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Biomedical subjects

A Keyser

Publications and source records attributed to A Keyser.

At least 37 records · Page 2Linked to original sources
PubMed2000

Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed.

PURPOSE: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. METHODS: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. RESULTS: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. CONCLUSIONS: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.

Animals↗
PubMed2000

Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings.

PURPOSE: To describe imaging findings and their neuropathologic correlate in patients with cerebrotendinous xanthomatosis (CTX). MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images in 24 patients with symptoms (mean age at time of imaging, 37 years; mean disease duration, 18 years) were reviewed for site and frequency of brain, spinal cord, and Achilles tendon involvement. Two patients died, and imaging findings were compared with postmortem neuropathologic findings. RESULTS: Apart from nonspecific supratentorial atrophy and deep white matter changes, more typical hyperintense lesions were seen on T2-weighted images in the dentate nucleus (in 79% of patients), globus pallidus, substantia nigra, and inferior olive and extended into adjacent white matter as disease progressed. In these locations, lipid crystal clefts and perivascular macrophages, neuronal loss, demyelination, fibrosis, and reactive astrocytosis were found at microscopic examination. Hypointensity was sometimes found on T2-weighted images in the dentate nucleus and was related to deposition of hemosiderin and calcifications. CT depicted fewer lesions; all had low attenuation, except for the calcifications. Spinal cord MR imaging revealed increased signal intensity in the lateral and dorsal columns on T2-weighted images. Achilles tendon xanthomas displayed intermediate signal intensity on T1- and T2-weighted images. CONCLUSION: The typical pattern of MR imaging findings reflects the classic histopathologic findings and should prompt the diagnosis of CTX.

Adolescent↗
PubMed1999

Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis.

The effects of combination therapy with chenodeoxycholic acid (CDCA) and simvastatin on serum cholestanol, low-density lipoprotein (LDL) cholesterol, and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis (CTX) who were on long-term treatment with CDCA. The patients were treated with a combination of CDCA 750 mg daily and an increasing dose of simvastatin from 10 mg to 40 mg daily for a period of 6 months. We found a significant effect of this combination therapy compared with CDCA alone in terms of decreasing the serum cholestanol and LDL cholesterol levels, particularly with a daily dose of 40 mg simvastatin. The mean cholestanol level decreased from 9.27 micromol/L (baseline) to 6.69 micromol/L (40 mg simvastatin), while the mean LDL cholesterol level decreased from 5.08 mmol/L (baseline) to 3.04 mmol/L (40 mg simvastatin). No side effects were reported, and there were no effects on the clinical condition, cerebral magnetic resonance imaging (MRI), visual evoked potentials, and electroencephalographic features. We conclude that a combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol, and lathosterol in adult CTX patients treated with long-term CDCA. Whether this combination treatment will be effective for the long-term prevention of neurological deterioration and atherosclerosis remains to be established.

Adult↗
PubMed1999

Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis.

We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX). MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. Post-mortem examination of one of the patients showed extensive myelin loss in these columns. An array of genotypes was found in these patients. We conclude that 'spinal xanthomatosis' is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of 'chronic myelopathy'.

Adult↗
PubMed1998

Ileus in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes.

PATIENT: A 39-year-old woman with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) who developed paralytic ileus and died of irreversible shock. METHODS: Abdominal X-ray, autopsy using light microscopy, electron microscopy and mitochondrial DNA analysis. RESULTS: Paralytic ileus was diagnosed. Several hours after admission the patient died from irreversible shock. At autopsy, ultrastructural examination of the small intestine revealed abnormal accumulation of mitochondria in smooth muscle cells. DNA analysis of the intestinal tissue showed a tRNALeu(UUR) A-->G transition at nucleotide position 3243 of the mitochondrial DNA. The amount of mutated mitochondrial DNA was markedly higher in the lamina muscularis than in the mucosa: 30% vs; 8%. CONCLUSIONS: Paralytic ileus may be due to mutated mitochondrial DNA which ultimately leads to smooth muscle dysfunction in the small intestine. Recognizing mitochondrial DNA abnormalities as a new etiopathogenetic factor of paralytic ileus may become more important in clinical medicine in the near future.

Adult↗
PubMed1998

The whiplash syndrome: a psychophysiological and neuropsychological study towards attention.

