Gene/Protein Disease Symptom Drug Enzyme Compound
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Ten patients with severe dementia due to Alzheimer's disease (AD) or multi-infarct dementia (MID) or both, were treated with the precursor amino acids of the neurotransmitters serotonin and dopamine. The precursor amino acids (PAA) were given orally in a preparation that included tyrosine (4 gm daily) and 5-hydroxy-tryptophan (5-HTP) (800 mg daily), plus carbidopa (100 mg daily) as an aromatic amino-acid decarboxylase inhibitor. Diagnosis was established by an electroencephalogram, brain scan, computerized axial tomographic scan, and in one case by necropsy findings. Serial clinical evaluations and measurements of neuropsychologic function were performed. Levels of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) were determined before and after administration of probenecid. Side effects of the PAA therapy were diarrhea, drowsiness, nausea, vomiting and agitation, all of which were controlled by reducing the dosage. One patient with MID and one with AD+MID showed clinical and psychologic improvement, but the others did not improve. Analysis of the cerebrospinal fluid for HVA and 5-HIAA before and after the probenecid test indicated some improvement in the metabolic turnover of these acid metabolites of serotonin and dopamine after administration of their precursor amino acids.
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PMID:Neurotransmitter precursor amino acids in the treatment of multi-infarct dementia and Alzheimer's disease. 30 Nov 48

Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
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PMID:Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships. 173 48

A 38 year-old laborer experienced solvent intoxication during each of two spray paintings of a dump truck and other heavy equipment in an enclosed, unventilated garage. The paint base consisted primarily of toluene and methyl ethyl ketone. Nausea, headaches, dizziness, respiratory difficulty and other symptoms began after exposures. Over the next several days he developed impaired concentration, memory loss and cerebellar signs including an intention tremor, gait ataxia and dysarthria. MRI of the brain and EGG early in the work-up were normal, although later MRIs demonstrated fluid collection over the left parietal area. Examination by a toxicologist and neurologist revealed likely toxic encephalopathy with dementia and cerebellar ataxia. Three formal neuropsychological assessments over 2 1/2 years quantified cognitive, motor and behavioral changes. Despite similar findings in chronic exposure to these solvents, lasting sequelae following acute exposure have not been widely reported.
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PMID:Chronic neuropsychological and neurological impairment following acute exposure to a solvent mixture of toluene and methyl ethyl ketone (MEK). 174 49

Within the health care of the elderly with prevention, diagnosis, therapy, rehabilitation, nursing care and social service, diagnostic procedures are of great importance to avoid under- and over-diagnosis. Many diagnostic difficulties exist in elderly patients such as changed reference values, changed normal values and changed signs and symptoms. Well-known examples of conditions which are likely to be under-diagnosed include depression and urinary incontinence. Examples are given from the cardiopulmonary field where e.g. dyspnoea showed to be very common, but in only 36% of males and 52% in females related to cardiac failure or pulmonary disease. The most common symptom of acute myocardial infarction in elderly patients was shown to be dyspnoea, whereas chest pain occurred in only one fifth of the cases. In another study of patients with ulcer disease loss of appetite and weight, nausea and anemia were more common than abdominal pain and heartburn. In peritonitis patients, abdominal pain was observed in only just more than half of the cases and guarding and/or abdominal rigidity in about one third. In patients with suspect age dementia a detailed investigation showed the prevalence of organic dementia to be 89% whereas 3% had treatable dementia and 8% non-dementia conditions. In geriatric long-term patients the mean hearing loss in the speech area was about 50 dB, in spite of the fact that only about 10% of the patients had hearing aids. The need for nursing diagnosis is also obvious. It is concluded that a detailed multidisciplinary diagnostic investigation procedure is very important in geriatric medicine.
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PMID:The importance of diagnostic procedures to ensure quality of health care in geriatric medicine. Examples from recent studies. 198 60

Identification of 5-HT receptor subtypes--5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 (possibly A and B), 5-HT3 subtypes, and possibly 5-HT4--has encouraged the manufacture of 5-HT receptor inhibitors with greater subtype specificity. However, it appears that the receptors interact, and drugs initially thought to be specific may have multiple actions. For some conditions such as anxiety/depression, almost all receptors are implicated. Clinical studies provide clear evidence that manipulation of the 5-HT system has a role in treating depression, anxiety, obsessional illness, migraine, and eating disorders. Interactions between the various receptor subtypes make it difficult to identify specific clinical functions. The 5-HT1A receptors may be involved in aggression, anorexia, and hypotension. The 5-HT1B receptors may be involved in aggression, while the 5-HT1C receptors may play a role in central aversion systems and anxiety/depression. The role of the 5-HT1D receptors remains speculative; 5-HT2 receptors appear to be involved in depression, anxiety, appetite, sleep, vasoconstriction, and hypertension. Many drugs that are effective in treating migraine are potent 5-HT2 antagonists. 5-HT3 antagonists at high doses are effective in treating nausea and at low doses in treating anxiety. Treatment of aggression, suicidal behaviour, addiction behaviour, memory impairment, dementia, and schizophrenia with 5-HT inhibitors requires further testing.
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PMID:Is there a relationship between serotonin receptor subtypes and selectivity of response in specific psychiatric illnesses? 269 41

Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects.
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PMID:Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. 332 59

