Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacokinetics, safety, and tolerance of linopiridine ([3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one]; DuP 996) a potential therapeutic agent for Alzheimer's disease, were assessed in double-blind, placebo-controlled, randomized studies in which single oral doses were given to 64 healthy young or elderly males. Young subjects received escalating doses of 0.5 to 55 mg, whereas elderly subjects were given doses of 20 to 45 mg. Linopirdine plasma and urine samples were quantified after liquid extraction by a specific HPLC method using UV detection. In both groups, linopirdine disposition was characterized by rapid absorption (mean Tmax, < 1 hr) and elimination (mean t1/2, 0.4-3.2 hr). Urinary excretion of unchanged drug was negligible. The pharmacokinetic parameters showed large inter- and intrasubject variability. Linopirdine was well-tolerated in both young and elderly volunteers. The most frequently reported adverse event was headache. The subjects who received linopirdine did not experience clinically important changes in vital signs, electrocardiograms (ECGs), electroencephalograms (EEGs), or clinical laboratory evaluations.
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PMID:Single-dose pharmacokinetics, safety, and tolerance of linopirdine (DuP 996) in healthy young adults and elderly volunteers. 775 10

During the past 2 decades, great advances have been made in the treatment of ulcer disease. This has involved the development of new drugs that are not only well tolerated, but are relatively inexpensive. The lack of significant adverse effects has revealed a degree of tolerability that, to write a review of the adverse effects, poses a difficult task. Most of the adverse effects are related to an excessive reaction to the relevant pharmacological characteristic that mediates the therapeutic response. The drug dosage can be reduced, freeing the patient of the adverse reaction, but leaving behind a background activity adequate to produce a therapeutically beneficial effect. The adverse effects of H2-antagonists fall into 2 groups. Firstly, there are poorly defined symptoms that have a prevalence similar to that in the community; these include headache, giddiness, dizziness, fatigue, constipation and diarrhoea. Secondly, they may delay the metabolism of drugs metabolised by the the cytochrome P450 system, and rarely be androgenic. Many antacids and the site-protective agent sucralfate contain aluminium, which can be absorbed, producing elevation of serum aluminium levels. In view of the possible association of aluminium with Alzheimer's disease, anxiety has arisen as to whether aluminium from these sources may, in those on prolonged treatment, cause Alzheimer's disease. However, the evidence so far indicates that aluminium is not a risk factor for Alzheimer's disease. The association of gastric cancer with achlorhydria has led to the fear that long term use of potent acid inhibitors may cause cancer. This fear has been accentuated by the observation that some rats, given omeprazole over their lifetime, developed carcinoid tumours of the stomach. However, enthusiastic research, both clinical and epidemiological, indicates that drug-induced achlorhydria is unlikely to be a problem in humans. Site protective agents have a role in certain conditions such as pregnancy where the systemic effect of a drug may produce adverse effects.
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PMID:A comparative overview of the adverse effects of antiulcer drugs. 776 37

We report the findings of a total population survey of Thugbah community in the Eastern Province of Saudi Arabia (SA) to determine its point prevalence of neurological diseases. During this two-phase door-to-door study, all Saudi nationals living in Thugbah were first screened by trained interviewers using a pretested questionnaire (sensitivity 98%, specificity 89%) administered at a face-to-face interview. Individuals with abnormal responses were then evaluated by a neurologist using specific guidelines and defined diagnostic criteria to document neurological disease. The questionnaire was readministered blind by a neurologist to all those with abnormal responses and a 1-in-20 random sample of those without abnormal responses, respectively. The family members of an individual with an abnormal response were also screened to improve accuracy. A total of 23,227 Saudis (98% of the eligible subjects) were screened and those residing in Thugbah on the reference date (22,630) were used to calculate the point prevalence rates. Forty-two percent of those screened were in the first decade of life and only 1.5% were more than 60 years old. There were marginally more females (50.2%) than males (49.8%). Consanguineous marriages especially between first cousins were present in 54.6%. The demographic characteristics of Thugbah community were similar to those in other parts of SA. The overall crude prevalence ratio (PR) for all forms of neurological disease was 131/1,000 population. All subsequent PRs are per 1,000 population. Headache syndromes were the most prevalent disorder (PR 20.7). The PR for all seizure disorders was 7.60, and the epilepsies (6.54) were more frequent than febrile convulsions (0.84). Mental retardation, cerebral palsy syndrome, and microcephaly were common pediatric problems with PRs of 6.27, 5.30 and 1.99, respectively. Stroke, Parkinson's disease, and Alzheimer's disease were uncommon with respective PRs of 1.8, 0.27 and 0.22. Central nervous system (CNS) malformations (0.49) such as hydrocephalus and meningomyelocele were more prevalent than spinal muscular atrophy (0.13), congenital brachial palsy (0.13) and narcolepsy (0.04). Multiple sclerosis was rare (0.04). Osteoarthritis and low back pain syndromes were the main non-neurological conditions seen. The major medical diseases that may be neurologically relevant were diabetes mellitus, hypertension, and connective tissue disorders.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A community survey of neurological disorders in Saudi Arabia: the Thugbah study. 827 77

