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At least 1,117 records · Page 62Linked to original sources
PubMed2001

Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteers.

AIMS: The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. METHODS: The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules). RESULTS: The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. CONCLUSIONS: These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.

Adult↗
PubMed2006

Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6.

Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson's disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimicking the clinical picture of PD with earlier onset and slower progression. Genetic data demonstrated PARK6 to be caused by mutations in the protein PINK1, which is localized to mitochondria and has a serine-threonine kinase domain. To study the effect of PINK1 mutations on oxidative stress, we used primary fibroblasts and immortalized lymphoblasts from three patients homozygous for G309D-PINK1. Oxidative stress was evident from increases in lipid peroxidation and in antioxidant defenses by mitochondrial superoxide dismutase and glutathione. Elevated levels of glutathione reductase and glutathione-S-transferase were also observed. As a putative cause of oxidation, a mild decrease in complex I activity and a trend to superoxide elevation were detectable. These data indicate that PINK1 function is critical to prevent oxidative damage and that peripheral cells may be useful for studies of progression and therapy of PARK6.

Adult↗
PubMed2004

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress.

The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Brain↗
PubMed1988

Does the study of anaerobic metabolism give quantitative information on left ventricular dysfunction during exercise?

The anaerobic threshold (AT) has been proposed as an index to assess the functional status of patients with chronic heart failure. The focus of this report was to evaluate in post-myocardial infarction patients the utility of the AT for (a) assessing the severity of exercise-induced left ventricular impairment, (b) determining the responses obtained from different treatments and (c) prescribing exercise training. We found that the AT level was lower in patients with abnormal haemodynamic patterns during exercise. The AT was correlated to different degrees of exercise-induced left ventricular impairment. The nitrate and calcium-antagonist effects have been evaluated in patients with abnormal exercise haemodynamics. The resting and exertional results were in agreement with the vasodilator effects. Moreover, the time from onset of exercise to the appearance of the AT was significantly increased by the treatments. Thus, AT during pharmacological treatments may be a non-invasive useful parameter for assessing their haemodynamic effects. Finally, a 4-week intermittent training programme based on AT level was evaluated in patients with abnormal resting and exertional haemodynamics. The results showed an improvement of the exercise cardiovascular tolerance without negative effects on left ventricular function. Therefore, the AT seems to be useful when prescribing a rational and individualized training programme.

Adult↗
PubMed1978

Taste dysfunction and changes in zinc and copper metabolism during penicillamine therapy for generalized scleroderma.

The taste function and the zinc and copper levels in serum and urine were followed for up tp 16 weeks in ten patients who were started on penicillamine therapy for generalized scleroderma (9 patients) and rheumatoid arthritis (one patient). During therapy the serum zinc concentration remained unchanged, whereas the serum copper concentration increased significantly during the first 4--5 weeks and then tended to decrease. Urinary copper rose significantly and remained considerably above the upper normal limit throughout the study. Six of the patients complained after about 4--5 weeks of a decreased taste function, which was gradually restored whether the medication was stopped or continued. The alterations in the taste acuity for sweet, salt, sour, and bitter significantly paralleled the variations in urinary copper before as well as during therapy. Thus, the patients who showed the most pronounced loss of taste, had a lower urinary copper output than those whose taste acuity was less disturbed.

Adult↗
PubMed2001

Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control.

Destruction and dysfunction of pancreatic beta-cells, resulting in absolute and relative insulin deficiency, represent key abnormalities in the pathogenesis of type 1 and type 2 diabetes, respectively. Following the discovery of amylin, a second beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli, it was realized that diabetes represents a state of bihormonal beta cell deficiency and that lack of amylin action may contribute to abnormal glucose homeostasis. Experimental studies show that amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation through several centrally mediated effects. These include a suppression of postprandial glucagon secretion and a vagus-mediated regulation of gastric emptying, thereby helping to control the influx of endogenous and exogenous glucose, respectively. In animal studies, amylin has also been shown to reduce food intake and body weight, consistent with an additional satiety effect. Pramlintide is a soluble, non-aggregating, injectable, synthetic analog of human amylin currently under development for the treatment of type 1 and insulin-using type 2 diabetes. Long-term clinical studies have consistently demonstrated that pre-prandial s.c. injections of pramlintide, in addition to the current insulin regimen, reduce HbA(1c) and body weight in type 1 and type 2 diabetic patients, without an increase in insulin use or in the event rate of severe hypoglycemia. The most commonly observed side effects were gastrointestinal-related, mainly mild nausea, which typically occurred upon initiation of treatment and resolved within days or weeks. Amylin replacement with pramlintide as an adjunct to insulin therapy is a novel physiological approach toward improved long-term glycemic and weight control in patients with type 1 and type 2 diabetes.

