IUIL). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 ± 3.2 vs. 13.9 ± 3.2 h; AUC, 874 ± 301 vs. 939 ± 272 ng/L/h) and levonorgestrel (half-life, 17.7 ± 5.2 vs. 23.1 ± 9.8 h; AUC, 27.5 ± 9.6 vs. 30.0 ± 12.0 μg/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment. Conclusions: At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A.     

Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy women

PURPOSE: This study was designed to evaluate whether levetiracetam, a novel antiepileptic drug (AED), influences the pharmacokinetics of steroid oral contraceptives. METHODS: During a run-in phase, 18 healthy female patients received an oral contraceptive containing ethinyl estradiol, 0.03 mg, and levonorgestrel, 0.15 mg, for the first 21 days of two consecutive menstrual cycles. In a subsequent double-blind, randomized, two-way crossover treatment phase, subjects received either levetiracetam, 500 mg, or placebo twice daily concomitant with the oral contraceptive. Plasma concentrations of ethinyl estradiol and levonorgestrel were measured on days 14 and 15 of the two treatment periods for the evaluation of the 24-h kinetic parameters, and an additional sample was collected on day 21 to determine the trough plasma concentrations. Serum progesterone and luteinizing hormone (LH) levels were determined on days 13, 14, 15, and 21 of each cycle of the treatment phase. RESULTS: The plasma concentration-time curves and pharmacokinetic parameters of ethinyl estradiol and levonorgestrel were not statistically different during concomitant treatment with either levetiracetam or placebo. The ratios of the log-transformed geometric mean areas under the plasma concentration-time curves (AUCs), maximal (Cmax) and minimal (Cmin) plasma concentrations, and trough concentrations on day 21 (C21) ranged from 99.12 to 99.96% for ethinyl estradiol and from 97.13 to 99.41% for levonorgestrel. The 90% confidence intervals of these ratios were well within the 80 to 125% acceptance range for lack of interaction. Serum progesterone and LH concentrations were fairly constant during the run-in and treatment phases and remained markedly below their respective physiologic levels. Safety and menstrual-bleeding patterns were comparable during levetiracetam and placebo administration. CONCLUSIONS: Levetiracetam does not affect the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and levonorgestrel, and on the basis of serum progesterone and LH levels, it does not affect the contraceptive efficacy.     

Effect of Topiramate on the Pharmacokinetics of an Oral Contraceptive Containing Norethindrone and Ethinyl Estradiol in Patients with Epilepsy

Summary: Purpose: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. Methods: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-μg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200f and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. Results: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100–400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC_0–24) values for ethinyl estradiol were 18–30% lower in cycles 2 through 4 compared with cycle 1 (p 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7–33.0% higher (p 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T_max values determined during topiramate therapy were not significantly different from those at baseline. Conclusions: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing 235 μg of ethinyl estradiol.     

Developmental neurotoxicity of endocrine disrupters: focus on estrogens

A number of different environmental compounds are proposed to interact with the endocrine system (i.e., endocrine disrupters). Many of these have estrogenic effects in vitro and/or in vivo. Recent reviews have focused attention on the need for assessing the neurotoxicity of these compounds following developmental exposure. This attention comes in part from the literature on the effects of developmental exposure to exogenous estrogen on later behavioral and neuropathological alterations. A review of the ongoing neurobehavioral and neuropathological studies at the National Center for Toxicological Research on four such estrogen mimics (genistein, methoxychlor, nonylphenol, and ethinyl estradiol) is presented with results indicating that intake of a sodium solution is sensitive to these estrogen mimics. Developmental dietary exposure in male and female rats resulted in increased consumption of the sodium solution. Volume of the sexually dimorphic nucleus of the medial preoptic area was reduced by genistein, nonylphenol, and ethinyl estradiol exposure in males. The regulatory impact of these data and the directions for future research are discussed.     

Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects

PURPOSE: To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure. METHODS: This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m(2). The BMI of the remaining four groups was < or =27 kg/m2. RESULTS: Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated. CONCLUSIONS: TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.     

Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial

The estrogen hypothesis of schizophrenia postulates that estrogen exerts a protective effect against schizophrenia and that this partly explains the observed sex differences in premorbid adjustment, onset age, treatment response, and illness course. It has been suggested that estrogen supplementation can augment the treatment effects of antipsychotics. The purpose of the present investigation was to access the efficacy of ethinyl estradiol as an adjuvant agent in the treatment of premenopausal women with chronic schizophrenia in an 8-week, double-blind, and placebo-controlled trial. Eligible participants in the study were 32 women of childbearing age with schizophrenia. All patients were inpatients, in the active phase of illness, and met DSM-IV criteria for chronic schizophrenia. Patients were allocated in a random fashion, 16 to haloperidol 15 mg/day plus ethinyl estradiol 0.05 mg/day and 16 to haloperidol 15 mg/day plus placebo for an 8-week, double-blind, placebo-controlled study. Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of haloperidol and ethinyl estradiol showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms as well as Positive and Negative Syndrome Scale (PANSS) total scores. Although the means Extrapyramidal Symptoms Rating Scale (ESRS) for the placebo group were higher than ethinyl estradiol group, the differences were not significant over the trial. A significant difference was observed between the overall mean biperiden dosages in the two groups. The results of this study suggest that estrogen may be an effective adjuvant agent in the management of women of childbearing age with chronic schizophrenia. Nevertheless, results of larger controlled trials are needed before recommendation for a broad clinical application can be made.     

Peripheral glucose metabolism and insulin sensitivity in Alzheimer's disease

Twenty-four patients with Alzheimer's disease and matched controls were examined with reference to metabolic parameters such as peripheral insulin and glucose metabolism, serum lipid concentrations and blood pressure levels. Blood glucose levels and insulin response were measured during an intravenous glucose tolerance test and peripheral insulin sensitivity was estimated with the hyperinsulinemic euglycemic clamp technique. There were no differences recorded between the two groups in glucose metabolism, triglyceride, cholesterol or HDL-cholesterol levels. The patients with Alzheimer's disease had significantly lower blood pressure levels, which partly could be explained by ongoing treatment with neuroleptics and antidepressives. Previous findings of higher insulin levels in Alzheimer's disease could not be verified.     

Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration.

The minimum exposure to estrogen required to cause estrogen-withdrawal migraine has been studied by giving long-acting estradiol valerate to four women and short-acting estradiol benzoate to two women. It was found that several days of exposure to high estrogen levels were needed to cause migraine on estrogen withdrawal. Oral administration of estrogen supplements in the form of estradiol valerate or as conjugated equine estrogens during the premenstrual phase in four women did not significantly affect plasma levels of estradiol, nor was it effective in preventing menstrual migraine.     

Measurement of tricyclic antidepressant levels in an outpatient clinic.

Although definitive studies regarding the correlation between tricyclic antidepressant plasma levels and therapeutic effect are lacking, preliminary data suggest that measurement of tricyclic antidepressant plasma levels provides a rational approach to improve clinical management of the depressed patient. Data were collected to determine if the routine measurement of plasma tricyclic antidepressant levels was practical in a large clinic population, and to determine if such levels could improve patient care. Individual differences in drug metabolism and frequent unreliable ingestion of medication make the measurement of drug plasma levels the only sure means of determining if a patient is receiving a fair therapeutic trial on a particular tricyclic antidepressant. Plasma analysis revealed both the failure to ingest adequate amounts of medication as prescribed and also the abuse of medications. Although generalizations regarding individual variation in drug metabolism or generalizations concerning drug compliance do little to improve patient care, whenever such problems are met on an individual basis, many clinical management problems can be resolved.     

