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Biomedical subjects

A Sherwin

Publications and source records attributed to A Sherwin.

At least 19 recordsLinked to original sources
PubMed2000

Effect of anticonvulsants on sleep.

The intensive study of seizures via serial 24-hour EEG-video monitoring has allowed enhanced observation of sleep patterns among epilepsy patients and has revealed that disturbed rest is common in this population. Previous work has shown that sleep deprivation of any type can exacerbate seizure activity, leading to speculation that the intrinsically poor sleep in these patients may serve as a threshold-lowering factor, and that this factor might be partially reversed by effective antiepileptic drugs (AEDs). However, to better understand this interaction, it is necessary to know whether the sleep disorder of epilepsy is caused by repetitive ictal events or whether it is part of a process that causes epilepsy to emerge in the first place. In addition, to separate and analyze the sleep effects of AEDs, one must compare studies of normal controls, which have only rarely been accomplished, with studies of drug-free patients, which are difficult to achieve. As little as is known about the detailed effects of AEDs on sleep architecture, even less is known about the mechanisms by which AEDs might cause such effects. Nevertheless, there is great potential for those undertaking such work, due to the wealth of basic science accumulating in the field of sleep mechanisms and the prodigious amount of information already amassed in the area of anticonvulsant mechanisms.

Anticonvulsants↗
PubMed1999

Congenital malformations due to antiepileptic drugs.

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Abnormalities, Drug-Induced↗
PubMed1999

Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.

Anticonvulsants↗
PubMed1997

Phospholipid biosynthetic enzymes in human brain.

Growing evidence suggests an involvement of brain membrane phospholipid metabolism in a variety of neurodegenerative and psychiatric conditions. This has prompted the use of drugs (e.g., CDPcholine) aimed at elevating the rate of neural membrane synthesis. However, no information is available regarding the human brain enzymes of phospholipid synthesis which these drugs affect. Thus, the objective of our study was to characterize the enzymes involved, in particular, whether differences existed in the relative affinity of substrates for the enzymes of phosphatidylethanolamine (PE) compared to those of phosphatidylcholine (PC) synthesis. The concentration of choline in rapidly frozen human brain biopsies ranged from 32-186 nmol/g tissue, a concentration similar to that determined previously for ethanolamine. Since human brain ethanolamine kinase possessed a much lower affinity for ethanolamine (Km = 460 microM) than choline kinase did for choline (Km = 17 microM), the activity of ethanolamine kinase in vivo may be more dependent on substrate availability than that of choline kinase. In addition, whereas ethanolamine kinase was inhibited by choline, and to a lesser extent by phosphocholine, choline kinase activity was unaffected by the presence of ethanolamine, or phosphoethanolamine, and only weakly inhibited by phosphocholine. Phosphoethanolamine cytidylyltransferase (PECT) and phosphocholine cytidylyltransferase (PCCT) also displayed dissimilar characteristics, with PECT and PCCT being located predominantly in the cytosolic and particulate fractions, respectively. Both PECT and PCCT exhibited a low affinity for CTP (Km approximately 1.2 mM), suggesting that the activities of these enzymes, and by implication, the rate of phospholipid synthesis, are highly dependent upon the cellular concentration of CTP. In conclusion our data indicate different regulatory properties of PE and PC synthesis in human brain, and suggest that the rate of PE synthesis may be more dependent upon substrate (ethanolamine) availability than that of PC synthesis.

Adult↗
PubMed1996

George A. Savoy, visionary benefactor of Canadians with epilepsy, and the history of the Savoy Foundation for Epilepsy.

George A. Savoy was born in Cohoes, New York, in 1873. He left the U.S.A. in 1921 to manage the Canadian branch of a large manufacturer of ledgers and looseleaf registers. This company was asked to supply Professor Jasper's laboratory with rolls of plain unlined paper and it was George Savoy who later developed fanfolded and lined EEG paper, which was first used at the Montreal Neurological Institute. He also had personal contacts with Wilder Penfield concerning their mutual interest in the needs of patients with epilepsy. He was a successful industrialist involved with several charitable organizations funding programmes for people with epilepsy. He was opposed to the sectarianism then prevalent in Quebec, which was unfamiliar to him, and in reaction built his own institution, Dieppe House, a home for people with epilepsy, later renamed < >. It was to operate without regard to race, language or religion. In 1971, his son Harold and other generous donors decided to create a foundation to support research in epilepsy. The Foyer Savoy was sold in 1988 and the proceeds used to increase the endowment of the foundation. His grandson George M. Savoy is the current president. The fourth generation is also represented by Caroline Savoy, daughter of the president, who joined the board of directors in 1992. The foundation will distribute from $300,000 to $400,000 yearly to researchers from many different countries working in the field of epilepsy in universities and hospitals throughout Canada.