Amyloid↗
PubMed1999

[Mechanisms of aphasia recovery and brain imaging].

Aphasia recovery may depend on right hemisphere or non-lesioned left hemisphere structures, pre-morbid brain language organization, and de novo learning of language. Here we review the brain imaging evidence supporting these different hypotheses. CT-scan studies have investigated the prognosis value of size and site of left hemisphere lesions. The size of the lesion is a global but not an individual predictor of the initial severity and subsequent recovery of aphasia. Studies on the site of the lesion have given different results for verbal expression and comprehension. There is no consensus on a single critical site for recovery of verbal expression in non-fluent aphasia, which may depend on sub-cortical more than cortical extend of the lesion. Conversely the extend of the lesion in the superior temporal gyrus emerges as a critical negative factor for comprehension recovery. Rest measurements of brain metabolism have consistently shown that aphasia severity depends much more on the degree of dysfunction of language-related areas in the left hemisphere than on the site of the lesion it-self. This suggests that aphasia recovery may depend on metabolic dysfunction recovery in peri-lesional structures. More recently, activation studies have shown consistent right hemisphere activation during language tasks in aphasic subjects, but their role in recovery remains debated. It is likely limited, and may depend on atypical pre-morbid language lateralization. Left hemisphere activations are also found in aphasic patients. They are often relocalized in peri-lesional areas, and emerge in most studies as the main factor of aphasia recovery.

Aphasia↗
PubMed2002

Myocardial blood flow, metabolism, and inotropic reserve in dogs with dysfunctional noninfarcted collateral-dependent myocardium.

UNLABELLED: There is intense controversy as to the mechanisms underlying chronic but reversible left ventricular (LV) ischemic dysfunction. The aim of this study was to investigate the physiology underlying this condition in a canine model of noninfarcted collateral-dependent myocardium. METHODS: Six mongrel dogs were instrumented with ameroid constrictors on the left circumflex and right coronary arteries and a partial occluder on the left anterior descending coronary artery. The animals were followed up for 6 mo. Every 6 wk, measurements of regional wall thickening (M-mode echo), myocardial blood flow ((13)N-ammonia PET), oxygen consumption ((11)C-acetate PET), and glucose uptake ((18)F-FDG PET) were obtained. After 6 mo, myocardial blood flow reserve (during adenosine infusion) and regional contractile reserve (during infusion of a low dose of dobutamine) were also investigated. RESULTS: Following ameroid implantation, regional thickening decreased in the posterior wall (to 34% +/- 13% of baseline; P < 0.001) but not in the septum. Resting myocardial blood flow (56 +/- 10 vs. 58 +/- 15 mL.[min.100 g](-1)), myocardial oxygen consumption (21 +/- 3 vs. 22 +/- 3 J.[beat.100 g](-1)), and insulin-stimulated glucose uptake (39 +/- 8 vs. 42 +/- 11 micromol.[min.100 g](-1)) were similar among dysfunctional and normal segments. Myocardial blood flow reserve was blunted in dysfunctional versus normal segments (3.7 +/- 0.5 vs. 5.2 +/- 1.5; P = 0.06). With dobutamine, wall thickening (to 69% +/- 8% and 77% +/- 11%, respectively) and oxygen consumption (to 36 +/- 5 and 39 +/- 5 J.[beat.100 g](-1), respectively) improved to the same extent in both segments. As a consequence, mechanical efficiency decreased in septal but remained unchanged in posterior segments during infusion of dobutamine. Biopsy specimens from both walls were free from any morphological alterations. CONCLUSION: Our data indicate that ameroid occlusion in dogs induces sustained reduction in regional contraction, which occurs despite normal levels of transmural blood flow and recruitable inotropic reserve. Since myocardial perfusion reserve was blunted, such perfusion-contraction mismatch could reflect repetitive stunning.