Whiplash patients often have physical, psychosomatic and cognitive complaints, although clear neurological and neuropsychological signs of damage are absent. However, in some studies a functional loss of attention was found. In order to compare attentional dysfunctions in whiplash patients with age-matched controls, attention was measured neuropsychologically with the aid of the PASAT, and psychophysiologically with the aid of the prepulse inhibition paradigm. In addition, the reactivity for intense acoustic stimulation was investigated. The POMS and the SCL-90 were used to evaluate psychological and somatic signs. The results showed that whiplash patients (n=24) had lower scores on the PASAT and higher scores on the questionnaires compared to healthy controls (n=21). However, no group differences could be determined on the psychophysiological variables. Furthermore, the PASAT and prepulse inhibition data did not correlate. The lower PASAT scores indicate that whiplash patients seem to have deteriorated divided attention, but an attention deficit as measured with the prepulse inhibition paradigm is not disclosed. Finally, there were no signs of a heightened reactivity of the auditory system, which casts doubts on a presumed heightened sensitivity for sound in whiplash patients.

Acoustic Stimulation↗
PubMed1997

[Neurofibromatosis type 2].

Neurofibromatosis type 2 (NF2) is a complex and progressively disabling disease, resulting from development of multiple central nervous system tumours. Two case studies, one of a woman who suffered hearing problems from the age of 17 and one of a man with cataract as the first symptom at the age of five, illustrate the complex course of the disease. The first patient died of her disease, the second due to a traffic accident. It is necessary to anticipate the frequent development of new neoplasms. The regular communication between the various disciplines involved in the patient's care is instrumental to reach this goal. This multidisciplinary approach should also play a part in the screening of patients at risk for NF2.

Adult↗
PubMed1997

Tremor in Latin texts of Dutch physicians: 16th-18th centuries.

In his monograph An essay on the shaking palsy (1817), James Parkinson mentioned tremor and propulsion to be the most important signs of the disease that he was describing. In this article, we study aspects of the history of one of the signs that he mentioned, that is, tremor, and see how the meaning of this term evolved since its description by Galen, particularly in the period from the 16th to the 18th centuries. We'll pay attention to the development of a distinction made between action tremor and rest tremor. Work by the following authors is covered: Pratensis and Forestus (16th century); Tulp, Van Beverwijck, an Sylvius (17th century); and Boerhaave and Van Swieten (18th century). Not all authors made the distinction, originally noticed by Galen, between action tremor and rest tremor. Parkinson tremor probably was observed but was classified among the tremors of the elderly. The meaning of palpitation changed through the ages and finally was applied only to pathologic heart and artery pulsations. Sylvius and Van Swieten were the only authors in this study who clearly distinguished between action and rest tremor. They are discussed in Parkinson's monograph.

Geriatrics↗
PubMed1997

Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects.

PURPOSE: We reviewed the literature to determine whether an analysis of published data could clarify the relationship between antiepileptic drug (AED) polytherapy and adverse affects (AE). We highlight the problems encountered. METHODS: We made a Medline-search for articles published between 1974 and 1994 reporting the number of AE and doses or serum levels of every AED, per patient or treatment group, and used the PDD/DDD ratio to calculate AED load per patient from doses or the OSL/AToxL ratio to do so from serum levels of individual drugs. The PDD/DDD is the sum of ratios of the actual prescribed daily doses divided by the published average therapeutic dose of each drug. The OSL/AToxL is the sum of each observed serum level divided by its average toxic level. RESULTS: We retrieved 118 trial reports. Most had to be excluded because of incomplete reporting of concomitant medication or AE. The data of the 15 articles selected for further analysis indicate a relationship between drug load and number of AE. We noted no relationship between the number of AEDs administered and AE. In add-on studies, the difference in neurotoxicity between the active and placebo arm may be obscured if the relative increase in drug load is small, as exemplified by the study of McGuire et al.. CONCLUSIONS: Articles reporting add-on trials of new AEDs generally do not provide detailed information about the basic medication to which the new AED is added, which makes calculation of total drug load impossible. Furthermore, often only frequency of AE is reported, not severity or development of tolerance, making it difficult to judge the impact of AE. However, despite the paucity of available information, we present some evidence that toxicity in AED polytherapy may be related to total drug load, rather than to the number of drugs administered. Therefore, the present trend to reject polytherapy for fear of increased toxicity is not warranted, which removes one of the objections to initiating specific research to prove or disprove the value of AED combinations as long as the drug load is appropriate.

Anticonvulsants↗
PubMed1997

Adverse effects in epilepsy therapy. Wait and see or go for it?