Canada↗
PubMed1994

Elevated dopa decarboxylase activity in living brain of patients with psychosis.

The hypofrontality theory of the pathogenesis of schizophrenia predicts that cortical lesions cause psychosis. During a search for abnormalities of catecholaminergic neurotransmission in patients with complex partial seizures of the mesial temporal lobe, we discovered an increase of the rate of metabolism of an exogenous dopa tracer (6-[18F]fluoro-L-dopa) in the neostriatum of a subgroup of patients with a history of psychosis. When specifically assayed for this abnormality, patients with schizophrenia revealed the same significant increase of the rate of metabolism in the striatum. The finding is consistent with the theory that a state of psychosis arises when episodic dopamine excess is superimposed on a trait of basic dopamine deficiency in the striatum. The finding is explained by the hypothesis that cortical insufficiency, a proposed pathogenetic mechanism of both disorders, causes an up-regulation of the enzymes responsible for dopa turnover in the neostriatum as well as the receptors mediating dopaminergic neurotransmission.

Adult↗
PubMed1994

Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients.

We treated 19 patients with Rasmussen's syndrome (chronic encephalitis and epilepsy)--a rare progressive disorder of unknown etiology causing focal epilepsy, hemiparesis, and intellectual deterioration--with intravenous immunoglobulins, high-dose steroids, or both, to control seizures and improve the end point of the disease. Ten of 17 patients receiving steroids, and eight of nine patients receiving immunoglobulins, had some reduction of seizure frequency in the short term. Improvement in hemiparesis was slight. The effect of these drugs in ameliorating the end point of the disease in the long term remains unknown, and further multicenter studies with standardized protocols are warranted.

Adolescent↗
PubMed1993

Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease.

We followed 16 patients with a variety of mitochondrial diseases over one to four periods of treatment (2 months each) with coenzyme Q10 plus vitamins K3 and C, riboflavin, thiamine, and niacin, using independent measures of oxidative metabolism to assess efficacy. There were large (> threefold) increases in serum coenzyme Q10 concentrations with treatment, but no measure of oxidative metabolism showed significant improvement with treatment for the group, nor did any individual patient show significant, reproducible, objective clinical improvement. The results suggest that coenzyme Q10 plus vitamin therapy does not significantly improve mitochondrial oxidative metabolism in patients with mitochondrial disease in general. Any clinical benefit that may follow from short-term administration appears slight.

Adenosine Triphosphate↗
PubMed1992

Improved pregnancy outcome in epileptic women in the last decade: relationship to maternal anticonvulsant therapy.

The prevalence of abnormal pregnancy outcomes in the offspring of 103 epileptic women, followed prospectively during pregnancy between 1982 and 1989, was compared with that in the previous study of 119 pregnancies by Dansky et al from the same institution. Our results have shown a significant decrease in the prevalence of major malformations, as compared with the previous study: 8.8% vs 24.1% (P < 0.01). Monotherapy was more frequent and the mean number of drugs used during pregnancy was significantly smaller in the present study. Phenytoin, phenobarbital and primidone were prescribed less frequently in the present study, whereas carbamazepine and valproic acid were used more frequently. Plasma levels of valproic acid during pregnancy were higher in mothers of malformed babies. In the present study, plasma folate levels were significantly higher, and more patients were taking folate supplements during pregnancy. In conclusion, the type and number of drugs used during pregnancy, as well as the plasma concentrations and serum folate levels, may determine the frequency of abnormal outcomes.

Abnormalities, Drug-Induced↗
PubMed1991

Phenytoin toxicity due to interaction with clobazam.

The benzodiazepine antiepileptic drug clobazam can be added to existing AED treatment, usually without clinical toxicity. We report 3 patients in whom the addition of clobazam led within several weeks to clinically obvious phenytoin (PHT) intoxication in patients who had been taking maximum tolerable PHT doses. Symptoms and high PHT levels resolved with lowering the PHT dose. Clobazam and norclobazam levels were not elevated. This interaction is probably related to interference with hepatic degradation of PHT. Clinicians should be aware of possible PHT intoxication in patients starting clobazam.

