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PubMed2002

Perioperative management of a child with glycogen storage disease type III undergoing cardiopulmonary bypass and repair of an atrial septal defect.

The glycogen storage diseases (GSD) are a heterogenous group of inherited disorders involving one of the several steps of glycogen synthesis or degradation. Type III GSD, also known as Cori's or Forbe's disease, results from a deficiency of the enzyme, amylo-1,6-glucosidase, which is responsible for the breakdown or debranching of the glycogen molecule during catabolism. As a result of this deficiency, inadequate glycogen breakdown occurs, resulting in hypoglycaemia during periods of fasting or stress, as well as storage of excessive glycogen, predominantly in the liver. Glycogen accumulation in the liver leads to hepatogmegaly and, in some instances, hepatic dysfunction with cirrhosis in the third and fourth decades of life. Additionally, deficiency of the enzyme in skeletal and cardiac muscle can lead to skeletal muscle weakness and cardiomyopathy. We present a 28-month-old girl who presented for anaesthetic care for cardiopulmonary bypass and closure of an atrial septal defect. The potential perioperative implications of GSD type III are discussed.

Anesthesia↗

PubMed1999

Effects of lipid-lowering drugs on left ventricular function and exercise tolerance in dyslipidemic coronary patients.

Previous studies suggested that certain lipid-lowering drugs such as statins suppress ubiquinone, affect mitochondrial function, and may have deleterious effect on skeletal or cardiac muscles with potentially serious clinical consequences, especially in patients with established coronary heart disease and left ventricular dysfunction. In this double-blind study, we assessed the effects of 20 mg simvastatin (S, n = 32) or 200 mg micronized fenofibrate (F, n = 32, control group) on rest and exercise left ventricular function in hypercholesterolemic survivors of a previous Q-wave acute myocardial infarction. Left ventricular radionuclide imaging was performed at rest and during submaximal exercise and global and segmental (nine segment regional wall-motion score) ejection fractions were measured before treatment and 12 weeks later. Serum ubiquinone was reduced after treatment (p = 0.03) in the S but not the F group, whereas total and low-density lipoprotein (LDL) cholesterol were significantly reduced in both groups. Before treatment, mean global ejection fraction was 52.1+/-12.2% and 49.3+/-11.8% at rest in F and S patients, respectively, and increased (56.0+/-13.7% in F and 52.1+/-12.9% in S) at peak exercise (no difference between groups). After treatment, the increase in ejection fraction tended to be lower in S (0) than in F (+3.8%) but not significantly. However, ejection fraction at rest increased after treatment in S (p = 0.009) but not in F. Subgroup analyses indicated that the improvement in rest ejection fraction in S was essentially observed in patients with ejection fraction <40% (n = 8, +6%), whereas it was stable in patients with ejection fraction >40% (+1.8%). Finally, the numbers of akinetic or hypokinetic segments at rest and during exercise were not different in the two groups before and after treatment. Mean maximal exercise load (113+/-23 watts in F vs. 104+/-27 W in S before treatment) was not modified by the treatment (111+/-21 and 104+/-27 W). Thus a 12-week lipid-lowering treatment with either S or F did not negatively alter left ventricular function during exercise in dyslipidemic patients with established coronary heart disease and did not affect their ability to exercise. The improvement in left ventricular function at rest after simvastatin in patients with left ventricular dysfunction warrants confirmation in further studies with large sample size.

Blood Pressure↗

PubMed2007

Effect of physical activity and muscle morphology on endothelial function and arterial stiffness.

Physically active persons have a reduced risk of atherosclerotic disease. Arterial stiffness and endothelial dysfunction are important risk factors for cardiovascular disease. A high proportion of type I (slow-twitch) muscle fibers in skeletal muscle is associated with a favorable cardiovascular risk profile. We tested physical activity and muscle fiber-type distribution as determinants of endothelial function and arterial stiffness in middle-aged men. Fifty-four men (median age 58) who underwent a muscle biopsy in 1984 were re-studied in 2003. Aortic pulse wave velocity (PWV) and pulse wave reflection were assessed by applanation tonometry. Endothelial function was tested by examining the effects of salbutamol and nitroglycerin on pulse wave reflection. In multiple regression analyses aortic PWV (R2=0.51) correlated positively with age (P=0.017), BMI (P=0.001), and systolic blood pressure (P=0.004). A high augmentation index (R2=0.33) was associated with smoking (P<0.001), high LDL cholesterol (P=0.02), and elevated diastolic blood pressure (P=0.03). Impaired endothelial function (R2=0.37) was associated with high age (P=0.04), high LDL cholesterol (P=0.017), high triglycerides (P=0.027), and high physical activity (P=0.005). Muscle fiber-type distribution is not a determinant of arterial stiffness or endothelial function. Impaired endothelial function was observed in physically active men, underlining the need for further research.

