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)

The primary metabolite of morphine, morphine-6-beta-glucuronide (M-6-G), is reported to contribute to the effects of morphine. The authors investigated the effects of M-6-G on the central nervous system (CNS) after short-term intravenous (i.v.) administration by employing both electroencephalograph (EEG) power spectra analyses and clinical signs as indicators of opioid effects. Three dosages of M-6-G, one dosage of morphine (bolus 10 mg/70 kg and 3.5 mg/70 kg/hour for 4 hours), a combination of morphine and M-6-G, and placebo were administered to 20 healthy volunteers as i.v. bolus plus i.v. infusion for 4 hours. M-6-G was dosed to produce steady state plasma concentrations that were either identical, 2 times, or 3 times higher than the M-6-G plasma concentrations observed after administration of morphine. The EEG background activity and clinical effects were recorded 3.5 hours after the infusion started. M-6-G failed to produce effects on any of the investigated EEG or clinical parameters at the doses tested. In contrast, morphine produced a significant increase in the alpha 1 and delta power of the EEG. In addition, morphine increased the subjects' ratings of tiredness, sickness, vertigo, and drowsiness, and decreased their level of performance in a tracking task. It was concluded that after short-term i.v. administration, M-6-G does not affect the CNS at the doses tested. Therefore, its contribution to clinical effects of morphine after short-term administration is questionable. The missing CNS effects were probably caused by the slow brain permeability of M-6-G, which in short-term treatment might not attain effective CNS concentrations.
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PMID:No contribution of morphine-6-glucuronide to clinical morphine effects after short-term administration. 984 92

As has been demonstrated in binding studies the two opioids tilidine (CAS 27107-79-7)/naloxone (CAS 357-08-4) and tramadol (CAS 36282-47-0) differ in regard to their affinities to the opioid receptor site. Therefore it is of interest to evaluate whether such a difference in opioid affinity is also seen in the pharmacological effects of clinically relevant doses in man. Following institutional approval by the local ethical committee and informed consent, 12 volunteers received oral doses of tramadol (100 mg), tilidine/naloxone (100 mg) and placebo, respectively, in a randomized, double-blind cross-over design. In order to determine the degree of constipation, oral-caecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripheral and central mediated effects were compared to placebo. Tramadol as well as tilidine/naloxone induced a significant (p < 0.05) prolongation of oral-caecal transit when compared to placebo. However, prolongation of oral-caecal transit was significantly longer in the tilidine/naloxone (p < 0.05) than in the tramadol group. Compared to tramadol, the pronounced constipating effect of tilidine/naloxone is likely to be due to the 10 fold higher affinity of that drug to the peripheral opioid receptor sites in the intestinal tract, which are responsible for normal propulsion. Such difference in binding is underlined by a central effect, the pupillary light reflex response. The amount of constriction of the iris to light was reduced after both opioids. Again, tilidine/naloxone significantly reduced (p < 0.001) the pupillary light reflex when compared to tramadol. Other side effects such as tiredness, nausea, emesis and dry mouth were more often reported after tilidine/naloxone than after tramadol (40% versus 15%; p < 0.05). Vertigo and perspiration were more often reported after tramadol than after after tilidine/naloxone (58% and 78% versus 8%; p < 0.01). All these data support the findings that while tramadol is considered an opioid, it does not mediate its main clinical relevant properties via binding at the opioid receptor. More likely, due to its monoaminergic reuptake mechanism, to a lesser extent opioid-like effects are induced.
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PMID:Effects of tramadol and tilidine/naloxone on oral-caecal transit and pupillary light reflex. 1068 12

The Parnes and Price-Jones "Particle Repositioning Maneuver" (PRM) was used to treat Paroxysmal Positional Vertigo (VPP) in 36 consecutive cases, studying both any induced secondary nystagmus and any persistent Paroxysmal Positional Nystagmus (PPNy) upon repetition of the Hallpike positioning after 15 minutes (re-test). The purpose of the study was to evaluate the ability to use secondary Ny and the retest to predict maneuver effectiveness. Although the PRM was quite effective (PPNy disappeared in 86% of the cases after a single session), the low observation frequency reduced the feasibility of using secondary Ny. On the other hand the systematic introduction of the Hallpike re-test into clinical practice does not offer the desired cost/benefit ratio because of the time required to prevent false negatives due to PPNy fatigue. In fact, secondary Ny was only evoked in 12 out of 36 cases (33%) and of these only 9 out of 36 (25%) presented direction congruous with canalolith release (liberating Ny). The predictive value of evoked liberating Ny appeared further reduced by the persistence of PPNy upon subsequent re-testing in two cases and in one case by the persistence of the disorder upon follow-up. The Hallpike test appears a more reliable indicator of effectiveness as it proved in agreement with subsequent clinical findings in 80% of the cases. The present results lead one to conclude that, when using PRM in cases where no secondary liberating Ny was found (75%), we should rely on the high effectiveness of this procedure (86% of the cases resolved in a single session) rather than perform a Hallpike retest. Thus it is possible to select a small number of patients (22%) still presenting PPNy (positive retest) and requiring repetition of the therapeutic maneuver.
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PMID:[Effectiveness indices in "Particle Repositioning Maneuver" by Parnes and Price-Jones]. 1073 26