A comparison of the effects of melengestrol acetate with a combination of hydrocortisone acetate and medroxyprogesterone acetate and with other steroids in the treatment of experimental allergic encephalomyelitis in Wistar rats

Summary The following steroids were administered to female Wistar rats (Manor Farms or Purina) either at the time of sensitization or later when experimental allergic encephalomyelitis (EAE) was established — melengestrol acetate (MGA^®), medroxyprogesterone acetate (MPA or Provera^®), hydrocortisone acetate (HCA), estradiol, estradiol cypionate, ethinyl estradiol, estriol, mestranol, testosterone cypionate and nortestosterone.In accord with published work (Greiget al., 1970) MGA proved to be an effective therapeutic agent for the treatment of EAE while HCA was less effective. Of the other steroids ineffective alone, did potentiate the action of HCA in reducing the paralysis. Histologically, the combination of MPA with HCA also was superior to either one alone in one experiment; in a second experiment of longer duration in which a higher dose of HCA was used there was little difference.None of the compounds or combinations of compounds was as effective as MGA (25 mg/kg/week for 3 weeks) in the treatment of EAE. This compound appears to have unique therapeutic effects, both clinically and histologically.Presented in part at the International Congress of Allergology, Florence, Italy, 1970.     

Two estrogen replacement therapies differentially regulate expression of estrogen receptors alpha and beta in the hippocampus and cortex of ovariectomized rat

As estrogens have been implicated in altered cognitive function associated with menopause, the purpose of the present study was to determine the regulatory effects of different estrogen preparations on the expression of estrogen receptor subtypes in the hippocampus and cortex of ovariectomized rats. The expression of estrogen receptor mRNA and protein was determined with RT-PCR and immunohistochemistry, respectively. Two estrogen reagents, Premarin and Progynova, were used in the present study. Premarin, a conjugated equine estrogen, down-regulated ER alpha expression in the hippocampus and cortex of ovariectomized rats and had no effect on levels of ER beta expression in the same two regions. However, Progynova (valerate estradiol) was shown to up-regulate ER beta expression in the hippocampus and cortex and had no effect on the levels of ER alpha expression. Our present data suggest that different estrogen reagents used in estrogen replacement therapy could have different regulatory effects on the expression of estrogen receptor subtypes, which might, at least in part, explain why clinically, different estrogen preparations have distinct estrogenic effects on target organs.     

Grapefruit juice as a contraindication? An approach in psychiatry

The authors investigated in this preliminary study the influence of grapefruit juice on the metabolism of two tricyclic antidepressants. An increase of plasma concentrations is observed indeed for many drugs when administered concomitantly with grapefruit juice. This effect was mainly attributed to inhibition of cytochrome P450 1A2 and 3A4 enzymes by naringenin. These isoenzymes are involved too in the metabolism of many psychotropic drugs. Only two benzodiazepines (midazolam and triazolam) were studied in the conditions of grapefruit juice association. All these studies are performed in healthy subjects and with a study design very different from the clinical conditions. On the basis of these considerations, the authors hypothesized that grapefruit juice should inhibit tricyclic antidepressant metabolism and thus increase the bioavailability of these drugs. They want to precise if this possible drug plasma level increase could be clinically important for depressed patients. Fourteen depressed inpatients were selected for the study. Seven of them received amitriptyline (100 to 150 mg/d) and the seven others clomipramine (112.5 to 225 mg/d). Tricyclic antidepressant and desmethylated metabolite plasma levels were determined on four occasions. The first and second day samples were obtained to determined the plasma level intraindividual variability of antidepressants. On the third and fourth days, plasma levels were determined after an oral coadministration of the antidepressant and 250 ml of pure and fresh grapefruit juice. One patient was excluded from the study due to the coadministration of clomipramine and fluvoxamine. There is indeed a major drug-interaction between these two drugs, and the tricyclic antidepressant plasma levels of this patient were in the toxic range, without side effect. In this group of patients, there was no metabolic interaction between amitriptyline and grapefruit juice. But the mean plasma levels of clomipramine and desmethylclomipramine increased after coadministration of this juice (+4.5% and +10.5% respectively). The authors concluded that with these preliminary results, the potential clinical relevance of this interaction cannot be estimated.     