SDZ ENA 713 (ENA 713) is an acetylcholinesterase inhibitor being developed as a potential treatment for Alzheimer's disease (AD). A prior Phase II safety and efficacy study used an upper dose limit of 6 mg/day ENA 713. The present study was designed to assess the safety and tolerability of higher doses of ENA 713 in probable AD patients. Fifty AD patients (22M; 28F, mean age 68 yrs, range 45-90) were assigned to a fixed, nine-week dose escalation schedule in which they were randomized to receive up to 12 mg/day of ENA 713 bid (n=20) or tid (n=20), or placebo (n=10) followed by a one-week washout. Mg/day dose escalation for the bid and tid ENA 713 groups was identical, beginning with 2 mg/day on Days 1 to 3 and escalating to 12 mg/day in Weeks 8 and 9. Doses through 12 mg/day were well tolerated. Most adverse events were mild to moderate in severity and of limited duration, most commonly headache, nausea, dizziness, and diarrhea. Three of forty patients on ENA 713 discontinued, all due to adverse events. Two experienced nausea and vomiting; the third experienced an unrelated mild atrial fibrillation.
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PMID:Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease. 861 73

Since 1984, there has been a great interest in the phenomenon of a particular seasonally recurrent mood disorder called seasonal affective disorder (SAD) or winter depression and its treatment: the phototherapy. Seasonal affective disorder is a syndrome described by Rosenthal in 1984. This mood disorder is characterized by depression with onset recurrent in autumn or winter and spontaneous spring or summer remission. It is associated with hypersomnia, anergia, increased appetite, weight gain and carbohydrate craving. The population prevalence in the north of the USA is estimated between 3 and 5%, but it changes with sex, age and also latitude. A long time ago, we know that animals are photoperiod sensitive and that the melatonin secretion in mammals is suppressed by the light. In 1980, Czeiler reported for the first time that human melatonin secretion can be suppressed by high light exposure (+/- 1500 lux). In 1982, Rosenthal, Lewy and al. reported an antidepressant effect of light exposure of a manic-depressive patient. The phototherapy was born. To treat the SAD, the most common procedure of phototherapy is to expose the subject during 2 hours early in the morning, between 06:00 and 09:00 AM. The subject is sitting before a light screen, he can work and has to fix the screen one time every minute. The most common side effects are headache, eyestrain, muscle pain. The ocular phototoxicity is controversed and it seems to be potentially dangerous if phototherapy is associated with tricyclic antidepressants, neuroleptics and other medication containing a tricyclic, heterocyclic or porphyrin ring system. Since this finding, many questions are asked about photoperiod and its effects in the human being. Lewy proposes for the winter depression the hypothesis of a phase delayed circadian rhythm, that can be treated by a morning light exposure. At the present time, many trials are going on to study the effects of phototherapy in other problems like insomnia, maladaptation to night work, jet lag and Alzheimer disease.
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PMID:[Seasonal affective syndrome and phototherapy: theoretical concepts and clinical applications]. 868 79