Aged↗

PubMed2001

Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover.

A recently identified function of leptin is to protect nonadipose tissues from the nonoxidative metabolic products of long-chain fatty acids (FAs) during periods of overnutrition by increasing the beta-oxidative metabolism of surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as ceramide increase in nonadipose tissues, including the pancreatic islets and heart, and cause nitric oxide-mediated lipotoxicity and lipoapoptosis. The triacylglycerol content in nonadipocytes provides a useful index of overall nonoxidative metabolism. In normal animal tissue, triacylglycerol is maintained within a narrow range; even when the caloric intake is excessive, compensatory FA-induced upregulation of oxidation prevents overaccumulation. However, if leptin is deficient or if leptin receptors (Ob-R) are nonfunctional, this autoregulatory system does not operate, and triacylglycerol content rises in nonadipose tissues. This provides a source of excess FAs that enter potentially toxic pathways of nonoxidative metabolism leading to apoptosis of certain tissues. FA overload in skeletal muscle causes insulin resistance; in myocardium, it impairs cardiac function; and in pancreatic islets, it causes beta-cell dysfunction, apoptosis, and diabetes. All abnormalities in these tissues can be blocked by troglitazone, an inhibitor of FA accumulation.

Animals↗

PubMed2000

[Heart failure: symptomatic treatment versus prognostic modification].

While the prognosis of patients with heart failure is related to the progression of left ventricular dysfunction and to the activation of several regulatory systems--neurohormones, cytokines and others--the symptoms relate to hemodynamic and skeletal muscle disturbances. This is why the relief of symptoms by pharmacological intervention is not always accompanied by an improvement in prognosis. Hemodynamic improvement is no longer the main issue of therapy. The antagonism of the neurohormonal and other regulatory systems, as a means to influence prognosis, stands as the main challenge for the future. Until now only ACE inhibitors, beta-blockers, spironolactone, the combination of nitrates and hydralazine, and heart transplantation have achieved this goal.

Cardiovascular Agents↗

PubMed2000

[Cardiomyopathy associated with mitochondrial disorders].

With understanding the biochemical and molecular characteristics of mitochondrial disorders, several point mutations or deficient of mitochondrial DNA have been identified in patients with mitochondrial dysfunction. The clinical manifestations of this disorders are heterogeneous and most patients show abnormality of the central nervous system, skeletal muscle, heart, kidney or these combinations. Especially, cardiac involvement is very important because it is determinant factor for the prognosis. There are two types of cardiac manifestation; cardiomyopathy and cardiac conduction defects. The former is usually hypertrophic, but dilated forms have been demonstrated. The latter is well known as one of three main symptoms in Kearn-Sayre syndrome. We discuss the pathogenesis, pathology and clinical manifestation of mitochondrial cardiomyopathy.

Cardiomyopathies↗

PubMed2000

[Physical training in the treatment of heart failure].

Exercise training leads to an increase in functional capacity and reduction of symptoms in patients with chronic heart failure. The benefit of training is explained particularly by its impacts on peripheral blood flow and metabolism of skeletal muscle. The appropriate exercise training as to its form and intensity is safe in patients with severe left ventricular dysfunction.

Exercise Therapy↗

PubMed1999

Effect of growth hormone on adipose tissue and skeletal muscle lipoprotein lipase activity in humans.

