Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity in in vitro and in in vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study. Doses ranged from 50 to 1060 mg/m2/d x 3 days. Due to the possibility of local hemolysis with concentrations > 1.5 mg/ml, drug was administered in solutions containing < or = 1.5 mg/ml. Because large volumes were needed at the higher dose levels, the infusion duration was increased from 2 hours to 4 hours. Mild to moderate nausea, vomiting, fatigue, dizziness and headaches were observed. Myelosuppression was the dose limiting toxicity. The recommended phase II dose and schedule was determined to be 800 mg/m2/d x 3d every 3 weeks. 773U82-HCl plasma concentration-time data were analyzed using a two-compartment pharmacokinetic model. The t1/2 beta averaged 6 hours and the total body clearance was 75.9 L/hr/m2. The volume of distribution (Vdss) was large, averaging 470 L/m2.
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PMID:Phase I evaluation of 773U82-HCl in a two-hour infusion repeated daily for three days. 148 1

Gastric mucosal damage was produced in rats after pyloric ligation by intragastric administration of 200 mg/kg aspirin diluted in 2 ml 150 mmol/l HCl. The animals in the control group received 2 ml saline solution, or submitted to pyloric ligation only. The animals were killed 4 h after the pyloric ligation, when the number and severity of gastric lesions (ulcers), and the gastric fundic mucosal level of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), cyclic adenosine monophosphate (cAMP) and lactate, were noted and measured. The adenylate pool (ATP + ADP + AMP) and the energy charge (ATP + 0.5ADP). (ATP + ADP + AMP)-1 were calculated. It was found that: the gastric H+ output decreased significantly in the pylorus-ligated plus aspirin-treated animals; the number and severity of gastric lesions increased significantly in the pylorus-ligated aspirin-treated animals; the extent of ATP transformation into the ADP decreased significantly in the pylorus-ligated aspirin-treated animals; the extent of ATP transformation into the cAMP decreased significantly during the aspirin treatment; the values of adenylate pool and of "energy charge" remained unchanged in the different groups of animals. It is concluded that: the decreased H+ output in the pylorus-ligated plus aspirin-treated group can be obtained by the decreased extent of ATP transformation into the ADP by membrane ATPase, and the biochemical changes in the gastric mucosa indicate a decreased energy turnover.
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PMID:Biochemical background of the development of gastric mucosal damage in pylorus-ligated plus aspirin-treated rats. 300 88

The in vitro deproteinized vastus lateralis muscle buffer capacity, carnosine, and histidine levels were examined in 20 men from 4 distinct populations (5 sprinters, 800-m runners; 5 rowers; 5 marathoners; 5 untrained). Needle biopsies were obtained at rest from the vastus lateralis muscle. The buffer capacity was determined in deproteinized homogenates by repeatedly titrating supernatant extracts over the pH range of 7.0-6.0 with 0.01 N HCl. Carnosine and histidine levels were determined on an amino acid AutoAnalyzer. Fast-twitch fiber percentage was determined by staining intensity of myosin adenosinetriphosphatase. High-intensity running performance was assessed on an inclined treadmill run to fatigue (20% incline; 3.5 m X s-1). Significantly (P less than 0.01) elevated buffer capacities, carnosine levels, and high-intensity running performances were demonstrated by the sprinters and rowers, but no significant differences existed between these variables for the marathoners vs. untrained subjects. Low but significant (P less than 0.05) interrelationships were demonstrated between buffer capacity, carnosine levels, and fast-twitch fiber composition. These findings indicate that the sprinters and rowers possess elevated buffering capabilities and carnosine levels compared with marathon runners and untrained subjects.
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PMID:Buffering capacity of deproteinized human vastus lateralis muscle. 396 4

The antihypertensive effect of moxonidine X HCl X H2O (MOX) was compared with that of clonidine X HCl (CLON) in a randomized double-blind crossover study in 20 hypertensive outpatients (BP range 154-178/96-108 mmHg). After 2 weeks without antihypertensive medication, either MOX 0.2 mg daily or CLON 0.2 mg daily was given and the dose was titrated until the diastolic blood pressure fell below 90 mmHg. The first treatment period was continued for 2 weeks and, after crossover without a wash-out period, it was followed by the second treatment for a further 2 weeks. Within the first 4 days of administration 0.2-0.4 mg of either agent caused a significant decrease in BP (p less than 0.001) from a mean of 166/100 mmHg to 149/86 mmHg after CLON (approx. -10/-14%), and 163/99 mmHg to 146/84 mmHg after MOX (approx. -10/-15%). No significant difference in the fall in BP or pulse rate was detected between the two drugs. In the mean daily dose of 0.3 mg both drugs showed the same antihypertensive activity, but on CLON a higher incidence of side effects (p = 0.003) was noted, and after discontinuation of therapy a more rapid rise in BP (systolic BP p less than 0.01, diastolic BP p less than 0.02) was found. 17 patients on CLON complained of side effects, especially tiredness and dry mouth, whilst only 6 patients on MOX were affected (p = 0.003).
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PMID:Crossover comparison of moxonidine and clonidine in mild to moderate hypertension. 649 95

