Gene/Protein Disease Symptom Drug Enzyme Compound
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In the literature enlarged/increased cross-sectional area (CSA) of type I muscle fibres has been reported as a morphological mark of work-related localised myalgia in the descending part of the trapezius muscle of women. These studies did not use enough subjects or lacked an adequate control group. The recording of surface electromyograms (EMG) is central to the research field of work-related myalgia. However, the influence of intrinsic muscle properties such as the effect of muscle fibre distribution upon surface EMG has to be better understood in order properly to evaluate this method as a possible diagnostic and preventive tool. This study had two aims. Firstly, it investigated the muscle fibre distribution and CSA in work-related myalgia in trapezius muscles. Secondly, the multivariate relationships among muscle morphology and histochemistry [ragged-red (RR) fibres, and cytochrome-c-oxidase-negative-fibre changes] EMG, perceived fatigue, and biomechanical output of shoulder flexions were analysed. The raw data have been presented in an earlier study. The participants in this study were 25 female cleaners with work-related myalgia of the trapezius muscle and 25 female cleaners not experiencing work-related myalgia of this muscle. The control group comprised 21 healthy female teachers who had not been exposed to highly repetitive work or static muscle work. Smaller CSA of type II fibres were found in cleaners compared to teachers. In this study the CSA of type I fibres of the trapezius muscles associated with myalgia were no greater than in muscles without myalgia. The prevalence of RR fibres together with age, fibre type proportions, CSA and working as a cleaner correlated with the ability to relax as recorded electromyographically. The relative mean frequency of the EMG of the trapezius muscle correlated with the prevalence of RR fibres, but it did not correlate with the proportions and CSA of different fibre types. Low biomechanical outputs and low signal amplitude increases of the EMG during the test were associated with high proportions of type -IIB fibres. The smaller CSA of type II fibres in cleaners might have reflected a different muscle activation pattern due to different occupational demands in cleaners than in teachers. Morphological or histopathological variables can influence the three EMG variables investigated.
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PMID:Fibre type proportion and fibre size in trapezius muscle biopsies from cleaners with and without myalgia and its correlation with ragged red fibres, cytochrome-c-oxidase-negative fibres, biomechanical output, perception of fatigue, and surface electromyography during repetitive forward flexions. 1148 43

Paroxetine inhibits cytochrome P(450) 2D6, which is involved in the metabolism of mirtazapine. The possible drug-drug interaction between two pharmacologically distinct antidepressants, mirtazapine and paroxetine, has been investigated in a randomized, three-way crossover study in 24 healthy male and female subjects. After a titration phase of 3 days, each subject received single daily doses of 30 mg mirtazapine, 40 mg paroxetine or the combination for 6 days. Assessments included serial blood sampling for pharmacokinetics at steady state, cognitive testing using the test battery of CDR Ltd, a visual analogue mood rating scale (Bond and Lader) and the Leeds Sleep Evaluation Questionnaire. Paroxetine inhibits the metabolism of mirtazapine, as shown by increases of approximately 17% and 25% of the 24 h AUC's of mirtazapine and its demethyl metabolite, respectively. Mirtazapine did not alter the pharmacokinetics of paroxetine. The combined administration of mirtazapine and paroxetine probably does not alter cognitive functioning or result in major changes on the visual analogue mood rating scale and Sleep Evaluation Questionnaire, compared with the administration of either drug alone. The incidence of adverse events was lower during combined administration of mirtazapine and paroxetine than during administration of either drug alone. Fatigue, dizziness, headache, nausea, anxiety and somnolence were the most common adverse events during combined administration. These data suggest that the combination of mirtazapine and paroxetine is unlikely to lead to clinically relevant drug-drug interactions and can be used without dose adjustment of either drug. The combination may even be better tolerated than either drug alone. Copyright 2001 John Wiley & Sons, Ltd.
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PMID:Mirtazapine and paroxetine: a drug-drug interaction study in healthy subjects. 1240 53