Lipoprotein lipase (LPL) is involved in clearing triglyceride-rich chylomicrons and very-low-density lipoprotein particles from the bloodstream, providing free fatty acids to particular adipose tissue for storage and to skeletal muscle tissue for oxidation and energy production. Although the same gene (chromosome 8p22) encodes LPL, the enzyme activity is regulated in a tissue-specific manner. Dysfunction of the LPL enzyme has been implicated in the pathogenesis of dyslipidemia (high triglyceride and low high-density lipoprotein (HDL) cholesterol), early arteriosclerosis, and the pathogenesis of obesity. Treatment with growth hormone (GH) both in vivo and in vitro results in a pronounced reduction (often up to 50%) of LPL activity in adipose tissue in humans. The specific level of messenger ribonucleic acid, however, is not generally affected by GH treatment in adipose tissue, indicating that the effect of GH is mediated at a post-translational level. The GH-mediated reduction in adipose tissue LPL activity may be involved in the reduction in adipose tissue mass commonly seen after prolonged GH treatment in GH-deficient adults and GH treatment in obese subjects. LPL activity in adipose and skeletal muscle tissue is generally regulated in a reciprocal manner by, for example, fasting, feeding, insulin and epinephrine. A high level of LPL activity, particularly in skeletal muscle tissue, has been found to be associated with a beneficial lipoprotein profile (low triglyceride and high HDL cholesterol). In investigations where obese but otherwise healthy women were treated with GH, and in another study where adults with GH deficiency were treated for 4 months with GH, we found no effects of GH on either skeletal muscle LPL activity nor on skeletal muscle LPL gene expression. In conclusion, GH has a pronounced inhibitory effect on adipose tissue LPL activity, which is mediated at a post-translational level. The GH-induced reduction in adipose tissue mass may be partly mediated by this effect on adipose tissue LPL. GH has no effects on LPL activity in skeletal muscle, which may be related to the fact that GH has no or only minor effects on plasma triglyceride and HDL cholesterol levels. Finally, GH is not, unlike for example insulin and catecholamines, involved in antagonistic regulation of LPL in muscle and adipose tissue.

Adipose Tissue↗

PubMed1984

Altered potassium flux and myocardial dysfunction during sepsis.

Untreated septic shock results in depletion of extracellular fluid, cellular swelling, increased intracellular sodium, and decreased intracellular potassium concentrations in primate skeletal muscle. The Langer rabbit heart interventricular septal preparation was used to determine whether similar changes occur in cardiac muscle during sepsis. Rabbit septa (n = 17) were perfused with control and septic rabbit plasma plus red blood cells. Tissue contractility (developed tension [DT] and rate of tension change [dP/dt]) was followed, plasma cations were measured (Na+, K+, Ca2+, H+), perfusion pressure (PP) was monitored, and 42K efflux was determined. The effect on 42K efflux caused by the addition of potassium chloride to control plasma was determined. During perfusion with septic plasma there was significant decline of septal function (P less than 0.001). In 12/17 experiments DT fell 77.8 +/- 21.4% and dP/dt fell 75.8 +/- 24.8% from control values (means +/- 1 SD). All septa recovered when perfusion with control plasma was resumed. If [K+] was increased in control plasma during 42K washout, the percentage increase of effluent counts per minute per minute correlated with the percentage rise of control plasma [K+] (r = 0.95, P less than 0.001). During perfusion with septic plasma there was no similar correlation (r = 0.277). 42K efflux increased during septic plasma perfusion independent of the differences between control and septic plasma [K+], demonstrating abnormal myocardial K+ efflux. An abnormal efflux of K+ is seen during septic plasma perfusion similar to that described in primate skeletal muscle. It is associated with and may be a mechanism of action for the observed fall of contractility.

Animals↗

PubMed1999

Myoblast cell grafting into heart muscle: cellular biology and potential applications.

This review surveys a wide range of cellular and molecular approaches to strengthening the injured or weakened heart, focusing on strategies to replace dysfunctional, necrotic, or apoptotic cardiomyocytes with new cells of mesodermal origin. A variety of cell types, including myogenic cell lines, adult skeletal myoblasts, immoratalized atrial cells, embryonic and adult cardiomyocytes, embryonic stem cells, tetratoma cells, genetically altered fibroblasts, smooth muscle cells, and bone marrow-derived cells have all been proposed as useful cells in cardiac repair and may have the capacity to perform cardiac work. We focus on the implantation of mesodermally derived cells, the best developed of the options. We review the developmental and cell biology that have stimulated these studies, examine the limitations of current knowledge, and identify challenges for the future, which we believe are considerable.

