The pathophysiology of leg cramping during dialysis and the use of carnitine in its treatment.

Leg cramping is a common side effect of hemodialysis, and this is frequently treated by the administration of carnitine, but this is not effective in every patient. Alkalosis is a key component of the etiology of leg cramping during hemodialysis sessions. This is mediated through the binding of calcium ions to serum albumin, which causes hypocalcemia, and an increase in the release of calcium ions from the sarcoplasmic reticulum. Normally the calcium pump on the sarcoplasmic reticulum consumes ATP and quickly reuptakes the released calcium ions, which rapidly stops excessive muscle contractions. Thus, carnitine deficiency results in prolonged muscle contraction because of ATP depletion. However, during ATP production, carnitine is only involved up to the stage of acyl-CoA transport into mitochondria, and for the efficient generation of ATP, the subsequent metabolism of acyl-CoA is also important. For example, ß-oxidation and the tricarboxylic acid cycle may be affected by a deficiency of water-soluble vitamins and the electron transport chain requires coenzyme Q10, but statins inhibit its production. The resulting accumulation of excess long-chain acyl-CoA in mitochondria inhibits enzymes involved in energy production. Thus, carnitine administration may be used more effectively if clinicians are aware of its specific physiologic roles.

Quinine induced simvastatin toxicity through cytochrome inhibition - a case report.

BACKGROUND: Nocturnal leg cramps are painful, involuntary muscle contractions commonly seen in elderly. While mostly harmless, they can severely impair quality of life and often disrupt sleep. Adverse drug effects may be responsible for a fraction of nocturnal leg cramps but often go unrecognized, resulting in additional prescribing intended to deal with adverse effects that might be better addressed by reduction, substitution, or discontinuation of the offending agent. CASE PRESENTATION: An 87 year old female presented as outpatient in family medicine with nocturnal leg cramps which had been present for five years and increasingly burdened her quality of life. She had been using quinine 200 mg once daily for symptomatic relief but the cramps kept returning with increasing intensity. During clinical examination we found neither structural nor neurological or metabolic disorders that explained her symptoms. When doing a medication analysis, we found that she was taking a statin together with quinine. Quinine is a cytochrome P450 isoenzyme 3A4 inhibitor, the very enzyme which is involved in the metabolism of most statins. Therefore the use of both substances simultaneously increases blood levels of the statin thereby increasing the risk of side effects including symptomatic myopathy and myalgia. After discontinuing both medications, the patient was, and remained, symptom free. CONCLUSION: This case report describes a possible medication interaction that has rarely been noted in literature.

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.

[Pharmacokinetic and analgesic properties of the injectable dosage form of a new imidazobenzimidazole derivative RU-1205 with kappa agonist activity].

Pharmacokinetic properties of imidazobenzimidazole derivative compound RU-1205 were investigated after subcutaneous administration to rabbits as a substance and a dosage form (lyophilisates for injection) at a dose of 25 mg/kg. The lyophilisate was characterized by high values of the relative bioavailability. In tests, the "hot plate" and "vinegar cramps" the dosage form and the substance exhibited the same analgesic effect.

Increased HCN channel driven inward rectification in benign cramp fasciculation syndrome.

Muscle cramps are a common complaint associated with sudden painful involuntary contractions of a muscle. The mechanisms responsible for muscle cramps are still not clear. Axonal excitability and multi-unit electromyography studies were performed in 20 patients suffering from benign cramp fasciculation syndrome, not currently on medication. The measures of axonal excitability suggested greater inward rectification, indicative of an increase in Ih. Mathematical modelling suggested that the data were best explained by depolarization of the voltage dependence of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Parameters associated with polarization of resting membrane potential were not changed. These findings suggest that a role for HCN channels may become apparent during the rhythmic discharge associated with a voluntary contraction. Consistent with this view, patients had higher motor unit discharge rates than healthy controls during maximal voluntary effort.

The inhibitory effect of shakuyakukanzoto on K+ current in H9c2 cells.