Adult↗
PubMed1991

Developmental anterobasal temporal encephalocele and temporal lobe epilepsy.

The authors describe the association between an antero-basal temporal lobe encephalocele and medically intractable temporal lobe epilepsy in three patients treated successfully by surgery. Two men and one woman, aged 26 to 37 years (mean 31 years), had onset of complex automatism and generalized seizures in their second and fourth decades (mean age 22.7 years). They had been epileptic for 6 to 14 years (mean 8.3 years) before surgery. Preoperative electroencephalograms localized ictal epileptic activity to the left mesial temporal lobe in all cases, and neuropsychological testing revealed dominant temporal lobe dysfunction. Magnetic resonance (MR) imaging demonstrated an anteromedial basal temporal encephalocele extending into the pterygopalatine fossa through a bone defect at the base of the greater sphenoid wing in the region of the foramen rotundum and pterygoid process, a discrete center of embryonal chondrification. At surgery, the encephaloceles were found in front of the uncus, and an area of gliosis extended from the encephalocele to the amygdalohippocampal region. All patients have been seizure-free following anterior temporal resection and amygdalohippocampectomy including the encephalocele. These three cases delineate a condition of disordered embryogenesis wherein a developmental anterobasal temporal encephalocele acts as the substrate for temporal lobe epilepsy. This lesion may be diagnosed preoperatively with MR imaging and should be considered in the differential diagnosis of late-onset temporal lobe epilepsy.

Adult↗
PubMed1990

Add-on trial of clobazam in intractable adult epilepsy with plasma level correlations.

Clobazam, a novel benzodiazepine, was used as an add-on agent in 47 adult patients with intractable epilepsy and a variety of seizure types. A greater than 75% reduction in seizure frequency was observed in 42% (18) of the patients and a greater than 50% reduction in 65% (29) of the patients which was sustained over a mean follow-up period of 13.3 (+/- 5.6) months. Nine patients had to discontinue the drug due to minor adverse effects or increased seizures. Possible tolerance developed in 6 patients. Plasma levels of the active metabolite N-desmethylclobazam were linearly related to dosage and appeared to correlate with both therapeutic and toxic responses. Clobazam appears to be a safe and effective add-on antiepileptic for a wide variety of seizure types in intractable epilepsy.

Adult↗
PubMed1989

In vivo quantification of blood-brain transfer and binding of [125I]HEAT, an alpha 1-adrenoceptor antagonist.

The uptake and binding constants of [125I]iodo-2-[beta-(4-hydroxyphenyl)-ethyl-amino-methyl]tetralone ( [125I]HEAT) in rat brain were determined in vivo. The initial clearance of the radioligand from blood to brain, K1, was calculated from the initial uptake of the radioligand; it averaged 0.21 +/- 0.01 (SD) ml g-1 min -1, consistent with an initial extraction of 25% (i.e., one-quarter of the blood flow). The most strongly binding regions included the olfactory bulb, thalamic nuclei, medial geniculate body, and cerebral cortical layers. We identified saturable, specific binding in frontal cortex layers 1, 5a, and 5c (motor region), frontal cortex layers 3+4, ventral thalamic nuclei, medial geniculate body, striatum, cerebellum, and olfactory bulb. Addition of unlabeled ligand depressed binding in all regions to the same low level (partition coefficient) of 0.8 ml g-1. Displacement of [125 I]HEAT binding by unlabeled HEAT yielded a global affinity constant (KDVd) of 34 +/- 8 pmol g-1 and receptor densities (Bmax) that varied from 50 pmol g-1 in cerebellar cortex and caudate nucleus to 200 pmol g-1 in the region of highest specific binding, the medial geniculate body.

Adrenergic alpha-Antagonists↗
PubMed1989

Metabolism of prostaglandin D2 by human cerebral cortex into 9 alpha, 11 beta-prostaglandin F2 by an active NADPH-dependent 11-ketoreductase.

