Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers

The effects of the enantiomers of mexiletine were tested on sodium currents of frog skeletal muscle fibers recorded by means of the three vaseline gap voltage clamp method and compared with the effects produced by tocainide enantiomers. The R-( – ) mexiletine produced a tonic block of the sodium current, elicited by single depolarizing test pulses from the holding potential of – 100 mV to – 20 mV, with an IC₅₀ of 43.9 ± 1 M, whereas the corresponding S-( + ) enantiomer produced the same effects at about twofold higher concentrations. A similar stereoselectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-( – ) and S-( + ) enantiomers of mexiletine and tocainide produced a further use-dependent block of sodium currents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behaviour led to a significant lowering of the IC₅₀ values with respect to the tonic block but the eudismic ratios ([IC₅₀S-( + )]/[IC₅₀R( – )]) and the relative potency between mexiletine and tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h) , suggesting a high-affinity interaction with the inactivated sodium channels. Again a stronger potency of R-( – ) vs. S-( + ) enantiomers and of mexiletine vs. tocainide was observed. The excitability characteristics recorded from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to block sodium current. Thus a concentration-related increase in the threshold current required to elicit an action potential was observed along with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membrane. Again the R-( – ) isomers were more potent than the S-( + ) ones and mexiletine was more effective than tocainide. These data corroborate the presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enantiomers during both tonic and use-dependent block suggest that the increase in the apparent affinity of the receptor during statedependent conformational changes of the channel does not enhance its stereospecificity. The decrease in effective concentration upon high frequency stimulation supports the potential usefulness of low doses of R-( – ) mexiletine in the treatment of the abnormal hyperexcitability of the myotonic muscles, with a likely reduction of unwanted side effects.     

Ultrasound of femoral head cartilage: a new method of assessing bone age

This paper analyses the relationship between the thickness of the anterior femoral head cartilage (FHC), as measured by ultrasound, and some anthropometric parameters, such as height, weight, skeletal and chronological age. In addition, it provides standard norms for FHC thickness in a paediatric population. Both hips were examined in 213 consecutive subjects (99 boys and 114 girls), aged 1.9–14 years. Seventy-four subjects underwent hand and wrist X-rays for skeletal maturation: 32 of these were dropped from the study because a discrepancy as high as two standard deviations was found between their skeletal and their chronological age. The thickness of FHC correlated strongly with skeletal and chronological age, standing height and body weight. A side difference of 0.2 mm in FHC was considered to be abnormal. The study population was divided into 13 groups according to chronological age and values of FHC for boys and girls are provided for each group. It is suggested that the magnitude of hyaline FHC is a valuable feature in the evaluation of skeletal maturation in children.     

Non-invasive assessment of skeletal kinetics using fluorine-18 fluoride positron emission tomography: evaluation of image and population-derived arterial input functions

To measure regional skeletal kinetics using fluorine-18 fluoride positron emission tomography (PET) it is necessary to know the concentration of radioactive tracer being delivered to bone by arterial plasma with relation to time, the arterial input function (IFa). Methods by which IFa can be derived without arterial sampling are attractive because of their relative technical simplicity and the reduction in possible morbidity to the subject. We have compared the use of a scaled population input function (IFp) and a corrected image-derived input function from the aorta (IFi) with an IFa directly measured from a radial artery line in ten normal postmenopausal women. Both of the aforementioned methods rely only on a small number of discrete venous samples. Each subject had a dynamic PET acquisition of the lumbar spine performed after the intravenous injection of 180 MBq ¹⁸F-fluoride. Both the IFp and the IFi were compared with the IFa in terms of the accuracy of determination of six parameters. These were: plasma clearance of fluoride to bone mineral (K _i), unidirectional plasma clearance to total bone tissue (K ₁) and individual rate constants k ₂, k ₃ and k ₄, calculated using non-linear regression with a three-compartment model, and the plasma clearance to bone mineral calculated using the Patlak method (K _pat). For both the IFp and the IFi method the root mean square errors for K _pat and K _i were similar and small (<8.2%). The errors in determining K ₁ and the rate constants k ₂ to k ₄ are larger by either method, but with a small advantage using the IFp method. It is concluded that the use of either non-invasive method for determining the arterial plasma input function is suitable for the measurement of the most important parameters, K _i and K _pat, in these subjects. Received 8 April and in revised form 11 July 1999     

Macromorphology and histology of intramuscular hemorrhages in cases of drowning

In a prospective autopsy series of 39 cases of fatal drowning, the detailed dissection of the skeletal muscles of the neck, anterior / posterior trunk and the upper extremities in layers revealed intramuscular hemorrhages of different size and shape in 20 cases (51.3 %). Light microscopy examination showed a premortal (vital/agonal) type of muscular alteration in 7 (50 %) out of 14 macroscopical hemorrhage-positive cases. These hemorrhages and histological muscle alterations are attributed to agonal convulsions, hypercontraction and overexertion of the affected muscle groups. As long as no cutaneous or subcutaneous hematomas above the hemorrhages can be found, these autopsy findings (with special reference to histology) can serve as an additional criterion concerning the differentiation of drowning and another cause of death. Received: 31 July 1998 / Received in revised form: 31 August 1998     