Pesticides, such as parathion, are metabolized by cytochrome p-450 system to paraoxon, which is a potent cholinesterase inhibitor. Paraoxonase (PON) catalyzes the hydrolysis of these toxic metabolites and protects against pesticide toxicity. A glutamine/arginine (Gln/Arg) polymorphism at amino acid position 192 of PON has been described. The Arg/Arg genotype is associated with higher serum paraoxonase activity compared to Gln/Gln. The Arg/Gln genotype is associated with intermediate serum PON activity. The potential association between PON genotype and symptoms of chronic pesticide toxicity was examined among 100 farm workers. As part of a cross-sectional study of pesticide toxicity among mixed-race farm workers in the Western Cape. South Africa, 100 farm workers were genotyped for polymorphism of the paraoxonase gene at amino acid position 192. Subjects with two or more of the following symptoms were considered to have evidence of chronic toxicity: abdominal pain, nausea, rhinorrhea, dizziness, headache, somnolence, fatigue, gait disturbance, limb numbness, paresthesias, limb pain, or limb weakness. In multivariable logistic regression analysis, the independent predictors of chronic toxicity were previous history of head trauma resulting in loss of consciousness (OR 2.8, 95% CI = 1.7-6.7), having worked as a pesticide applicator (OR 5.4, 95% CI = 3.2-8.9), and having one of the two "slow metabolism" (Gln/Gln or Gln/Arg) genotypes (OR 2.9, 95% CI = 1.7-6.9). Furthermore, the prevalence of chronic toxicity increased in a stepwise fashion from 15% among pesticide nonapplicators with a "fast metabolism" (Arg/Arg) genotype, to 42.9% among pesticide nonapplicators with "slow metabolism" (Gln/Gln or Gln/Arg) genotypes, to 58.8% among pesticide applicators with "fast metabolism" genotype, and 75.0% among pesticide applicators with "slow metabolism" genotypes (P = 0.001). Age, number of years on the job, smoking history, alcohol history, education level, plasma or red blood cell cholinesterase level, or previous history of acute organophosphate poisoning were not statistically significant predictors of chronic toxicity. The PON genotype is an important determinant of a farmworker's susceptibility to chronic pesticide poisoning.
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PMID:Association between human paraoxonase gene polymorphism and chronic symptoms in pesticide-exposed workers. 1262 27

During aerobic cell growth, mitochondria must meet energy demand either by adjusting cellular mitochondrial content or by adjusting ATP production flux, allowing a constant growth yield. On respiratory substrate, the Ras/cAMP pathway has been shown to be involved in this process in the yeast Saccharomyces cerevisiae. We show that of the three cAMP protein kinase catalytic subunits, Tpk3p is the one specifically involved in the regulation of cellular mitochondrial content when energy demand decreases. In decreased energy demand, the Deltatpk3 mitochondrial enzymatic content decreases leading to a subsequent decrease in the cellular growth rate. Moreover, enzymatic content decreases in the Deltatpk3 isolated mitochondria, suggesting that the amount of cellular mitochondria is not affected, but rather that the mitochondria are modified. Our study points to an important decrease in the cytochrome c content in the Deltatpk3 mitochondria, which leads to a decrease in the slipping process at the level of cytochrome-c-oxidase.
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PMID:The yeast cAMP protein kinase Tpk3p is involved in the regulation of mitochondrial enzymatic content during growth. 1562 Mar 72