1. Twelve healthy subjects received 10 mg morphine HCl delivered transdermally from an occlusive reservoir applied to a small area of skin, painlessly de-epithelialised by vacuum suction. On a separate occasion, 10 mg morphine HCl was given as an i.v. infusion over 20 min. 2. Venous blood samples were collected serially for 72 h and assayed for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) by h.p.l.c. Pupil size, salivation, and central nervous effects (nausea, fatigue, headache, feeling of heaviness and dysphoria/euphoria) were also measured. 3. After transdermal application morphine was absorbed by a first-order process to produce relatively constant plasma drug concentrations over 11 h. The absolute bioavailability of transdermal morphine was 75% (65-85%; 95% CI). The plasma concentrations of both M6G and M3G were lower after transdermal administration than after i.v. infusion, and a considerable delay (of up to 1 h) was observed before the metabolites were detectable. AUC ratios for M3G and M6G relative to morphine were similar after both modes of administration. 4. Non-analgesic effects were less pronounced at the lower plasma drug and metabolite concentrations observed after transdermal delivery than after the i.v. infusion of morphine. 5. Transdermal administration of morphine warrants investigation as an alternative route of morphine delivery.
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PMID:Transdermal administration of morphine to healthy subjects. 791 76

Because cocaine causes a rapid sympathetic response and central euphoria, we tested whether it would improve endurance or alter carbohydrate metabolism during high-intensity activity. Thirty male rats (10 animals/group) were injected intraperitoneally with either saline (S) or one of two doses of cocaine-HCl (12.5 (C-1) or 20.0 (C-2) mg.kg-1 b.w.). Ten minutes later they began gradually running on a rodent treadmill. Within 2 min they were running at 56 m.min-1 until fatigued. The run time to exhaustion (mean +/- SE) for C-2 (569 +/- 97 s) was less than S (859 +/- 71) and C-1 (923 +/- 65) (P < 0.05) and 25% shorter (marginally insignificant) than a pretreatment run (754 +/- 67 s) (P > 0.05). Plasma lactate concentrations at exhaustion were 4.0 +/- 0.5 (S), 7.3 +/- 1.1 (C-1), and 13.9 +/- 2.5 (C-2) mmol (P < 0.05, S vs C-2). Lactate concentrations in white vastus muscle were also elevated by C (4.7 +/- 0.6 (S), 8.1 +/- 1.3 (C-1), and 15.0 +/- 3.7 (C-2) mumol.g-1, (P < 0.05, S vs C-2)], which correlated with the reduction in glycogen content in both C groups (9.9 +/- 2.3 (C-2), 10.3 +/- 1.2 (C-1), vs 33.9 +/- 2.0 (S) mumol.g-1]. These results show that, in spite of its purported stimulatory effect, cocaine treatment (20 mg.kg-1) immediately prior to intense exercise causes accelerated glycogen degradation and lactate accumulation in white vastus muscle during exercise and premature fatigue.
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PMID:Effects of cocaine on glycogen metabolism and endurance during high intensity exercise. 805 9

The human muscle buffer value (beta) is most frequently determined by either fixed acid titration of a homogenate ["in vitro" beta (beta vit)] or measurement of the change in lactate concentration (delta [La]) relative to the change in muscle homogenate pH after high-intensity exercise ["in vitro" beta = - delta [La]/delta pH (beta viv)]. We sought to compare beta viv, determined after isometric and dynamic exercise to exhaustion (approximately 60 s), with beta vit. Resting (R) and postexercise (E) biopsy samples were taken from vastus lateralis muscles of 43 human volunteers. Freeze-dried muscle was homogenized (30 mg/ml) in NaF (0.01 M) for the measurement of muscle pH (R and E). beta vit was determined by HCl (0.01 M) titration of the homogenate over the pH range 7.1-6.5. Muscle lactate was measured by enzymatic assay. There was no significant difference between beta viv determined after isometric (n = 35) or dynamic (n = 8) exercise to fatigue (170 vs. 168 mmol H+.kg dry muscle mass-1.pH-1, respectively; P > 0.05). Values for beta vit in the corresponding muscle samples (R) were approximately 7-8% lower (156 +/- 25 vs. 157 +/- 18 mmol H+.kg dry muscle mass-1.pH-1, respectively). There was no significant difference (P = 0.278) between the measured decline in muscle homogenate pH after exercise and the reduction in pH predicted from beta vit and delta [La], indirectly confirming the lack of any significant difference between beta viv and beta vit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Determination of human skeletal muscle buffer value by homogenate technique: methods of measurement. 822 58

