Midazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1-2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25-0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37 +/- 0.45 h) did not differ significantly ('t' = 2.04, df = 10, p greater than 0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74 +/- 0.45 h). The terminal half-life, (t 1/2), of midazolam in plasma was 1.77 +/- 0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383 +/- 0.0941 . kg-1 . h-1. The first pass effect, F, determined experimentally (0.36 +/- 0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%-0.028%).
Summary The alimentary symptoms found in 107 consecutive cases of Parkinsonism have been compared with those found in 96 control subjects. Chewing difficulty, drooling of saliva, dysphagia, frequent heartburn and constipation all occurred significantly more often in Parkinsonism than in controls, and of these symptoms only the incidences of dysphagia and heartburn did not correlate with increasing disability from Parkinsonism. There was relatively little correlation between alimentary symptoms and ætiological type of Parkinsonism, though chewing difficulty occurred particularly in Parkinsonism following encephalitis lethargica, and constipation in paralysis agitans. The alimentary symptoms of Parkinsonism may be due to dorsal vagal nuclear and basal ganglia lesions, and to side effects of drug therapy.
Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be.
OBJECTIVE- To study the possible dose dependence of the foetal malformation rate after exposure to sodium valproate in pregnancy METHODS- Analysis of records of all foetuses in the Australian Registry of Antiepileptic Drugs in Pregnancy exposed to valproate, to carbamazepine, lamotrigine or phenytoin in the absence of valproate, and to no antiepileptic drugs. RESULTS- The foetal malformation rate was higher (P<0.05) in the 110 foetuses exposed to valproate alone (17.1%), and in the 165 exposed to valproate, whether alone or together with the other antiepileptic drugs (15.2%), than in the 297 exposed to the other drugs without valproate (2.4%). It was also higher (P<0.10) than in the 40 not exposed to antiepileptic drugs (2.5%). Unlike the situation for the other drugs, the malformation rate in those exposed to valproate increased with increasing maternal drug dosage (P<0.05). The rate was not altered by simultaneous exposure to the other drugs. Valproate doses exceeding 1400 mg per day seemed to be associated with a more steeply increasing malformation rate than at lower doses and with a different pattern of foetal malformations. CONCLUSIONS- Foetal exposure to valproate during pregnancy is associated with particularly high, and dose-dependent risks of malformation compared with other antiepileptic drugs, and may possibly involve different teratogenetic mechanisms.
SUMMARYThis brief report covers an analysis of 7 years outcome data from the Australian Register of Antiepileptic Drugs in Pregnancy. In studying the control of antiepileptic drug-treated epileptic seizures during pregnancy, it was found that pregnancy had little influence on antiepileptic drugtreated epileptic seizure disorders. Seizures during pregnancy occurred in 49.7% of 841 antiepileptic drug (AED) treated pregnancies in women with epilepsy. Epilepsies that were active in the year before pregnancy tended to increase the risk of intrapartum and postpartum seizures. The risk of seizures during pregnancy was 50-70% less if the prepregnancy year was seizure free, and decreased relatively little more with longer periods of prepregnancy seizure control. Once there had been 1 year's freedom from seizures there seemed relatively little further advantage in deferring pregnancy to avoid seizures returning while pregnant. KEY WORDS: Epilepsy, Register, Women, Outcomes, Seizure freedom.The literature indicates some controversy about the worsening or improvement of epilepsy during pregnancy (Knight & Rhind 1975;Schmidt, 1982;Gjerde et al., 1988; Scheffler 1990;Vidovic & Della Marina, 1994; Costa et al., 2005). We present here outcome data from the Australian Register of Antiepileptic Drug Treated Pregnancies to assess the behavior of epileptic seizures from a substantial series of 841 antiepileptic drug (AED)-treated pregnancies in women with epilepsy (WWE). This may help guide practitioners managing epilepsy in pregnancy. MATERIALS AND METHODSSince 1999, the Australian Register (Vajda et al., 2006) has collected data on fetal malformations in the offspring of AED-treated pregnancies in WWE, in women who did Recruitment into the Register has been entirely voluntary, pregnant women being referred by medical practitioners, lay organizations, or learning about the project via advertisements or from nurses or fellow patients. All patient contact with the Register has been by telephone, with interviews at recruitment, at 28 weeks of pregnancy, at 4 weeks postpartum, and at 1 year after childbirth. Data on personal, occupational, past, family, medical, obstetric, social, nutritional, and recreational activities were obtained, especially as relevant to epilepsy, Data were recorded in a computerized proforma, into which at interview details of the seizure disorder present, whether seizures had occurred, and other relevant information, were included. Keeping detailed seizure diaries, although attempted, proved impracticable. Medical details were confirmed by contact with treating medical practitioners. Patients' identifying data were kept in a separate register, for confidentiality.Relevant details of the patients' epilepsies and other characteristics were extracted from the Register database into Excel spreadsheets. Data analysis utilized linear regression or confidence interval methods. 172
The Register has already produced important information for the management of pregnant women with epilepsy in Australia, but greater rates of recruitment into the Register are desirable to allow it to achieve its full potential.
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