Animals↗
PubMed1991

Diurnal fluctuations of arterial ketone body ratio in normal subjects and patients with liver dysfunction.

To explore the metabolic aspects of chronic liver disease, diurnal changes of arterial ketone body ratio (acetoacetate/3-hydroxybutyrate), reflecting hepatic mitochondrial redox potential, were investigated in normal subjects, patients with chronic liver disease (Child's class A or B), and patients with hepatic failure (Child's class C). Ketone body ratio in normal subjects increased after breakfast from 0.96 to 2.00, after lunch from 2.17 to 2.38, and after dinner from 1.23 to 2.55 with blood glucose level ranging from 103 to 141 mg/dL (5.7 to 7.8 mmol/L). By contrast, the ketone body ratio in the Child A or B group changed little and remained within a range of 0.70-1.35 despite a large change in blood glucose level from 102 to 176 mg/dL (5.7 to 9.8 mmol/L). Ketone body ratio in Child's class C remained near or below 0.4 with no response to glucose administration, despite a marked elevation in blood glucose level. These results indicate that hepatic mitochondrial redox potential undergoes diurnal changes in sharp response to meals in normal liver function but that these fluctuations are absent in patients with liver damage (Child's class A, B, and C). Furthermore, it remains at low levels in severe liver failure (Child's class C). It is also suggested that hepatic mitochondrial redox potential plays an important role in the regulation of blood glucose levels.

Acetoacetates↗
PubMed1989

[Indicators of lipid metabolism and aminotransferase activity in girls with dysfunctional uterine hemorrhage].

In a study of 42 girls, aged 12 to 15 years, including 27 patients with dysfunctional uterine bleedings (DUB) and 15 normal controls, the levels of glucose, total lipids, beta-lipoproteins, total cholesterol, as well as beta-lipoprotein, triglycerides, nonesterified fatty acid (NEFA) cholesterol and aminotransferrase activity were compared. NEFA levels were found to be increased fivefold over the normal values in DUB patients.

Adolescent↗
PubMed2001

Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia.

Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with severe liver disease. Although the molecular basis for the neurological disorder in HE remains elusive, elevated ammonia and its chief metabolite glutamine are believed to be important factors responsible for altered cerebral functions, including multiple neurotransmitter system(s) failure, altered bioenergetics, and more recently oxidative stress. Accumulated evidence suggests that direct interference of ammonia at several points in cerebral energy metabolism, including glycolysis, TCA cycle, and the electron transport chain, could lead to energy depletion. Additionally, recent studies from our laboratory have invoked the possibility that ammonia and glutamine may induce the mitochondrial permeability transition in astrocytes, a process capable of causing mitochondrial dysfunction. Altered mitochondrial metabolism appears to be an important mechanism responsible for the cerebral abnormalities associated with HE and other hyperammonemic states.

Brain↗
PubMed2003

[Arterial hypertension, its metabolic aspects and kidney function in patients after hemorrhagic fever with renal syndrome].

AIM: To characterize late convalescence after hemorrhagic fever with renal syndrome (HFRS), i.e. metabolic disorders and their relation with arterial pressure (AP) and renal function. MATERIAL AND METHODS: 202 HFRS convalescents were followed up with measurements of AP, purin, carbohydrate and lipid metabolisms, study of glomerular and tubular dysfunctions. RESULTS: A stable rise of arterial pressure registered in 24% HFRS convalescents was associated with intraglomerular hypertension, affected concentration ability of the kidneys and tubular transport of beta 2-microglobulin in the presence of metabolic disorders: hyperuricemia, hyperinsulinemia and hyperlipidemia of type IIa. A significant correlation was found between arterial hypertension and renal dysfunction and metabolic disorders. CONCLUSION: Late convalescence after HFRS is characterized by glomerular and tubular dysfunctions, persistent elevation of AP and hormonal-metabolic atherogenic and diabetogenic disturbances.