The effects of almitrine bimesylate and doxapram HCl on isometric force produced by in vitro rat diaphragm were studied during direct muscle activation at 37 degrees C. Doxapram and almitrine ameliorate respiratory failure clinically by indirectly increasing phrenic nerve activity. This study was carried out to investigate possible direct actions of these agents on the diaphragm before and after fatigue of the fibers. Two age groups of animals were chosen [6-14 wk (group 1) and 50-55 wk (group 2)] because it is known that increasing age decreases a muscle fiber's resistance to fatigue. Muscle strips were isolated from both group 1 and group 2 and directly stimulated (2-ms pulse duration, 5-15 V) to produce twitch tensions of 1.3 and 2.1 N/cm2, respectively. At low concentrations, doxapram (</=20 microg/ml) and almitrine (</=12 microg/ml) had no effect on twitch contraction or 100-Hz tetanic tension. However, 40 microg/ml doxapram and 30 microg/ml almitrine increased twitch tension by 9.0 +/- 1.4 and 11.6 +/- 1.9%, respectively, in animals of group 2 (n = 5). A fatigue protocol consisting of low-frequency stimulation (30-Hz trains, 250-ms duration every 2 s for 5 min) caused a reduction of twitch tension in animals of group 1 (48 +/- 4% of control) and group 2 (28 +/- 4% of control). At 90 min postfatigue, the twitch tension recovered to 72 +/- 3 and 42 +/- 2% of control values in group 1 and group 2, respectively. In the presence of doxapram (20 microg/ml), there was a significant increase in the recovery of twitch tension at 90 min in group 1 and group 2 (84.5 +/- 3.2 and 80.1 +/- 2.8%, respectively) compared with controls at 90 min postfatigue. In the presence of almitrine (12 microg/ml), there was a full recovery from fatigue in group 1 animals (100% of control) and a recovery to 95.6 +/- 2.1% of control in group 2 animals at 90 min. These results demonstrate a significant improvement in the rapidity and magnitude of recovery from fatigue in the rat diaphragm muscle in the presence of both doxapram and, especially, almitrine. These effects may be due to changes in intracellular calcium, ADP/ATP ratios, or oxygen free radical scavenging.
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PMID:Almitrine and doxapram decrease fatigue and increase subsequent recovery in isolated rat diaphragm. 921 44

The anti-fatigue effect of dicethiamine hydrochloride (DCET) was assessed and compared to that of thiamine hydrochloride (VB(1)HCl) in rats. The absorbability and tissue distribution of thiamine after oral administration of DCET and VB(1)HCl were also examined. To create fatigued animals, male SD rats were placed in plastic cages containing 1.5cm of water for 5 consecutive days. The extent of fatigue was evaluated by a weight-loaded forced swimming test. After oral administration of DCET or VB(1)HCl to non-fatigued rats, blood and tissues were serially collected to determine the concentrations of thiamine and its phosphate esters. Pharmacokinetic analysis was performed to examine the thiamine profile in the body after administration of DCET or VB(1)HCl. Swimming time was significantly shorter for the fatigued vehicle group than the non-fatigued group. DCET (30 and 100mg/kg) significantly prolonged the swimming time compared to the fatigued vehicle group. The anti-fatigue effect of VB(1)HCl (70.1mg/kg) was not significant in our set of results. Both DCET and VB(1)HCl were rapidly absorbed into the circulating blood as thiamine and eventually became localized in the organs. Thiamine was distributed at higher concentrations to the blood, heart, thigh muscles, cerebellum, hippocampus, and thalamus after administration of DCET compared to VB(1)HCl. These results indicate that DCET is a vitamin B(1) derivative that has excellent absorbability and transformability in tissues and suggest that DCET as an oral therapy may be useful against combined mental and physical fatigue, such as that often encountered in contemporary society.
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PMID:Anti-fatigue effect of dicethiamine hydrochloride is likely associated with excellent absorbability and high transformability in tissues as a Vitamin B(1). 2030 27

Chitooligosaccharides (COS), oligosaccharides composed of two to seven glucosamine residues, are known to exhibit various biological activities. In this study, we investigated the effects of COS in an in vivo mouse sleep deprivation-induced fatigue model in an effort to develop a functional food with anti-fatigue efficacy. Male Balb/c mice were orally administered 500 mg (kg d)(-1) of COS lactate or COS HCl for 2 weeks, and severe fatigue was induced by sleep deprivation. To evaluate the extent of fatigue, the swimming time, representing the immobility time, was measured in a forced swim test. As a result, oral intake of COS lactate-manifested anti-fatigue effects could be observed by the attenuation of fatigue-induced body weight loss and shorter immobility period. In addition, COS lactate was shown to alleviate the fatigue-induced increase in cortisol and lipid peroxidation and a decrease in superoxide dismutase (SOD) activity. Of particular note, the oral administration of COS lactate increased the mitochondrial membrane potential and the mitochondrial number significantly, indicating that COS lactate may enhance mitochondrial function. In support of this, COS lactate increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and cytochrome c (Cyt C) mRNA, indicating that it may increase mitochondrial biogenesis. These results suggest that COS lactate can be an effective anti-fatigue functional food, and this anti-fatigue effect may result from, at least in part, the enhancement of mitochondrial biogenesis and the inhibition of free radical generation.
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PMID:Effects of chitooligosaccharide lactate salt on sleep deprivation-induced fatigue in mice. 2060 1


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