Head upright tilt table testing has become an accepted method to measure an individual's predisposition to autonomically mediated periods of hypotension and bradycardia severe enough to cause frank syncope. At the same time it has become increasingly apparent that less profound falls in blood pressure, while not sufficient to result in loss of consciousness, may cause symptoms such as near syncope, vertigo, and dizziness. We describe a subgroup of adolescents that have a mild form of autonomic dysfunction that exhibit disabling symptoms such as postural tachycardia and palpitations, extreme fatigue, lightheadedness, exercise intolerance, and cognitive impairment. During baseline tilt table testing at a 70 degrees angle, these patients demonstrated a heart rate increase of > or = 30 beats/min (or a maximum heart rate of > or = 120 beats/min) within the first 10 minutes upright (not associated with profound hypotension), which reproduced their clinical symptom complex. Similar observations have been made in the adult population and has been termed the postural orthostatic tachycardia syndrome (POTS). We report that POTS may also occur in adolescents and represents a mild, potentially treatable form of autonomic dysfunction that can be readily identified during head upright tilt table testing.
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PMID:The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive impairment in adolescents. 1075 Jan 35

The aim of this prospective study was to compare epidemiological data and clinical features in children and adults with tick-borne encephalitis (TBE). Patients with aseptic meningitis diagnosed at the University Medical Centre, Department of Infectious Diseases, Ljubljana, Slovenia, from June to August 1997, in whom the diagnosis of TBE was ascertained by the presence of serum IgM antibodies against TBE virus, who were serologically negative for Borrelia burgdorferi sensu lato and had a negative PCR CSF result on enteroviral infection, were included in the study. Out of 213 patients with aseptic meningitis, 80 (37.56%) fulfilled inclusion criteria. There were 20 children and 60 adults. In both groups males predominated. Virtually all patients had headache and fever, and more than 50% suffered from vomiting. The majority of patients in both groups recalled a tick bite, had a biphasic course of the illness, and was found to have obviously expressed meningeal signs. In both groups the median CSF leukocyte count was somewhat lower than 100 x 10(6)/l with a predominance of lymphocytes. Children were more often given antibiotics during the initial phase of TBE than adults (p = 0.0095). Several other statistically significant distinctions (p < 0.05) were found including the frequency of fatigue, malaise, vertigo, photophobia, myalgias, arthralgias, as well as elevated CSF albumin and protein concentration, elevated albumin quotient and IgG quotient; all these findings were more often present in adults. In addition a longer duration of fever, more frequent need for anti-edematous treatment and longer hospitalization were found in adults. Direct comparison of clinical and epidemiological characteristics of TBE in children and adults revealed differences in several clinical and laboratory features and corroborates the previous conclusion that TBE in childhood is a milder illness than TBE in adults.
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PMID:Comparison of the epidemiological and clinical features of tick-borne encephalitis in children and adults. 1078 89

TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.
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PMID:TNP-470: an angiogenesis inhibitor in clinical development for cancer. 1106 Jul 50

Familial episodic ataxias are unusual hereditary disorders of early onset characterized by recurrent episodes of ataxia. Most patients recover fully between attacks, but some may develop progressive ataxia with cerebellar atrophy. There are two subtypes of episodic ataxia: type 1 (EA1), with interictal myokymia, and type 2 (EA2), with interictal nystagmus. Stress and fatigue can trigger ataxic spells, which can be responsive to acetazolamide. These clinical features are reminiscent of other channelopathies or paroxysmal neurologic disorders with progressive features caused by ion channel mutations. Familial episodic ataxias indeed are channelopathies. EA1 is caused by mutations in a potassium channel-encoding gene, whereas EA2 is caused by mutations in a calcium channel-encoding gene, which is also the disease-causing gene in spinocerebellar ataxia type 6 and several kindreds with familial hemiplegic migraine. Treatment with acetazolamide can be effective in decreasing the frequency of attacks and is generally well tolerated. Understanding the mechanism of action of acetazolamide and the functional consequences of these mutations will help one to develop a rational pharmacologic treatment for these disorders, which may share similar mechanisms with benign recurrent vertigo and more common forms of migraine.
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PMID:Familial Episodic Ataxias and Related Ion Channel Disorders. 1109 68