Animals↗

PubMed2006

Mitochondrial DNA mutations, energy metabolism and apoptosis in aging muscle.

Locomotor functional decline and loss in muscle mass with age is virtually a universal characteristic that has been documented in several species, including worms, fruit flies, rodents, non-human primates and humans. The age-related loss of muscle mass and strength (sarcopenia) represents an important risk factor for disability and mortality in older subjects and has been linked with cellular energy deficit and increased apoptosis at old age. Many key theories on aging describing the mechanisms underlying sarcopenia are now focused on the mitochondria because of their dichotomous role in controlling life and death processes within myocytes. Mitochondria represent the main producers of cellular energy in the form of adenosine triphosphate, but are also considered a key regulatory center of apoptosis. Unknown factors leading to a decrease in aerobic energy efficiency are linked with mitochondrial mutations which may result into apoptosis. Moreover, deregulation of autophagy (degradation and recycling of long-lived protein and organelles, such as the mitochondria) in post-mitotic tissue might also be responsible for the age-associated cellular energy failure. Alterations in specific signaling pathways, such as AMP-activated protein kinases, play a role in both cell survival response and apoptotic response depending on energy depletion. Evidence supports that apoptosis occurring in aging skeletal muscle may be due, in part, to the progressive decline in mitochondrial function and the resulting energy depletion within the cell. In turn, mitochondrial dysfunction is partly due to the accumulation of oxidative damage to macromolecules, including mitochondrial DNA, RNA and proteins, essential components for optimal functioning of mitochondria. Evidence concerning these series of events leading to energy depletion and apoptosis are discussed.

Aging↗

PubMed1996

[Structure and function of ClC chloride channels].

ClC chloride channels form a voltage-gated chloride channel family. It consists of at least 8 members of chloride channel, including the skeletal muscle-specific ClC-1 and the two very homologous kidney-specific chloride channels, ClC-K1 and ClC-K2. The dysfunction of ClC-1 is shown to lead to myotonia. Both ClC-K1 and ClC-K2 are involved in the transcellular chloride transport in the different nephron segments and may be involved in certain disorders of tubular function. This review focuses on (1) the structure and function of ClC chloride channels and (2) the involvement of ClC chloride channels in human diseases.

Animals↗

PubMed1998

Adenovirus-mediated transfer of human acid maltase gene reduces glycogen accumulation in skeletal muscle of Japanese quail with acid maltase deficiency.

Acid maltase deficiency (AMD) causes a lysosomal glycogenosis inherited as an autosomal recessive trait. The infantile type of AMD (Pompe disease) leads to early death due to severe dysfunction of cardiac and respiratory muscles and no effective therapy is available. Replication-defective adenovirus vectors offer a promising tool for in vivo gene delivery and gene therapy. We constructed a recombinant adenovirus containing the human acid maltase (AM) cDNA downstream of the CAG promoter, composed of modified chicken beta-actin promoter and CMV IE enhancer (AxCANAM). Japanese quail with AMD was used for this study as an animal model for human AMD. When cultured fibroblasts from AMD quail were infected with AxCANAM, AM activity in the cells increased in proportion to the multiplicity of infection (MOI). When AxCANAM (4.5 x 10(8) PFU) was injected into unilateral superficial pectoral muscle of AMD quail, PAS staining showed that glycogenosomes disappeared and stainability of acid phosphatase was reduced in the injected area as compared with the contralateral muscle of the same birds. Biochemically, AM activity increased and glycogen content decreased in the injected muscle. Western blot analysis showed that AMD quail muscle injected with AxCANAM expressed human AM protein processed to active forms. These results suggest that the human AM cDNA transferred by an adenovirus vector was sufficiently expressed, leading to a marked reduction of the glycogen accumulation in the skeletal muscle of AMD quail.

Adenoviridae↗

PubMedDate not supplied

Altered endothelin-1 levels in acute lower limb ischemia and reperfusion.