Adolescent↗
PubMed1996

Pulmonary dysfunction in type 1 diabetes in relation to metabolic long-term control and to incipient diabetic nephropathy.

UNLABELLED: The available data on pulmonary function in type 1 diabetes are still conflicting. Recently, restrictive alterations of pulmonary function were demonstrated in type 1 diabetic patients with end-stage renal failure (diabetic nephropathy), whereas patients with kidney failure from other causes had normal pulmonary function test results. In this study, the prevalence and nature of pulmonary dysfunction in type 1 diabetes and the relationship of pulmonary function tests to incipient diabetic nephropathy and metabolic long-term control were analyzed. Pulmonary function tests were performed in long-standing type 1 diabetic patients (n = 39) with normal serum creatinine levels (< 1.3 mg/dl) and the results compared with those of healthy control (n = 44). The patients were divided into those with a normal urinary albumin excretion rate (AER; n = 21, < 30 mg/day) and those with microalbuminuria (n = 18, AER 30-300 mg/day). We found a significant reduction of the following pulmonary function tests (performed by standardized spirometry and wholebody plethysmography) as compared with controls (C) in diabetic patients with microalbuminuria (M) and in diabetic patients with normoalbuminuria (N): total lung capacity (TLC; % predicted: M 89.6, p < 0.004; N 98.5, p = NS; C 101.1), vital capacity (VC; % predicted: M 83.7, p < 0.001; N 90.2, p < 0.03; C 97.3), forced expiratory volume in 1 s (FEV1; % predicted: M 81.2, p < 0.002; N 88.8, p < 0.02; C 93.8), and diffusing capacity of the lung for CO (DLCO; % predicted: M 83.4, p < 0.04; N 92.4, p = NS; C 95.6). We also found a slight increase of the airway resistance (kPa/l/s: M 0.22, p < 0.03; N 0.2, p = NS; C 0.18). The differences in TLC (% predicted) between diabetic patients with normo- and microalbuminuria were significant (p < 0.04). Further a close relation of pulmonary function tests to metabolic long-term control (mean values of repeated HbA1c measurements) was observed: TLC (% predicted: M r= -0.61, p < 0.007, N p = NS), VC (% predicted: M r = -0.57, p < 0.01; N r= -0.59, p < 0.005), and FEV1 (% predicted: M r = -0.50, p < 0.03; N r= -0.62, p < 0.003). IN CONCLUSION: pulmonary dysfunction in long-standing type 1 diabetic patients is more pronounced in patients with increased AER. Typical features of restrictive pulmonary defects, namely a reduction of TLC (% predicted) plus DLCO (% predicted) were observed predominantly in patients with incipient diabetic nephropathy. The clear correlation of pulmonary function tests with HbA1c measurements stresses the importance of optimal metabolic long-term control in type 1 diabetes.

Adult↗
PubMed1996

Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging.

BACKGROUND: Prior neuroimaging studies have not consistently demonstrated a structural or functional abnormality of the caudate nucleus in patients with obsessive-compulsive disorder (OCD). However, there is theoretical support for some associated dysfunction of the caudate nucleus. METHODS: We examined volumes of the caudate nucleus and putamen with magnetic resonance imaging in 24 patients with adult-onset OCD and 21 control subjects, group-matched on age, race, education, and sex. Patients were relatively free from tics. To evaluate function (metabolism or blood flow) of the caudate nucleus, we performed a quantitative review, including a meta-analysis, of normalized data from functional neuroimaging studies that compared patients who had OCD with normal control subjects. RESULTS: All structural basal ganglia measures failed to exhibit differences between patients with OCD and matched normal control subjects. Patients did not demonstrate evidence of ventricular enlargement. Quantitative meta-analysis of the functional neuroimaging literature did not demonstrate a consistent abnormality of the caudate nucleus. CONCLUSIONS: We did not observe evidence of a structural abnormality of the caudate nucleus in patients with OCD. Prior reports of a structural aberration of the caudate nucleus were mixed. We also did not find strong support for relative caudate metabolic or perfusion dysfunction in the literature, although increased function in the frontal cerebral cortex was identified. The heterogeneous nature of this disorder may account for inconsistencies between studies. For example, ventricular enlargement or reduced caudate volume or blood flow might be evident in patients with soft neurological signs (eg, tics), while patients in the current study were relatively free from tics. Although theories of OCD suggest a dysfunction of the caudate nucleus, the structural and functional neuroimaging literature has not consistently verified this.