Shakuyakukanzoto (shao-yao-gan-cao-tang) is a commonly used Chinese traditional herbal medicine for the treatment of acute pain with muscle cramp. However, its mechanism of action is unclear. We previously reported that a low concentration of Kanzo (licorice) and isoliquiritigenin, a component of licorice, inhibited the potassium (K(+)) current in H9c2 cells. Therefore, in the present study, we examined the effects of Shakuyakukanzoto, Shakuyaku or Kanzo on the K(+) current (IKur) in H9c2 cells. Shakuyakukanzoto inhibited IKur in a concentration-dependent manner. The half-maximal concentration of Shakuyakukanzoto was approximately 1.3 mg/mL and the Hill coefficient was 1.2. The order of potency of inhibiting IKur was Kanzo>Shakuyakukanzoto>Shakuyaku. Glycyrrhizin, a major component of licorice, had no inhibitory effect on IKur. A small interfering RNA experiment indicated that IKur was most likely to be Kv2.1 in H9c2 cells. Our results suggest that Shakuyakukanzoto may normalize intracellular and extracellular K(+) balance by inhibiting IKur and reducing K(+) efflux, while the Na(+)-K(+) pump promotes K(+) influx into myofibers. Consequently, excess K(+) may be reduced from external space of myofibers. This may be a part of the Shakuyakukanzoto mechanism for improving muscle pain.

Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle.

OBJECTIVE: Suboptimal mitochondrial function has been implicated in several disorders in which fatigue is a prominent feature. Vitamin D deficiency is a well-recognized cause of fatigue and myopathy. The aim of this study was to examine the effects of cholecalciferol therapy on skeletal mitochondrial oxidative function in symptomatic, vitamin D-deficient individuals. DESIGN: This longitudinal study assessed mitochondrial oxidative phosphorylation in the gastrosoleus compartment using phosphorus-31 magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics in 12 symptomatic, severely vitamin D-deficient subjects before and after treatment with cholecalciferol. All subjects had serum assays before and after cholecalciferol therapy to document serum 25-hydroxyvitamin D (25OHD) and bone profiles. Fifteen healthy controls also underwent (31)P-magnetic resonance spectroscopy and serum 25OHD assessment. RESULTS: The phosphocreatine recovery half-time (τ1/2PCr) was significantly reduced after cholecalciferol therapy in the subjects indicating an improvement in maximal oxidative phosphorylation (34.44 ± 8.18 sec to 27.84 ± 9.54 sec, P < .001). This was associated with an improvement in mean serum 25OHD levels (8.8 ± 4.2 nmol/L to 113.8 ± 51.5 nmol/L, P < .001). There was no difference in phosphate metabolites at rest. A linear regression model showed that decreasing serum 25OHD levels was associated with increasing τ1/2PCr (r = -0.41, P = .009). All patients reported an improvement in fatigue after cholecalciferol therapy. CONCLUSIONS: Cholecalciferol therapy augments muscle mitochondrial maximal oxidative phosphorylation after exercise in symptomatic, vitamin D-deficient individuals. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could at least be partly responsible for the fatigue experienced by these patients. For the first time, we demonstrate a link between vitamin D and the mitochondria in human skeletal muscle.

Mild clinical and histopathological features in patients who carry the frequent and causative malignant hyperthermia RyR1 mutation p.Thr2206Met.

