Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new sabril research articles will be listed here shortly after becoming available to us.
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Retinopathy induced by drugs and herbal medicines.
Eur Rev Med Pharmacol Sci. 2008 Sep-Oct; 12(5): 293-8
Nencini C, Barberi L, Runci FM, Micheli L
Retina is the part of the eye suffering most damage from drugs. It is made up of a thin nervous membrane that covers the eye-ball internally, within the thickness of which three types of cells are ordered. In this paper we describe the drugs that are responsible for retinal side effects. Most commonly recognized drugs-induced retinopathy have a particular affinity for the retinal pigmented epithelium: antimalarials (quinine, hydroxychloroquine, mefloquine), phenothiazines, indomethacin, ethambutol, and desferrioxamine. Attention is especially focused on drugs more recently suspected of adverse reactions in the retina: vigabatrin, gabapentin, sildenafil, tamoxifen, isotretinoin, interferon, and omeprazole. Moreover, we referred some reports of retinopathy by herbal medicines and nutritional supplements (canthaxanthine, Gingko biloba L. and Glycyrrhiza glabra L.) This review is based on data published in scientific journals indexed by the PubMed and Medline databases. The last search of the literature was conducted in April 2008.
Epilepsia. 2008 Nov 12;
Tong X, Ratnaraj N, Patsalos PN
Summary Purpose: To investigate the pharmacokinetic interrelationship of vigabatrin in blood and the brain (frontal cortex vs. hippocampus) and to ascertain the relationship between brain extracellular vigabatrin concentrations and concurrent gamma-aminobutyric acid (GABA) concentrations. Methods: Sprague-Dawley rats were implanted with a jugular vein catheter for blood sampling, and microdialysis probes in the frontal cortex and hippocampus for extracellular fluid (ECF) sampling. Vigabatrin was administered intraperitoneally at two different doses (500 and 1,000 mg/kg), and blood and ECF were collected at timed intervals up to 8 h. Rats were freely moving and behaving. Vigabatrin (sera and ECF) and GABA (ECF) concentrations were measured with use of high performance liquid chromatography (HPLC). Results: Vigabatrin concentrations in blood rose linearly and dose-dependently, and vigabatrin rapidly appeared in the brain as evidenced by the detection of vigabatrin in the ECF of both the frontal cortex and hippocampus at time of first sampling (15 min). However, frontal cortex concentrations were twofold greater than those of the hippocampus. Furthermore, GABA concentrations increased five-fold in the frontal cortex but were unaffected in the hippocampus. In addition, GABA concentrations began to increase approximately 3 h after vigabatrin administration at a time when vigabatrin concentrations were in exponential decline. Conclusions: Vigabatrin distribution in the brain is region specific, with frontal cortex concentrations substantially greater than those seen in the hippocampus. Elevation of GABA concentrations did not reflect the concentration profile of vigabatrin but reflected its regional distribution.
Synapse. 2008 Nov 13; 63(2): 87-94
Demarco A, Dalal RM, Pai J, Aquilina SD, Mullapudi U, Hammel C, Kothari SK, Kahanda M, Liebling CN, Patel V, Schiffer WK, Brodie JD, Dewey SL
Preventing relapse poses a significant challenge to the successful management of methamphetamine (METH) dependence. Although no effective medication currently exists for its treatment, racemic gamma vinyl-GABA (R,S-GVG, vigabatrin) shows enormous potential as it blocks both the neurochemical and behavioral effects of a variety of drugs, including METH, heroin, morphine, ethanol, nicotine, and cocaine. Using the reinstatement of a conditioned place preference (CPP) as an animal model of relapse, the present study specifically investigated the ability of an acute dose of R,S-GVG to block METH-triggered reinstatement of a METH-induced CPP. Animals acquired a METH CPP following a 20-day-period of conditioning, in which they received 10 pairings of alternating METH and saline injections. During conditioning, rats were assigned to one of four METH dosage groups: 1.0, 2.5, 5.0, or 10.0 mg/kg (i.p., n = 8/group). Animals in all dosage groups demonstrated a robust and consistent CPP. This CPP was subsequently extinguished in each dosage group with repeated saline administration. Upon extinction, all groups reinstated following an acute METH challenge. On the following day, an acute dose of R,S-GVG (300 mg/kg, i.p.) was administered 2.5 h prior to an identical METH challenge. R,S-GVG blocked METH-triggered reinstatement in all four groups. Given that drug re-exposure may potentiate relapse to drug-seeking behavior, the ability of R,S-GVG to block METH-triggered reinstatement offers further support for its use in the successful management of METH dependence. Synapse 63:87-94, 2009. (c) 2008 Wiley-Liss, Inc.