(1) First-line treatment of multiple myeloma depends first and foremost on the patient's age. There is no standard treatment for relapses and the median survival time after the first relapse is only 12 to 15 months. (2) Bortezomib, a cytotoxic agent, inhibits the 26S proteasome involved in protein breakdown in mammalian cells. It is licensed for use in myeloma after multiple treatment failure. (3) Three dose-finding studies showed some effects of 1 mg/m2 and 1.3 mg/m2 bortezomib administered twice a week for two weeks, with each course followed by a 10-day treatment-free period. It is not known whether 1.3 mg/m2 is more effective than 1 mg/m2. (4) In a non comparative trial that included 202 patients with multidrug-resistant myeloma, progression-free survival time increased to a median of 6.6 months (compared to 3.3 months after previous relapses), and the median overall survival time was 7 months in the 75% of patients who did not respond and more than 15 months in the 25% of responders. However, given the heterogeneous nature of the study population the evidence from this trial is rather weak. (5) An unblinded comparative trial including 54 patients failed to show whether bortezomib 1.3 mg/m2 was more effective than bortezomib 1 mg/m2 in terms of clinical outcome. Another comparative trial including 669 patients indicated that bortezomib was more effective than dexamethasone in terms of the median time to disease progression (5.7 months versus 3.6 months). (6) Animal studies indicate that bortezomib is cardiotoxic and neurotoxic, and that the interval between the maximal tolerated dose and the fatal dose is very small. Experience with bortezomib use is too limited to know the possible clinical repercussions of these experimental findings. (7) Adverse effects were frequent and varied in clinical trials. They included fatigue, nausea and vomiting, diarrhea, anemia, thrombocytopenia and peripheral neuropathies. They affected 30% to 60% of patients overall, and were severe in about 10% to 20% of patients. Other adverse effects included hypotension, fever, headache, pain and dehydration. (8) Bortezomib is metabolised by cytochrome P 450 isoenzyme 3A4, and this implies a high risk of drug-drug interactions. (9) Each vial of bortezomib contains more of the drug than is needed for one injection. This is not only wasteful, but also carries a risk of overdosing, with potentially serious consequences, should the entire contents be injected by mistake. (10) Bortezomib may be used as a last resort in some patients with multiple myeloma, but the individual risk-benefit balance must be carefully weighed in each case.
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PMID:Bortezomib: new drug. A last resort in myeloma: modest efficacy, major risks. 1598 89

Clozapine, an atypical antipsychotic, depends mainly on cytochrome P4501A2 (CYP1A2) for its metabolic clearance. CYP1A2 is inducible by smoking, and lower plasma concentrations of clozapine are measured in smokers than in nonsmokers. Case reports have been published on the effects of discontinuing smoking in patients receiving clozapine, which might lead to elevated plasma concentrations and severe side effects. We present 2 cases on the consequences of smoking cessation in patients receiving this drug. In the first patient, smoking cessation resulted, within 2 weeks, in severe sedation and fatigue, with an approximately 3-fold increase of plasma clozapine concentrations. In the second patient, a very high plasma concentration of clozapine (3004 ng/mL) was measured 6 days following a 16-day stay in a general hospital, during which smoking was prohibited. In the latter patient, the replacement of omeprazole, a strong CYP1A2 inducer, by pantoprazole, a weaker CYP1A2 inducer, could have contributed, in addition to smoking cessation, to the observed strong increase of plasma clozapine concentrations. Genotyping of the 2 patients revealed that they were carriers of the AA genotype for the -164C>A polymorphism (CYP1A2*1F) in intron 1 of CYP1A2 gene, which has previously been shown to confer a high inducibility of CYP1A2 by smoking. Thus, at the initiation of clozapine treatment, smoking patients should be informed that, if they decide to stop smoking, they are encouraged to do so but must inform their prescriber beforehand. Also, because of the increased use of no-smoking policies in many hospitals, studies examining the consequences of such policies on the pharmacokinetics/pharmacodynamics of drugs metabolized by CYP1A2, taking into account different CYP1A2 genotypes, are needed.
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PMID:Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. 1604 15

Transcription profiling of genes encoding components of the respiratory chain and the ATP synthesizing apparatus of Mycobacterium tuberculosis was conducted in vivo in the infected mouse lung, and in vitro in bacterial cultures subjected to gradual oxygen depletion and to nitric oxide treatment. Transcript levels changed dramatically as infection progressed from bacterial exponential multiplication (acute infection) to cessation of bacterial growth (chronic infection) in response to host immunity. The proton-pumping type-I NADH dehydrogenase and the aa3-type cytochrome c oxidase were strongly down-regulated. Concurrently, the less energy-efficient cytochrome bd oxidase was transiently up-regulated. The nitrate transporter NarK2 was also up-regulated, indicative of increased nitrate respiration. The reduced efficiency of the respiratory chain was accompanied by decreased expression of ATP synthesis genes. Thus, adaptation of M. tuberculosis to host immunity involves three successive respiratory states leading to decreased energy production. Decreased bacterial counts in mice infected with a cydC mutant (defective in the cytochrome bd oxidase-associated transporter) at the transition to chronic infection provided initial evidence that the bd oxidase pathway is required for M. tuberculosis adaptation to host immunity. In vitro, NO treatment and hypoxia caused a switch from transcription of type I to type II NADH dehydrogenase. Moreover, cytochrome bd oxidase expression increased, but cytochrome c oxidase expression decreased slightly (nitric oxide) or not at all (hypoxia). These specific differences in respiratory metabolism during M. tuberculosis growth arrest in vitro and in vivo will guide manipulation of in vitro conditions to model bacterial adaptation to host immunity.
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PMID:Changes in energy metabolism of Mycobacterium tuberculosis in mouse lung and under in vitro conditions affecting aerobic respiration. 1622 31