Tourniquet-induced ischemia is often used in orthopedic and reconstructive procedures. This is associated with muscle damage and dysfunction, which limits tourniquet application time. Endothelin-1 (ET-1) is a potent vasoconstrictor, which has been implicated in ischemic conditions and ischemia-reperfusion injury. This study aimed to investigate the role of ET-1 in human skeletal muscle subjected to tourniquet-induced acute ischemia and reperfusion. Thirteen patients undergoing total knee replacement were studied. Plasma and muscle ET-1 concentrations were measured at the start of surgery, after an hour of acute ischemia, and 15 minutes following reperfusion. ET-1 receptor binding was also studied by use of autoradiography, and ET-1 mRNA expression investigated by use of real-time polymerase chain reaction (RT-PCR). Tissue ET-1 increased following the period of acute ischemia and persisted during reperfusion. ET-1 was associated with microvessels and macrophages in the muscle. No changes in circulating ET-1 levels, ET-1 mRNA expression, or ET-1 receptor binding were found. It is concluded that the ET-1 pathway is involved in acute ischemia and reperfusion and it may contribute to the muscle injury that occurs during surgical procedures.

Acute Disease↗

PubMed2003

Short communication: reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy.

Direct evidence confirming the hypothesis that a dysfunction of the mitochondrial respiratory chain (MRC) underlies the pathogenesis of hyperlactatemia associated with highly active antiretroviral therapy (HAART) is scarce. We studied mitochondrial DNA (mtDNA) content and MRC function in the skeletal muscle of an HIV-infected patient during an episode of symptomatic hyperlactatemia. Skeletal muscle biopsy was performed during the episode when the patient was symptomatic and 3 months later when the patient was clinically recovered. Assessment of mitochondria was performed using histological, polarographic, spectrophotometrical, and Southern blot and real time PCR DNA quantification methods. The histological study disclosed extensive mitochondrial impairment in the form of ragged-red fibers or equivalents on oxidative reactions. These findings were associated with an increase in mitochondrial content and a decrease in both mitochondrial respiratory capacity and MRC enzyme activities. Mitochondrial DNA content declined to 53% of control values. Mitochondrial abnormalities had almost disappeared later when the patient became asymptomatic. Our findings support the hypothesis that MRC dysfunction stands at the basis of HAART-related hyperlactatemia.

Acidosis, Lactic↗

PubMed2025

Integrated Multiomics Analyses of the Molecular Landscape of Sarcopenia in Alcohol-Related Liver Disease.

BACKGROUND: Skeletal muscle is a major target for ethanol-induced perturbations, leading to sarcopenia in alcohol-related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis-driven experiments, an integrated multiomics-experimental validation approach provides a comprehensive view of these interactions. METHODS: We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol-treated (ET) murine and human-induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol-related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+/NADH ratio), imaging and senescence-associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger. RESULTS: Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia-inducible factor 1α (HIF1α) during normoxia. Across preclinical and clinical models, HIF1α targets (n = 32 genes) and signalling genes (n > 100 genes) (n = 3 ATACseq, n = 65 phosphoproteomics, n = 10 acetylomics, n = 6 C2C12 proteomics, n = 106 C2C12 RNAseq, n = 64 hiPSC RNAseq, n = 30 hiPSC proteomics, n = 3 mouse proteomics, n = 25 mouse RNAseq, n = 8 human RNAseq, n = 3 human proteomics) were increased. Stabilization of HIF1α (C2C12, 6hEtOH 0.24 ± 0.09; p = 0.043; mALD 0.32 ± 0.074; p = 0.005; data shown as mean difference ± standard error mean) was accompanied by enrichment in the early transient and late change clusters, -log(p-value) = 1.5-3.8, of the HIF1α signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512 ± 872.1, p < 0.001) and mALD muscle, with decreased expression of electron transport chain components (CI-V, p < 0.05) and Sirt3 (C2C12: 0.067 ± 0.023, p = 0.025; mALD: 0.41 ± 0.12, p = 0.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364 ± 4558, p = 0.03; mALD: 40036 ± 18 987, p = 0.049). Ethanol-induced SAMP was observed across models (P16: C2C12: 0.2845 ± 0.1145, p < 0.05; hiPSCm: 0.2591, p = 0.041). MitoLbNOX treatment reversed redox imbalance, HIF1α stabilization, global acetylation and myostatin expression (p < 0.05). CONCLUSIONS: An integrated multiomics approach, combined with experimental validation, identifies HIF1α stabilization and accelerated post-mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.

Sarcopenia↗

PubMed1998

99mTc SESTAMIBI scintigraphic evaluation of skeletal muscle disease in patients with systemic sclerosis: diagnostic reliability and comparison with cardiac function and perfusion.