Further studies on a novel animal model of depression: Therapeutic effects of a tricyclic antidepressant

We have previously shown that rats given stress before open field testing have elevated activity in comparison with unstressed rats. This acute behavioral response may be eliminated by chronic stress and restored by pretreatment with the monoamine oxidase inhibitor pargyline. The present study replicated previous findings upon the effects of acute and chronic stress and extended results upon treatment to the class of tricyclic antidepressant drugs, using imipramine as a prototypic tricyclic antidepressant. Imipramine also restored both behavioral and psychoendocrine activity which was otherwise altered by chronic stress.     

Effects of tianeptine on 5-hydroxyindoles and on the morphine-induced increase in 5-HT metabolism at the medullary dorsal horn level as measured by in vivo voltammetry in freely moving rats

The present study, by the use of in vivo electrochemical detection of 5-hydroxyindole (peak ‘3’) in the bulbo spinal serotonergic system at the medullary dorsal horn (MDH) level, investigated the effects of the new tricyclic antidepressant (TCA) tianeptine, which has been shown to be a specific serotonin (5-HT) uptake enhancer. It was found that acutely administered tianeptine (10 mg/kg, i.p.) induced a marked significant increase in peak 3 within the dorsal horn, an in vivo observation which is in accordance with the biochemical properties of tianeptine as studied in forebrain structures. In addition, the effect of tianeptine on the morphine-induced increase in 5-HT metabolism was investigated, by comparison with the previous data obtained with the specific 5-HT uptake inhibitor femoxetine in the MDH. It was shown that tianeptine can display additive effect with morphine (10 mg/kg, i.p.) on 5-HT metabolism at the MDH level. These results are discussed in relation to the effects of classical TCAs and the particular properties of tianeptine.     

Small apomorphine-induced increase in the concentration of cytosol estrogen receptors in female rat hypothalamus and pituitary

A series of experiments was performed to investigate the previously-reported modulation of estradiol binding in female rat brain and pituitary gland by drugs that influence the dopaminergic system. Injection of the dopamine agonist, apomorphine, at minimum doses of 1-2 mg/kg body weight caused slight increases (in most cases, less than 10%) in the concentration of cytosol estrogen receptors in the mediobasal hypothalamus and anterior pituitary gland without influencing the concentration in the preoptic area. However, after subsequent injection of a saturating dose of estradiol, the level of nuclear estrogen receptors accumulating did not differ significantly between apomorphine-treated animals and vehicle-injected controls. These results extend, in part, previous reports that have shown an apomorphine-induced increase in the concentration of [3H]estradiol in brain and pituitary cell nuclei after an injection of [3H]estradiol. However, we failed to observe differences in the concentration of cytosol estrogen receptors as large as would be expected by previous work, and we failed to observe differences in the concentration of nuclear estrogen receptors after estradiol injection.     

Combined use of ECT and psychotropic drugs: Antidepressives and antipsychotics

Despite overall effectiveness of ECT and psychotropic drugs utilized separately in depressive illness and schizophrenic reactions, there are still a considerable number of patients in both diagnostical categories who are not responsive and treatment resistant. Efforts were spent in the past to combine both treatment approaches for these hard-core treatment resistant patients. This paper reviews previous investigations of the combined use of ECT and psychotropic drugs in the light of research methodology and theoretical framework behind their use. It concludes that although there is no theoretical justification, observed spectacular and long-lasting recoveries in some individual cases of chronic schizophrenia should compel the therapist to try ECT and psychotropic drug combinations. On the other hand, well designed blind controlled studies are needed to demonstrate the value of ECT and psychotropic drug combinations in obtaining faster recovery and longer remission in acute schizophrenia.It advocates the combination of ECT and antidepressives in depressive syndromes in spite of lack of controlled blind studies, merely because of recent theories which conceptualize the depression as a cholinergic dominance. ECT, which produces an instant sympathoadrenal activation, might be helpful to reverse the cholinergic predominance into the adrenergic one to be followed with tricyclic drugs which appear to be working in the same direction but suffering from a lag time before their peak therapeutic effect.