Cross-sensitivity of skin rashes with antiepileptic drug use.
Neurology. 2008 Nov 4; 71(19): 1527-34
Hirsch LJ, Arif H, Nahm EA, Buchsbaum R, Resor SR, Bazil CW
OBJECTIVE: To determine rates of cross-sensitivity of rash among commonly used antiepileptic drugs (AEDs) in patients with epilepsy. METHODS: The incidence of AED-related rash was determined in 1875 outpatients (> or =12 years), taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproic acid (VPA), or zonisamide (ZNS). We compared rates of rash for each AED in patients with vs those without a rash to 1) another specific AED; 2) any other AED; 3) any two other AEDs; and 4) any non-epilepsy medication. RESULTS: A total of 14.3% (269/1,875) of patients had a rash attributed to at least one AED; 2.8% had a rash to two or more AEDs. Of patients who had a rash to CBZ and were also prescribed PHT (n = 59), 57.6% had a rash to PHT (abbreviated as CBZ --> PHT: 57.6%); of patients who had a rash to PHT and were also prescribed CBZ (n = 81), rate of rash was 42% (i.e., PHT --> CBZ: 42%). Other results: CBZ --> LTG: 20% (n = 50); LTG --> CBZ: 26.3% (n = 38); CBZ --> OXC: 33% (n = 15); OXC --> CBZ: 71.4% (n = 7); CBZ --> PB: 26.7% (n = 30); PB --> CBZ: 66.7% (n = 12); LTG --> PHT: 38.9% (n = 36); PHT --> LTG: 18.9% (n = 74); PB --> PHT: 53.3% (n = 15); PHT --> PB: 19.5% (n = 41); OXC --> LTG: 37.5% (n = 8); LTG --> OXC: 20% (n = 15). There was evidence of specific cross-sensitivity between CBZ and PHT, and between CBZ and PB. CONCLUSION: Cross-sensitivity rates between certain antiepileptic drugs (AEDs) are high, especially when involving carbamazepine and phenytoin. Specific cross-sensitivity rates provided here may be useful for AED selection and counseling in individual patients.
Drug Metab Dispos. 2008 Nov 3;
Grigat S, Fork C, Bach M, Golz S, Geerts A, Schomig E, Grundemann D
In addition to its function as carnitine transporter, OCTN2 (human gene symbol SLC22A5) is widely recognized as a transporter of drugs. This notion is based on several reports of direct measurement of drug accumulation. However, a rigorous, comparative, and comprehensive analysis of transport efficiency of OCTN2 has not been available so far. In the present study, OCTN2 orthologues from human, rat, and chicken were expressed in 293 cells using an inducible expression system. Uptake of ASP(+), cephaloridine, ergothioneine, gabapentin, mildronate, pyrilamine, quinidine, spironolactone, tetraethylammonium, verapamil, and vigabatrin was determined by liquid chromatography - mass spectrometry. For reference, uptake of carnitine was measured in parallel. Our results indicate that OCTN2-mediated uptake of drugs was not significantly different from zero or, with tetraethylammonium and ergothioneine, was minute relative to carnitine. The carnitine congener mildronate, by contrast, was transported very efficently. Thus, OCTN2 is not a general drug transporter, but a highly specific carrier for carnitine and closely related molecules. Transport parameters (cellular accumulation, transporter affinity, sodium-dependence) were similar for mildronate and carnitine. Efficiency of transport of mildronate was even higher than that of carnitine. Hence, our results establish that OCTN2 is a key target of the cardioprotective agent mildronate, since it controls, as integral protein of the plasma membrane, cellular entry of mildronate and enables efficient access to intracellular targets. The highest levels of human OCTN2 mRNA were detected by real-time RT-PCR in kidney, ileum, breast, small intestine, skeletal muscle and ovary, but also in some heart and CNS tissues.