The diagnosis of skeletal muscle involvement in patients with systemic sclerosis (SSc) is usually based on clinical, laboratory, electromyographic, and bioptic evidence of muscle disorder, whereas SSc cardiac disease is well established by nuclear medicine techniques (radionuclide ventriculography and myocardial scintigraphy). Previous reports have retrospectively hypothesized a possible relationship between cardiac and muscle involvement in scleroderma patients. In order to improve overall diagnostic accuracy in the qualitative/quantitative assessment of skeletal muscle involvement in these patients and to compare these results with those obtained at the cardiac level, diethylenetriaminepentaacetic acid (DTPA)-99mTc radionuclide ventriculography and 99mTc SESTAMIBI myocardial and muscular scintigraphic examinations were performed in 10 SSc patients and in five healthy subjects. Muscular radioactivity, as assessed at thigh and calf levels by means of a segmental score, was significantly decreased in SSc patients in comparison with healthy subjects (global score value 15.6+/-2.2 vs 22.7+/-1.6, p<0.001), as well as right ventricular ejection fraction (RVEF, 34.3%+/-5.3 vs 53.6%+/-4.2, p<0.001) and myocardial segmental perfusion (global score value, 19.6+/-2 vs 25.9+/-1.1, p<0.01). The results show a high frequency of skeletal muscle involvement in patients with SSc. Moreover, scleroderma patients with muscle disorders, as evidenced by scintigraphy, show a comparable occurrence of cardiac involvement, even in the absence of clinical signs of cardiac dysfunction.

Cardiomyopathies↗

PubMed2001

Prescribing for multiple sclerosis patients in general practice: a case-control study.

OBJECTIVES: To examine the prescribing patterns for multiple sclerosis (MS) patients resident in Wales by general practitioners (GPs), compared to an age, gender and GP surgery matched control population. METHODS: Anonymised data for 1996 were obtained for all patients from 24 GP practices in the all-Wales General Practice Morbidity Database (GPMD). This covered 220 538 patient years at risk for 1996. Cases were selected as those with a Read code of MS at some point from 1993 to 1996 (therefore had consulted the GP at least once during this time). The controls were age, gender and surgery matched patients randomly selected from the GPMD. RESULTS: A total of 216 cases were identified, giving a prevalence of 97.9 per 105. Cases were prescribed a mean of 15 drugs each in 1996 compared to eight drugs for controls (P < 0.0005). Compared with controls, MS patients were prescribed significantly more laxatives, diuretics, hypnotics and anxiolytics, antidepressants, antiepileptics (mainly carbamazepine), corticosteroids, oxybutynin, vitamin B12 and skeletal muscle relaxants (predominantly baclofen; P < 0.05). Certain 'MS specific' drugs were not frequently prescribed, such as cytotoxic immunosuppressants (two cases), amantadine (one case) and isoniazid (no cases). No case was prescribed medication for erectile dysfunction. Over 80% (44/53) of corticosteroid prescriptions for MS were for oral prednisolone. Over one-third (39%, 9/23) of cases prescribed a corticosteroid received a 'chronic' course. Over one-third (5/14) of courses of selective-serotonin re-uptake inhibitors (SSRI) for cases were identified as subtherapeutic. CONCLUSIONS: MS patients were high users of prescribed medicines, having almost twice as many prescriptions from the GP compared to controls. GP prescribing often reflected available evidence from published controlled trials, hence cytotoxic immunosuppressants, drugs for fatigue and tremor were seldom prescribed, whereas drugs such as oxybutynin and skeletal muscle relaxants were frequently prescribed. However, the increased use of certain drugs compared to controls such as diuretics, vitamin B12, hypnotics and anxiolytics were unsubstantiated in the literature. Furthermore, no published well-controlled clinical trials were found utilizing oral prednisolone or assessing the possible therapeutic benefit of chronic courses of corticosteroids in MS, both of which were prescribed by the GP. The absence of medication for sexual dysfunction (prelicensing of sildenafil), a reportedly common MS problem, was discussed. The relatively high incidence of subtherapeutic courses of SSRIs needs further investigation, given the increased incidence of depression and suicide associated with MS.

Adolescent↗