A 14-year-old female with perinatally acquired HIV on boosted protease inhibitor (PI) therapy with atazanavir and ritonavir rapidly developed cushingoid features with excessive weight gain and moon facies within 2 weeks of receiving inhaled fluticasone/salmeterol for asthma treatment. Soon after discontinuing PIs and inhaled steroid, she required hospitalization for dyspnea, headache, muscle weakness, and extreme fatigue requiring hydrocortisone replacement therapy for presumed adrenal insufficiency. Cushing syndrome and adrenal suppression were very likely caused by elevated steroid systemic concentrations resulting from the cytochrome p450 interaction between the protease inhibitors and fluticasone. The Naranjo probability scale score of 5 suggests that the event was probably drug related. This is the first case report of fluticasone and PI-induced Cushing syndrome and adrenal suppression in a pediatric patient without a history of recent or concomitant treatment with systemic steroid therapy. Additionally, this case is unique as it is the most rapid (<2 weeks) presentation documented, thus far. Health care professionals should be conscious of this important drug-drug interaction in HIV-infected children and adolescents and be aware that rapid onset of hypercortisolism and adrenal suppression are possible.
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PMID:Cushing syndrome and severe adrenal suppression caused by fluticasone and protease inhibitor combination in an HIV-infected adolescent. 1759 45

Tomato (Solanum lycopersium L.) plants were grown hydroponically to investigate the changes of energy metabolism and adaptive mechanism in response to root restriction. Root restriction resulted in a significant increase in root lipid peroxidation and reduction in leaf net CO(2) assimilation rate, which was accompanied by increase of alcohol dehydrogenase (ADH; EC 1.1.1.1) and lactate dehydrogenase (LDH; EC 1.1.1.27) activities. Total, cytochrome pathway, and alternative pathway respirations were all decreased in the roots after 15 days of root restriction treatment. Accompanied with the decrease of ATP content, ratio of invertase/sucrose synthase activity was increased in the restricted roots together with a decrease in glucose content and an increase in fructose content. We concluded that the decreased energy synthesis under root restriction condition was partially compensated by the energy-conserving sucrose synthase pathway of sucrose metabolism.
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PMID:Decreased energy synthesis is partially compensated by a switch to sucrose synthase pathway of sucrose degradation in restricted root of tomato plants. 1876 22

Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) with negligible effects on any presynaptic or postsynaptic receptors. Milnacipran has unique pharmacokinetic and pharmacodynamic characteristics that distinguish it from the other marketed serotonin and norepinephrine reuptake inhibitors, venlafaxine, desvenlafaxine, and duloxetine such as equipotent serotonin and norepinephrine reuptake inhibition and a linear dose-concentration trend at therapeutic doses. The half-life of milnacipran is approximately 8 hours. In addition, milnacipran does not inhibit the cytochrome P 450 system, indicating minimal propensity for drug-drug interactions. The antidepressant efficacy of milnacipran has been clearly established in a number of randomized, double-blind, placebo-controlled clinical trials, and it has been widely used for treating major depressive disorder. Moreover, evidence suggests that milnacipran is effective and tolerable in the treatment of fibromyalgia and may have usefulness for fatigue and anxiety symptoms. The current paper reviews researches conducted to date that is relevant to the efficacy, tolerability, and mechanism of action of milnacipran in the treatment of depression, fibromyalgia, and other psychiatric syndromes. Future directions of research are also identified.
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PMID:Milnacipran: beyond a role of antidepressant. 1962 Aug 45


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