Adult↗
PubMed1993

Nutritional, hepatic, and metabolic effects of cachectin/tumor necrosis factor in rats receiving total parenteral nutrition.

BACKGROUND: In orally fed animals, infusion of cachectin/tumor necrosis factor (TNF) caused weight loss and muscular wasting, accompanied by anorexia. Despite muscle wasting, there were gains in weight and protein and DNA contents of the viscera, but no significant metabolic abnormalities. METHODS: To observe the effect of cachectin/TNF on the nutritional-metabolic status, and without the confounding effect of anorexia, cachectin/TNF was infused into rats receiving total parenteral nutrition in sufficient amounts to induce weight gain in controls at the same rate as in orally fed rats. RESULTS: TPN prevented loss of body weight, but cachectin-treated animals had reduced nitrogen retention and carcass weight. By contrast, there were gains in visceral protein levels, which in the liver was due to a marked proliferation of biliary epithelium. In addition, cachectin-treated animals receiving TPN developed hyperglycemia, hyperosmolality, diuresis, and dehydration. They also had azotemia and cholestasis. CONCLUSIONS: In the absence of the effects of anorexia, cachectin reduced nitrogen retention and caused metabolic and multisystem dysfunction, comparable with the effects of clinical sepsis.

Animal Nutritional Physiological Phenomena↗
PubMed1997

Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction.

Severe glutathione synthetase (GS) deficiency is a rare genetic disorder with neonatal onset. The enzymatic block of the gamma-glutamyl cycle leads to a generalized glutathione deficiency. Clinically affected patients present with severe metabolic acidosis, 5-oxoprolinuria, increased rate of hemolysis and defective function of the central nervous system. The disorder is inherited in an autosomal recessive mode and, until recently, the molecular basis has remained unknown. We have sequenced 18 GS alleles associated with enzyme deficiency and we detected missense mutations by direct sequencing of cDNAs and genomic DNA. In total, 13 different mutations were identified. Four patients were found to be compound heterozygotes and two individuals were apparently homozygous. Reduced enzymatic activities were demonstrated in recombinant protein expressed from cDNAs in four cases with different missense mutations. The results from biochemical analysis of patient specimens, supported by the properties of the expressed mutant proteins, indicate that a residual activity is present in affected individuals. Our results suggest that complete loss of function of both GS alleles is probably lethal. It is postulated that missense mutations will account for the phenotype in the majority of patients with severe GS deficiency.

Acidosis↗
PubMed2005

Incidence and pathogenesis of tumor lysis syndrome.

Tumor lysis syndrome (TLS) is a constellation of metabolic disturbances that may be observed in patients with malignancies. Clinically significant TLS can occur spontaneously, but most often is seen 48-72 h after initiation of cancer treatment. The metabolic abnormalities observed in patients with TLS include hyperkalemia, hyperuricemia, and hyperphosphatemia, which leads to secondary hypocalcemia. The precise incidence of TLS is not defined, risk factors being represented by large tumor burden, neoplasms with either high growth fraction or high sensitivity to chemotherapy, and by pre-existing impairment of renal function. Neither racial, nor sex predilection exists. The pathogenesis of TLS is related to the rapid tumor cell turnover or destruction, which may result in release of intracellular ions and metabolic byproducts into the systemic circulation. Acute renal failure (ARF) may frequently complicate TLS and is mainly due to renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine. Hemodynamic changes reducing glomerular flow due to still undefined mediators are also involved in TLS pathophysiology. Pre-existing volume depletion or renal dysfunction may worsen metabolic derangements and ARF. A good comprehension of TLS pathophysiology has provided the basis for an effective and rational treatment of this complication, adversely affecting the outcome of cancer patients.

Acute Kidney Injury↗