In homogenates of rat cerebral neocortex prostaglandin D2 (PGD2) was found to be quantitatively the main PG biosynthesized by a cytosolic PGD synthetase from endogenously released arachidonic acid. Amounts of 628 ng/g wet weight were found after 30-min incubation periods compared with basal levels of 2.3 ng/g wet weight. In human cerebral cortex, whether obtained at biopsy or postmortem, only small amounts of PGD2 (4.5-11.7 ng/g wet weight/30 min) were formed. Furthermore, PGD2, added to homogenates of human biopsy temporal cortex, was converted efficiently into 9 alpha,11 beta-PGF2 by a NADPH-dependent 11-ketoreductase as has been reported in other human tissues (liver and lung). PGF2 alpha was determined directly as the n-butylboronate derivative. It became clear that 9 alpha,11 beta-PGF2 was formed in considerably greater amounts than PGF2 alpha and that other metabolites are also formed. These results can account for the low amounts of PGD2 found in incubations of human brain tissue. The rat brain does not contain 11-ketoreductase activity. The present results indicate that the 9 alpha,11 beta-PGF2 must be considered along with other eicosanoids in pathophysiological situations in brain.

Adolescent↗
PubMed1988

Excitatory amino acids are elevated in human epileptic cerebral cortex.

We used intraoperative electrocorticography to identify and compare specimens from two groups of patients undergoing temporal lobectomy: (1) spiking cortex (12 patients)--epileptic activity recorded over much of the temporal convexity; and (2) nonspiking cortex (9 patients)--temporal convexity free of interictal spiking, epileptic activity confined to the hippocampus and/or amygdala. Comparative amino acid levels were (mumol/g protein, mean +/- SEM): glutamate--spiking 109.8 +/- 1.8, nonspiking 87.4 +/- 2.0 (p less than 0.001); aspartate--spiking 15.2 +/- 0.9, nonspiking 12.2 +/- 0.5 (p less than 0.05); GABA--spiking 15.0 +/- 1.0, nonspiking 13.9 +/- 1.4 (NS); taurine--spiking 14.5 +/- 0.8, nonspiking 12.2 +/- 0.8 (NS); and glycine--spiking 11.5 +/- 0.8, nonspiking 7.4 +/- 0.6 (p less than 0.01). Cortical epileptic activity appears to be associated with elevated concentrations of glutamate, aspartate, and glycine, but not GABA and taurine, perhaps indicating a relative imbalance between putative excitatory and inhibitory amino acid neurotransmitters.

Adolescent↗
PubMed1986

Stability of alpha-1 adrenoceptors in surgically excised human brain.

Alpha-1 adrenoceptor sites were measured in membranes prepared from nonepileptic superficial cortex following temporal lobectomy for lesions in deep medial structures. There was no significant change in receptor density (Bmax) or affinity (Kd) when paired samples were either frozen immediately or kept at room temperature for 24 hours before freezing and storage at -70 degrees C. Regional variability in the Bmax or Kd of alpha-1 adrenoceptor binding was not observed in serial samples from lateral temporal cortex. We previously reported a localized decrease in alpha-1 adrenoceptors in epileptic foci when compared to adjacent nonepileptic tissue obtained from the same patient. As nonepileptic control tissue from an adjacent gyrus is frequently not available in the same specimen, the stability of alpha-1 adrenoceptors justifies the use of postmortem brain for comparative studies.

Adolescent↗
PubMed1984

Enzyme changes in actively spiking areas of human epileptic cerebral cortex.

Five enzymes involved in glutamic acid, GABA, and catecholamine metabolism were measured in epileptic human brain. Electrocorticographically defined areas of focal spiking were compared with samples from surrounding nonspiking cortex. Comparative enzyme activities were as follows (mumol/h/g wet wt): glutamic acid dehydrogenase (GDH)--spiking 135.77 +/- 10.22 (mean +/- SEM), nonspiking 118.58 +/- 9.42 (p less than 0.001, N = 17); glutamic acid decarboxylase--spiking 10.63 +/- 0.95, nonspiking 9.96 +/- 1.10 (NS, N = 13); GABA-aminotransferase--spiking 36.49 +/- 1.05, nonspiking 36.46 +/- 1.48 (NS, N = 12); glutamine synthetase--spiking 96.94 +/- 3.81, nonspiking 96.52 +/- 4.10 (NS, N = 20); and tyrosine hydroxylase (TH; nmol/h/g)--spiking 16.23 +/- 2.39, nonspiking 10.67 +/- 1.95 (p less than 0.001, N = 14). Increased activity of GDH and TH may prove useful to characterize further areas of active spiking in human focal epilepsy.

Adolescent↗