OBJECTIVE: Malignant hyperthermia (MH) is a classically unapparent pharmacogenetic disorder of the skeletal muscles triggered by inhalational anesthetics or depolarizing muscle relaxants. The disposition to MH is inherited in an autosomal-dominant manner and is primarily due to mutations in the gene for the ryanodine receptor type 1 (RyR1). The present study intended to analyze whether mild muscular symptoms (elevation of the resting CK, cramps in the calves, slight calf hypertrophy) may be associated with susceptibility to MH and/or with histopathological changes. METHODS: A muscle biopsy was taken from 12 out of 44 blood relatives (three generations) of a large family and was investigated with the halothane/caffeine in vitro contracture test (IVCT). Afterwards a histological, histochemical and immunhistological examination was performed. Altogether in 29 persons the DNA was analyzed for mutations in the RyR1-gene. RESULTS: Eight persons were diagnosed as susceptible to MH (MHS) by the IVCT, 4 were MH negative. All MHS persons carried the MH causative c.6617C > T (Thr2206Met) mutation and showed slight clinical signs of a myopathy as well as mild biopsy changes with isolated hypotrophic fibers and disseminated small areas with reduction of oxidative staining (multi-minicore like lesions). The Thr2206Met mutation was identified in another further 9 relatives who also experienced mild myopathological features. Clinical MH incidents were not reported in this large family. CONCLUSION: The RyR1 Thr2206Met mutation is one of the most frequent mutations in the European MH population but carriers are normally healthy. In this study we could demonstrate that the MH causative Thr2206Met mutation may also be associated both with clinical symptoms of a mild myopathy and histopathological changes in the oxidative inter myofibrillar network.

Sodium balance during U. S. football training in the heat: cramp-prone vs. reference players.

U. S. football players with a history of heat cramps were evaluated for the effect of physical training, sodium intake, and loss of sweat sodium on whole blood sodium concentration (BNa). Athletes (n=14 males, 24+/-1 y) were recruited and studied based on medical history, age, and position. The reference group (R, n=8 without a cramping history) and cramp-prone group (C, n=6, history of whole-body cramps associated with extensive sweat loss during exercise in the heat) were measured for body mass and BNa (ISTAT) before and after team training of 2.2 h in hot conditions (WBGT=29-32 degrees C). Intake and loss of fluid and sodium were also measured to determine respective acute balance. In R, BNa was stable pre- to post-training (138.9+/-1.8 to 139.0+/-2.0 mmol/L) while it tended to decline in C (137.8+/-2.3 to 135.7+/-4.9 mmol/L), and three subjects in C had BNa values below 135 mmol/L (131.7+/-2.9 mmol/L). C consumed a greater percentage of total fluid as water (p<0.05). Mean sweat sodium concentration was (52.6+/-29.2 mmol/L for C and 38.3+/-18.3 mmol/L for R (p>0.05). Compared to R, C tended to experience a decline in BNa and greater acute sodium imbalance. These changes may place cramp-prone players at greater risks for developing acute sodium deficits during training.

[Use of dermo-adipose grafts in facial morphology restoration in cases of progressive partial lipodystrophy]. / Utilizzazione degli innesti dermoadiposi nel ripristino della morfologia del viso in casi di lipodistrofia parziale progressiva.

Two cases of partial progressive lipodystrophy syndrome with extensive soft tissue atrophy of the face and of the upper part of the trunk, with kidney and blood alteration, are presented. On the basis of the psysical examination and pathological history of the patients, blood and instrumental tests have been performed in both cases. The diagnosis of partial progressive lipodystrophy syndrome has been made and a surgical treatment with dermal fat graft from the inguinal region was proposed to the patients after several information and was performed to improve the facial contour. After a follow up of 18 months a resorption of 50% of dermal fat graft was found according to surgeons' expectations with a good esthetic improvement of the face.

Exertional myalgia syndrome associated with diminished serum ammonia elevation in ischemic exercise testing.

A 36-year-old man with chronic severe exertional myalgias had a normal serum lactate elevation and diminished serum ammonia elevation on an ischemic forearm exercise test (IFET). The IFET is commonly performed in the evaluation of patients with complaints of exertional myalgias, cramps, and rhabdomyolysis. The finding of a normal serum lactate elevation and a diminished serum ammonia elevation after ischemic exercise is usually considered indicative of myoadenylate deaminase deficiency. However, myoadenylate deaminase activity was normal in this man's muscle biopsy specimen. This case suggests that a diminished serum ammonia elevation in the IFET is not always indicative of myoadenylate deaminase deficiency, a disorder of ammonia production. A diminished serum ammonia elevation in the IFET could also reflect an impairment of net ammonia efflux from muscle into blood.