OBJECTIVES: Attention for adverse effects (AEs) is important for optimizing epilepsy treatment. However, a uniform strategy is lacking. In particular there appears to be a dichotomy between those who "wait and see" and those who "go for it", i.e. routinely check a list of AEs. Our intention is to identify the effects of different approaches. METHODS: Trial reports on carbamazepine or valproate monotherapy (Medline-search), and data from the Nijmegen Epilepsy Research Group were analyzed. RESULTS: Analysis suggests that for certain AEs, such as diplopia, dysarthria, affect and mood disturbances, headache, dizziness, gastro-intestinal disturbances, dermatological disturbances and idiosyncratic reactions, it does not matter which approach is chosen. However, sedation, cognitive impairments, sexual dysfunction, hair changes, nystagmus, gait disturbances, tremor and weight changes are reported more frequently when routinely checked. The value of routine laboratory monitoring is, however, questioned. CONCLUSIONS: Use of different strategies to detect AEs obstructs estimation of risks of AEDs. Baseline measurements and regular checking for those AEs, which are reported more frequently by authors who actively search for AEs, is advisable.

Anticonvulsants↗
PubMed1997

Newer anticonvulsant drugs: role of pharmacology, drug interactions and adverse reactions in drug choice.

In the last few years a number of new anticonvulsants have been introduced into clinical practice mainly as add-on therapy in patients who do not become seizure-free while receiving established anticonvulsants. Up to now, no single drug has been shown to be more effective at controlling seizures of a particular type than another, so other factors such as mechanism of action, pharmacokinetics, dosage regimens or the spectrum of adverse drug reactions and interactions are used when making a choice between one agent and another. The mechanism of action of tiagabine and vigabatrin is very specific; both agents increase gamma-aminobutyric acid (GABA) levels through inhibition of reuptake and catabolism respectively. However, the mechanism of action of gabapentin is unknown and those of felbamate, lamotrigine and topiramate are not sufficiently clarified as yet, and may be multiple. Great advances have been made in improving the pharmacokinetic characteristics of these newer anticonvulsants. Gabapentin and vigabatrin exhibit relatively ideal pharmacokinetic properties as they are not bound to proteins, are excreted mostly unchanged in the urine and show linear pharmacokinetics. Lamotrigine possesses a highly variable elimination half-life depending on the co-medication. Tiagabine is highly protein bound and zonisamide shows nonlinear pharmacokinetics; both these drugs are extensively metabolised. Problematic drug interactions between newer anticonvulsants and other drugs in general occur rarely when these agents are given concomitantly. However, in common with most new drugs, there are very few data on the use of the newer anticonvulsants in women of childbearing age. Studies done so far on interactions with oral contraceptives used low anticonvulsant dosages for a very short time. The newer anticonvulsants elicit adverse reactions that, while not being unique, are particularly associated with that drug. For example, felbamate may cause aplastic anaemia and fulminant liver failure, lamotrigine is prone to cause skin rash, and oxcarbazepine may cause symptomatic hyponatraemia. Topiramate and zonisamide cause kidney stones, and vigabatrin may induce psychiatric syndromes. Although highly diverse in structure and activity, these newer drugs offer new possibilities for treating refractory epilepsy. However, since no single factor can dictate the choice of drug nor predict the success of treatment, prescribing of these rather expensive drugs has to depend upon careful consideration of the aims of treatment, the characteristics of the drug and the needs of the individual patient.

Adult↗
PubMed1996

Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis.

This report concerns two new mutations in the sterol 27-hydroxylase gene in two patients with cerebrotendinous xanthomatosis (CTX). In a Surinam-Creole patient (patient A), a G deletion on position cDNA 546/547 in exon 3 led to a frameshift and the introduction of a premature termination codon. In a Dutch patient (patient B), a C-->T transition at position 496 in exon 3 also led to a premature termination codon. Patient A was homozygous for the mutation, whereas patient B was compound heterozygous, a C-->T transition also being found in exon 6 at position 1204. The two new mutations were confirmed by restriction analysis with the restriction enzymes FokI and MaeI, respectively.

Adult↗
PubMed1996

Use of antiepileptic drugs in a community-dwelling Dutch population.