We analyzed 26 cases of primary lymphoma of the central nervous system. There were 14 males and 12 females ranging in age from 5-76 years (median age 51 years, mean age 50.2 years). None had received organ transplantation or immunosuppressive therapy. The most common presenting symptoms were headache, mental changes, nausea, vomiting, and convulsions. The main neurological findings were hemiparesis, papilledema, visual field defects, and cranial nerve palsies. The most common finding in the cerebrospinal fluid (CSF) was high protein content; CSF cytology was positive in only one case. Computerized tomography was done in 14 cases; all showed a contrast-enhancing lesion. Angiography generally revealed an avascular mass. The most common location above tentorium was the frontal lobe; in four cases the tumor was infratentorial (cerebellum, 3 cases). In five cases there was diffuse involvement of the brain; all had severe dementia and diagnosis was not made until the autopsy. Histologically, the most common type was diffuse histiocytic or immunoblastic lymphoma according to Rappaport and the Working Formulation classification respectively. Radiation therapy alone in five patients gave a median survival of 17 months. Five patients received radiation and chemotherapy, and median survival was 16 months. Two patients developed ocular lymphoma 8 and 36 months later that was treated by radiation.
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PMID:Primary lymphoma of the central nervous system: a clinicopathologic analysis of 26 cases. 376 91

Among patients with renal failure, there have been impressive modifications of both the duration and quality of life as a result of dialysis, renal transplantation, and improved medical management. However, patients who have renal failure continue to manifest a variety of neurologic disorders. Patients with chronic renal failure who have not yet received dialytic therapy may develop a symptom complex progressing from mild sensorial clouding to delirium and coma, with tremor, asterixis, multifocal myoclonus, and seizures. Even after the institution of otherwise adequate maintenance dialysis therapy, patients may continue to be afflicted with more subtle nervous system dysfunction, including impaired mentation, generalized weakness, and peripheral neuropathy. The central nervous system disorders of both untreated renal failure and that persisting despite dialysis are referred to as uremic encephalopathy. The dialytic treatment of end stage renal disease has itself been associated with the emergence of two distinct, new disorders of the central nervous system: Dialysis dysequilibrium and dialysis dementia. The dialysis disequilibrium syndrome consists of headache, nausea, muscle cramps, obtundation and seizures, and is a consequence of the initiation of dialysis therapy in some patients. Dialysis dementia is a progressive, generally fatal encephalopathy which affects patients on chronic hemodialysis. This disease also appears to be a complication of the therapy for renal failure.
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PMID:Pathogenesis of dialysis encephalopathy. 636 3

Patients with renal failure may manifest a variety of neurologic disorders. Patients with chronic renal failure who have not yet received dialytic therapy may develop a symptom complex progressing from mild sensorial clouding to delirium and coma, with tremor, asterixis, multifocal myoclonus, and seizures. After the institution of adequate maintenance dialysis therapy, patients may continue to be afflicted with more subtle nervous dysfunction, including impaired mentation, generalized weakness, and peripheral neuropathy. These central nervous system disorders are referred to as uremic encephalopathy. The dialytic treatment of end-stage renal disease has itself been associated with the emergence of two distinct, new disorders of the central nervous system; dialysis dysequilibrium and dialysis dementia. The dialysis disequilibrium syndrome consists of headache, nausea, muscle cramps, obtundation, and seizures, and is a consequence of the initiation of dialysis therapy in some patients. Dialysis dementia is a progressive, generally fatal encephalopathy which affects patients on chronic hemodialysis. There are at least three different forms of dialysis encephalopathy: sporadic, epidemic; and that associated with renal disease in children. In addition to the foregoing neurologic diseases which are specifically related to uremia and/or dialysis, a number of other neurologic disorders occur with increased frequency in patients with end-stage renal disease on chronic hemodialysis. These include subdural hematoma, electrolyte disorders, vitamin deficiencies, drug intoxication, hypertensive encephalopathy, and acute trace element intoxication. Renal transplantation is associated with a variety of central nervous system infections, reticulum cell sarcoma, and central pontine myelinosis. The present manuscript will review the clinical, structural, and biochemical components of those neurologic disorders which are peculiar to the uremic state and its treatment with dialysis.
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PMID:Uremic encephalopathies: clinical, biochemical, and experimental features. 675 30

We report a 78-year old woman with 30 years history of rheumatoid arthritis and nephrotic syndrome, who developed right hemiparesis and renal failure recently. The patient was diagnosed as having rheumatoid arthritis in 1965, and had been treated with gold -sol, steroid hormone, and non-steroidal anti-inflammatory drugs intermittently. Later on her clinical course was complicated by nephrotic syndrome, however, her renal function was well compensated. Otherwise, she was apparently doing well until October of 1988 when she had an onset of anomic aphasia; she was 73-year-old at that time. She was admitted to our hospital; a cranial CT scan at that time revealed a low density area in the left temporal region, and she was diagnosed as suffered from an atherothrombotic infarction involving the left middle cerebral artery territory. She recovered soon and was discharged for out patient follow up with ticlopidine 100 mg/day. She was doing well until December 15, 1990, when she had an acute onset of nausea, vomiting, and speech disturbance; she was admitted to our hospital for the second time. On admission, she was alert, but she had motor aphasia, right hemiparesis, and dysarthria. A cranial CT scan revealed a low density area in the left temporal region extending into adjacent frontal and parietal areas including the angular gyrus; in addition, leukoaraiosis, cortical atrophy, and ventricular dilatation were noted (Fig. 1A, B). She was treated supportively, and she showed improvement in her aphasia, however, moderate weakness remained in her right upper and lower extremities. She was discharged for out patient follow up. She was doing well until May 21, 1993, when she developed difficulty in swallowing and speech. She became unable to take foods orally and she was admitted again on May 31. On admission, she was afebrile and BP was 120/80 mmHg. General physical examination was unremarkable except for pitting edema and multiple contracture of her joints. On neurologic examination, she was alert but appeared to have aphasia and dementia; she could utter only a few simple words, and was able to understand only simple questions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[A 78-year-old woman with rheumatoid arthritis, right hemiparesis, and renal failure]. 789 38


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