A retrospective study on aetiology based outcome of infantile spasms.
Seizure. 2008 Oct 29;
Karvelas G, Lortie A, Scantlebury MH, Duy PT, Cossette P, Carmant L
PURPOSE: The goal of this retrospective study is to review the causes of infantile spasms and to correlate aetiology with outcome. METHODS: All children diagnosed with infantile spasms between 1990 and 2003 at our institution were included. Charts were reviewed for the presence or absence of a defined aetiology/association, response to treatment, long-term epileptic and cognitive outcome. RESULTS: 80 out of 95 children are included in this review. 50 children (63%) had symptomatic spasms with disorders of cortical development being the most frequent cause followed by neonatal injury and tuberous sclerosis. Symptomatic children with developmental brain lesions responded at a rate of 54% to vigabatrin versus 62% for ACTH/prednisone, while other symptomatic aetiologies 83% responded to vigabatrin versus 63% for ACTH/prednisone. Cryptogenic spasms responded at a similar rate to both drugs. Other than children with cryptogenic spasms, very few went on to develop normally. Our results are however biased by on average more than 30 days of delay to diagnosis. None of our children developed Lennox-Gastaut syndrome but a number developed severe epilepsy with multifocal spikes. DISCUSSION: The aetiology and prognosis of infantile spasms is evolving. To improve outcome, we need to reduce the delay to diagnosis and develop prospective double-blind randomized clinical trials looking at not only the epileptic outcome but also cognitive outcome of these children.
[Seizure exacerbation caused by antiepileptic drugs]
Tidsskr Nor Laegeforen. 2008 Sep 25; 128(18): 2052-5
Nakken KO, Johannessen SI
BACKGROUND: In certain types of epilepsy, antiepileptic drugs can exacerbate the disease instead of improving it. MATERIAL AND METHODS: This review is based on a non-systematic literature search in Medline for the time-period 1990-2007, and our own clinical experience. RESULTS AND INTERPRETATION: As a consequence of treatment with antiepileptic drugs, patients with epilepsy may have more frequent and severe seizures of the type they had before, but also new seizure types or patterns, and even series of seizures or status epilepticus. Both old and new antiepileptic drugs may exacerbate seizures, but carbamazepine-induced generalized seizures (such as absence and myoclonic) are best documented. More than one pathophysiological mechanism is probably involved in drug-related exacerbation of seizures, such as sedative and pro-convulsive effects of high serum levels, drug-associated encephalopathy, and a paradoxical pharmacodynamic effect. Accurate epilepsy- and seizure classification is important in the treatment of all types of epilepsy. Atypical absences are sometimes mistaken for complex partial seizures. Such patients may be given drugs with a narrow spectrum such as sodium channel blockers (e.g. carbamazepine, phenytoin, oxcarbazepine) or GABAergic agents (e.g. vigabatrin, tiagabine) with an increased risk of seizure exacerbation. Those at greatest risk of experiencing drug-related seizure exacerbation are learning-disabled patients, children with severe epileptic encephalopathies, those with high seizure frequency and several seizure types, and those using polytherapy.
Clin Neurol Neurosurg. 2008 Oct 8;
Jaseja H
West syndrome (WS) or infantile spasms (IS) is a severe epileptic syndrome associated with poor prognosis and increased morbidity. The exact etio-pathogenesis of the disorder still remains elusive ant therefore the management continues to pose a challenge to the clinicians. Currently, adreno-corticotrophic hormone (ACTH), steroids and vigabatrin (VGB) form the mainstay of its treatment. However, the recent detection of an irreversible visual field defect observed in as high as 30-50% of children treated with vigabatrin has raised concern over the drug's usage. This brief paper is intended to highlight the significance of the irreversible visual toxicity in an already existent mentally challenged state in WS patients, which can lead to a worsening in the disability status of such patients. Therefore, based on the enhancement of handicap by VGB administration it is recommended that a comprehensive review be performed on its continuation in WS patients in order to prevent further deterioration of their quality of life (QOL).