Inconsistencies within results of case-control studies on Alzheimer's disease risk factors led to a search of the literature for a potential cofactor. Reduced cerebral blood flow was selected and literature was surveyed for evidence of a cerebral blood flow linkage with the more than 40 putative risks. Alcohol abuse, depression, head trauma, underactivity, old age, sleep disturbance, glucose utilization, Down's syndrome, and Parkinson's disease are risk factors where an association with reduced cerebral blood flow is documented. Studies were cited showing that improved cerebral blood flow is associated with factors thought to be helpful in Alzheimer's disease, such as education or occupational attainment, exercise, headache, smoking, and arthritis/anti-inflammatory drugs to the extent that aspirin is used. Sugar consumption is identified as a potential risk factor with glucose management in Alzheimer's disease also shown to involve reduced cerebral blood flow. An hypothesis is developed showing how compromised regional cerebral blood flow could fit as a cofactor for genetic, autoimmune, and neurotoxic aspects of Alzheimer's disease.
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PMID:Alzheimer's disease risk factors as related to cerebral blood flow. 873 67

Reduced cholinergic transmission is a key neurotransmitter dysfunction in Alzheimer's Disease (AD). NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor, has demonstrated activity in animal models of memory function, and was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days. Since AChE inhibitors are often tolerated differently in AD patients than in healthy volunteers, a randomized, placebo-controlled, double-blind, single-center, inpatient bridging study was conducted to determine the maximum tolerated dose (MTD) of NXX-066 in the target patient population. Seven consecutive panels of eight AD patients each (6 active, 2 placebo) received fixed oral doses of NXX-066 (20, 30, 40, 50, 60, 70, or 80 mg BID) for seven days. Initiation of each subsequent panel (dose group) was contingent upon the tolerability of lower dose levels. The MTD was determined to be 70 mg BID when four of six patients receiving 80 mg BID were prematurely discontinued from the study due to nausea and/or vomiting, accompanied in some patients by mild to moderate dizziness, headache, asthenia, and gastric symptoms. Wide variability in plasma levels of NXX-066 was observed in all dose panels. AChE inhibition in whole blood correlated with both maximum plasma concentration and dose; however, AChE inhibition was not predictive of adverse events. In this study, AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing. Further studies are warranted to examine whether differing tolerability between patients and healthy subjects or the reduced dosing interval explains these findings.
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PMID:NXX-066 in patients with Alzheimer's disease: a bridging study. 1021 Feb 64

The German philosopher Immanuel Kant (1724-1804) suffered, since his forties, from a migraine with aura which showed a significant exacerbation in his seventies, coinciding with the onset of symptoms of a senile dementia of Alzheimer's type. Recorded symptoms of Kant's migraine include recurrent scintillating scotomas, one episode of diplopia, two episodes of complete amaurosis and frequent headaches described as oppressions of the head. The said symptoms of Kant's migraine can be traced not only in his letters and in accounts of his contemporary biographers, but also in the philosopher's published work.
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PMID:[The migraine of Immanual Kant]. 1094 59

Two years after being successfully treated for biopsy confirmed primary angiitis of the central nervous system (PACNS), a 69-year-old woman presented with cognitive decline. In contrast to her first presentation, her altered mental function developed gradually, was not associated with headache or abnormal cerebrospinal fluid analysis, and did not improve with immunosuppression. Reevaluation of her original brain biopsy not only confirmed the presence of PACNS, but also revealed neuritic plaques and neurofibrillary tangles, suggesting a concurrent diagnosis of Alzheimer's disease. Cerebral angiogram did not suggest vasculitis and magnetic resonance imaging showed generalized cerebral atrophy supporting the diagnosis of Alzheimer's. This case illustrates that Alzheimer's dementia and PACNS can coexist in a single patient and that Alzheimer's disease should be considered when a patient with successfully treated PACNS presents with cognitive decline months or years after initial diagnosis.
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PMID:Primary angiitis of the central nervous system and Alzheimer's disease: clinically and pathologically evident in a single patient. 1112 90

Donepezil (donepezil hydrochloride, E-2020, Aricept, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer's disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author's clinical experience with the drug.
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PMID:The pharmacology of donepezil: a new treatment of Alzheimer's disease. 1124 55


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