We compared the treatment policy for patients with epilepsy in six Dutch cities, comprising 302, 149 inhabitants, with the treatment policies of a secondary referral center (a university hospital) and tertiary referral centers (outpatient departments of epilepsy centers). By comparing the prevalence of individuals receiving antiepileptic drugs in the six cities with the epidemiologic data for epilepsy in Rochester, Minnesota, we concluded that prescription data offer a suitable means by which to estimate the prevalence of epilepsy in a community. To compare prescriptions in cases of polytherapy, we normalized data by using defined daily doses published by the WHO Collaborating Center for Drugs Statistics Methodology and the Nordic Council on Medicines and concluded that the defined daily doses of antiepileptic drugs should be further elaborated. There is a need to obtain complete dose-response curves of equivalent antiepileptic drugs in humans. The trend of drugs use found in the six cities, the university hospital, and the epilepsy centers is, however, in accord with the expectations regarding primary, secondary, and tertiary referral centers.

Adolescent↗
PubMed1996

Towards a disability-oriented epidemiology of traumatic brain injury.

The aim of this study was to investigate the value of using a disability-oriented approach to the epidemiology of traumatic brain injury (TBI) in order to improve health administration by preventing long-term sequelae. The epidemiology of disease was established by registration system of inpatients which covers more than 99% of all hospital admissions in The Netherlands. Some international differences and national trends are discussed. The disability-related epidemiology was investigated by means of structured interviews, 3-7 years after the injury, in a clustered sample of 51 patients with major TBI according to the ICD-9-CM. The survey included evaluation scales such as the Sickness Impact Profile, the Barthel Index, and a Disability Rating Questionnaire. Concerning the disease-related epidemiological data, the overwhelming majority of all TBI patients went home, which suggests good recovery. Nevertheless, the disability-oriented research revealed long-term situational, cognitive and behavioral disabilities in at least 67% of the major-TBI population, whereas only 10% received any rehabilitation services at all after the acute-care period. It is concluded that preventive measures and a comprehensive service for brain injury survivors should be based both on disease and disability-oriented data.

Adult↗
PubMed1995

Neither dosage nor serum levels of antiepileptic drugs are predictive for efficacy and adverse effects.

In order to assess whether doses or serum levels are predictive for the efficacy and adverse effects of antiepileptic drugs (AEDs), measures for exposure to drug combinations have to be used. For doses, the ratio of the observed prescribed daily dose (PDD) and the average defined daily dose (DDD) considered effective for the main indication of the drug was used. In analogy for serum levels, the OSL/ATL ratio, i.e. the ratio of the observed serum level and the average therapeutic level was used. In polypharmacy these ratios can be summed as the are normalized measures of strength. The correlations of these ratios with outcome measures were studied in 200 patients attending out-patient clinics of special centres for epilepsy; half of these patients were treated with monopharmacy and half with polypharmacy. As outcome measures the following indices were used: the index of seizures, which quantifies seizure type and frequency, the seizure activity index, the neurotoxicity score, the systemic toxicity score, and the composite index of impairments, which is the sum of the seizure activity index and the neurotoxicity score and the systemic toxicity score. When all data were pooled, the correlation coefficient between the PDD/DDD ratio and the OSL/ATL ratio was 0.77. However, when the data were examined separately for the monopharmacy and polypharmacy groups, the correlation was 0.31 for the monopharmacy group and 0.50 for the polypharmacy group. Neither the PDD/DDD ratio nor the OSL/ATL ratio correlated with the composite index of impairments or with any of the individual indices. Factors such as the difficulty of titrating the endpoint of seizure suppression and the development of tolerance to adverse drug effects may perhaps be responsible for these findings. This observational study signals the problem.

Adult↗
PubMed1995

Conventional radiotherapy combined with carbogen breathing and nicotinamide for malignant gliomas.

High grade malignant gliomas are among the most radioresistant human tumors and total doses up to 80 Gy are inadequate to achieve long-term local control in most of the patients. Hypoxia has been demonstrated in primary brain tumors and may be one of the reasons for their radioresistance. In experimental models carbogen breathing and nicotinamide have been shown to act against hypoxia by different mechanisms and both modalities were tested in 16 patients with supratentorial malignant gliomas in combination with a conventional radiotherapy scheme (50 Gy in 25 daily fractions). The present study was performed to determine the feasibility and toxicity of conventional radiotherapy combined with carbogen breathing and nicotinamide. The unexpectedly high incidence of acute liver toxicity, the possible increase of subacute and late CNS toxicity, and the absence of a higher effectivity led us to reconsider this new treatment modality for patients with malignant gliomas.

Administration, Inhalation↗