Treatment of infantile spasms.
Cochrane Database Syst Rev. 2008; CD001770
Hancock EC, Osborne JP, Edwards SW
BACKGROUND: Infantile spasms (West's Syndrome) is a syndrome which includes a peculiar type of epileptic seizure, the spasms, and an electroencephalogram (EEG) abnormality often called hypsarrhythmia. Psychomotor retardation is frequently found at follow up. Approximately two thirds of affected infants will have a detectable underlying neurological abnormality, but still little is known about the pathophysiological basis for infantile spasms and treatment remains problematic. OBJECTIVES: To compare the effects of single pharmaceutical therapies used to treat infantile spasms in terms of control of the spasms, resolution of the EEG, relapse rates, psychomotor development, subsequent epilepsy, side effects, and mortality. SEARCH STRATEGY: Published data: Cochrane Epilepsy Group Specialised Register, CENTRAL (The Cochrane Library 2007, Issue 4), MEDLINE, EMBASE, and the reference lists of all retrieved articles.Unpublished data: ISRCTN Register (www.controlled-trials.com), correspondence with colleagues and drug companies, and requests at international conferences. SELECTION CRITERIA: All randomised controlled trials of the administration of drug therapy to patients with infantile spasms. DATA COLLECTION AND ANALYSIS: Data collection from all relevant publications was independently undertaken by three review authors using a standard proforma. Analysis included assessment of study quality and looking for sources of heterogeneity. MAIN RESULTS: We found 12 small RCTs (less than 60 patients enrolled) and two larger RCT (more than 100 patients enrolled). These 14 studies looked at a total of 681 patients treated with a total of nine different pharmaceutical agents. Overall methodology of the studies was poor, partly because of ethical dilemmas such as giving placebo injections to children. Two studies showed that placebo was not as good as active treatment in resolving the spasms. The strongest evidence suggested that hormonal treatment leads to resolution of spasms faster and in more infants than does vigabatrin. Responses without subsequent relapse may be no different. The same study suggests that hormonal treatments (prednisolone or tetracosactide) might improve the long-term developmental outcome compared with vigabatrin in infants not found to have an underlying cause for their infantile spasms. AUTHORS' CONCLUSIONS: To date, there have been few well-designed RCTs that considered the treatment of infantile spasms, and the numbers of patients enrolled have been small. Overall methodology has been poor, hence it is not clear which treatment is optimal in the treatment of this epilepsy syndrome. Hormonal treatment resolves spasms in more infants than vigabatrin but this may or may not translate into a better long-term outcome. If prednisone or vigabatrin are used then high dosage is recommended. Vigabatrin may be the treatment of choice in tuberous sclerosis. Resolution of the EEG features may be important but this has not been proven. Further research using large studies with robust methodology is still required.
Neuropsychiatr Dis Treat. 2008 Jun; 4(3): 619-25
Rocha L
Experiments using male CD1 mice were carried out to investigate the effects of subchronic (daily administration for 8 days) pretreatments with drugs enhancing GABAergic transmission (diazepam, 10 mg/kg, ip; gabapentin, 100 mg/kg, po; or vigabatrin, 500 mg/kg, po) on pentylenetetrazol (PTZ)-induced seizures, 24 h after the last injection. Subchronic administration of diazepam reduced latencies to clonus, tonic extension and death induced by PTZ. Subchronic vigabatrin produced enhanced latency to the first clonus but faster occurrence of tonic extension and death induced by PTZ. Subchronic gabapentin did not modify PTZ-induced seizures. Autoradiography experiments revealed reduced benzodiazepine receptor binding in several brain areas after subchronic treatment with diazepam or gabapentin, whereas subchronic vigabatrin did not induce significant receptor changes. The present results indicate differential effects induced by the subchronic administration of diazepam, vigabatrin, and gabapentin on the susceptibility to PTZ-induced seizures, benzodiazepine receptor binding, or both.