Dihydroergotoxine mesylate (DHETM, CAS 8067-24-1), the combination of the mesylates of four dihydrogenated ergot alkaloid derivatives (dihydroergocornine, dihydroergocristine, alpha-dihydroergocryptine and beta-dihydroergocryptine), is used mainly for age-related cognitive impairment. The bioavailability of DHETM was investigated in a cross-over study on 20 male healthy volunteers to whom two single doses of 9 mg DHETM were administered either in tablets (Orphol spezial) or in oral solution (Orphol forte). DHETM was assayed in serum with a double radioimmunoassay method displaying a satisfactory cross-reactivity with the principal components of DHETM. After administration of tablets the peak of DHETM was (mean +/- SE) 124 +/- 16 pg/ml, the tmax 1.15 +/- 0.21 h, the AUC 790 +/- 93 pg/ml x h and the terminal elimination half-life 7.54 +/- 1.23 h. After oral solution the peak of DHETM was 176 +/- 16 pg/ml, the tmax 0.50 +/- 0.04 h, the AUC 779 +/- 94 pg/ml x h and the terminal elimination half-life 6.13 +/- 0.76 h. The bioavailability of DHETM from tablets vs. that from oral solution differed only by a retard related to the dissolution time of DHETM from the tablets, but not for other pharmacokinetic parameters. The relatively high two single doses of 9 mg DHETM administered to the 20 subjects were well tolerated, causing only known and expected adverse reactions to DHETM (tiredness, headache and vertigo) that did not require discontinuation of the study.
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PMID:Bioavailability and pharmacokinetic profile of dihydroergotoxine from a tablet and from an oral solution formulation. 1121 21

It is well accepted that long-term administration of opioids results in a dose-related constipation. No data so far have demonstrated conclusively whether such constipation is also seen after intake of a controlled release formulation. It was therefore of interest to evaluate whether increasing doses of a controlled release formulation of dihydrocodeine (DHC, CAS 125-28-0) after oral administration also induces a dose-related increase in constipation. Additionally, it was of interest to study whether such a peripheral opioid-related side effect is also seen in another, central receptor-mediated effect, the constriction of the pupil, at clinically relevant doses. Twelve volunteers were given controlled release DHC (60 and 120 mg, respectively) or placebo orally within a randomized, double-blind cross-over study. In order to determine the degree of constipation, oro-cecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripherally and centrally mediated effects were compared to placebo. DHC at both dosages induced a significant (p < 0.01) prolongation of oro-cecal transit time when compared to placebo. However, prolongation of oro-cecal transit was not significantly longer when comparing the lower (60 mg) with the higher dose (120 mg). DHC also induced a significant (p < 0.005) depression of the pupillary light reflex from 53.9 mm (control) to 8.3 and 7.4 mm, respectively. Similar to intestinal transit, the pupillary light reflex was not significantly different among the two doses of DHC. Also, both dosages induced a similar amount of side effects. Tiredness and dry mouth were reported in 80% after both doses while vertigo was reported in 5% and 1% complained of headache. None of the volunteers reported nausea or emesis. It is concluded that opioid receptor sites, which are located in the plexus myentericus of the intestinal wall, are responsible for the delay in propulsion. Because of the controlled release of a fixed amount of DHC over time there is constant binding of the ligand followed by a constant conformational change of peripheral and central receptor sites. Thus constant release induces no dose-related increase in oro-cecal transit and inhibition of the pupillary light reflex.
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PMID:Dose-related effects of controlled release dihydrocodeine on oro-cecal transit and pupillary light reflex. A study in human volunteers. 1121 27

The human illness designated as possible estuarine-associated syndrome (PEAS) by the Centers for Disease Control and Prevention (CDC) has been associated with exposure to estuaries inhabited by toxin-forming dinoflagellates, including members of the fish-killing toxic Pfiesteria complex (TPC), Pfiesteria piscicida and Pfiesteria shumwayae. Humans may be exposed through direct contact with estuarine water or by inhalation of aerosolized or volatilized toxin(s). The five cases reported here demonstrate the full spectrum of symptoms experienced during acute and chronic stages of this suspected neurotoxin-mediated illness. The nonspecific symptoms most commonly reported are cough, secretory diarrhea, headache, fatigue, memory impairment, rash, difficulty in concentrating, light sensitivity, burning skin upon water contact, muscle ache, and abdominal pain. Less frequently encountered symptoms are upper airway obstruction, shortness of breath, confusion, red or tearing eyes, weakness, and vertigo. Some patients experience as few as four of these symptoms. The discovery that an indicator of visual pattern-detection ability, visual contrast sensitivity (VCS), is sharply reduced in affected individuals has provided an objective indicator that is useful in diagnosing and monitoring PEAS. VCS deficits are present in both acute and chronic PEAS, and VCS recovers during cholestyramine treatment coincident with symptom abatement. Although PEAS cannot yet be definitively associated with TPC exposure, resolution with cholestyramine treatment suggests a neurotoxin-mediated illness.
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PMID:Possible estuary-associated syndrome: symptoms, vision, and treatment. 1188 86


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