小型循环促进装置

利用循环脉动气压对受治者肢体逐节施以收缩和舒张动作,以促进四肢静脉血液和淋巴液的回流,装置在临床上对各类因循环障碍所致四肢浮肿、下肢静脉曲张及长期卧床患者静脉血栓形成均有较好的治疗、预防作用。     

The cardiotonic bipyridine AWD 122-60 inhibits adenosine triphosphate-sensitive potassium channels of mouse skeletal muscle

Summary The inhibition of ATP-sensitive potassium channels in mouse skeletal muscle by the cardiotonic bipyridine AWD 122-60 was investigated with the patch-clamp technique. In excised patches of the inside-out configuration, internally applied AWD 122-60 (10^–6–10^–3 mol/1) reversibly reduced the open-probability of single ATP-sensitive potassium channels. The agent shortened the periods of channel activity but did not affect the channel conductance. At positive membrane potentials channel inhibition by AWD 122-60 was more pronounced than at negative potentials, the drug concentrations producing 50% channel inhibition were 11 mol/l at + 40 mV and 29 mol/l at –40 mV. The Hill coefficients of the concentration-response curves were in the range between 0.5 and 0.6 for both potentials. milrinone (10^–4 mol/I), had no effects on ATP-sensitive potassium channels in skeletal muscle. potassium channels in heart muscle by AWD 122-60 are discussed. Send offprint requests to B. Neumcke at the above address     

Iodine-125 labeled phenylphosphonic acid: A new radiopharmaceutical for long-term investigations of the skeleton

A skeletal seeking radiopharmaceutical labeled with a long-lived radionuclide was developed to evaluate regional bone formation and its subsequent resorption. The agent is [phosphonate (phenylmethylene hydroxy) bis]-I-125 or I-125 PA. Tissue distribution studies in mice (N=16) showed approximately 40% of the administered dose to be retained by the skeleton up to 336 hours post IV injection. The percentage of the dose accumulated by the thyroid gland remained at less than 0.5%, indicating minimal deiodination of the I-125 PA. Whole body retention studies in the same species revealed a triexponential release pattern with the longest component comprising 33% of the dose with a biologic half-life of 962 days. A fractured rat tibia model was studied with I-125 PA and Tc-99^m MDP. Chronic loss of the I-125 PA relative to normal tibia was quantitated: five days (62.8%); 30 days (47.4%). Concomitant increased uptake of the Tc-99^m MDP was observed at the fracture site relative to normal: five days (186%); 30 days (1,041%). The above data suggest that I-125 PA can be utilized to measure acute bone formation and chronic resorption.     

Skeletal muscle involvement in infantile systemic hyalinosis

Infantile Systemic Hyalinosis is a rare autosomal recessive entity, characterised by deposition of hyaline material in skin and bone, often complicated by visceral involvement. The characteristic features are marked delay in motor milestones attributed to severe progressive flexion contractures of proximal and distal joints, and skin and mucosal hypertrophy and thickening, followed by failure to thrive. Pain secondary to osteolytic lesions is also a predominant feature. We report a patient with Infantile Systemic Hyalinosis, confirmed by the clinical findings, who also displayed clear evidence of proximal muscle weakness. Muscle biopsy revealed myopathic changes, which have not been reported previously. We suggest that skeletal muscle is involved in Infantile Systemic Hyalinosis and contributes to the characteristic poor outcome of these patients.     

Role of Clostridium perfringens phospholipase C in the pathogenesis of gas gangrene.

Gas gangrene is an acute and devastating infection most frequently caused by Clostridium perfringens and characterized by severe myonecrosis, intravascular leukocyte accumulation, and significant thrombosis. Several lines of evidence indicate that C. perfringens phospholipase C (Cp-PLC), also called alpha-toxin, is the major virulence factor in this disease. This toxin is a Zn²⁺ metalloenzyme with lecithinase and sphingomyelinase activities. Its three dimensional structure shows two domains, an N-terminal domain which contains the active site, and a C-terminal domain required for the Ca²⁺dependent interaction with membranes. Cp-PLC displays several biological activities: it increases capillary permeability, induces platelet aggregation, hemolysis, myonecrosis, decreases cardiac contractility, and is lethal. Experiments with genetically engineered Cp-PLC variants have revealed that the sphingomyelinase activity and the C-terminal domain are required for toxicity. The myotoxicity of Cp-PLC is largely dependent on its membrane damaging effect. In addition, it has been suggested that the alterations in the blood flow induced by this toxin also contribute to muscle damage. In gas gangrene, Cp-PLC dysregulates transduction pathways in endothelial cells, platelets and neutrophils leading to the uncontrolled production of several intercellular mediators and adhesion molecules. Thus, Cp-PLC alters the traffic of neutrophils to the infected tissue and promotes thrombotic events, enhancing the conditions for anaerobic growth.     

Health-related quality of life of patients with genetic skeletal dysplasias

While medical knowledge on genetic skeletal dysplasias has expanded, very little is known about the patients' health-related quality of life (HRQOL). To test the validity and sensitivity of the fifteen and sixteen dimensional measures of HRQOL in patients with chondrodysplasias, we examined 121 adults aged 16–54 and 19 adolescents aged 12–15 with achondroplasia, cartilage-hair hypoplasia and diastrophic dysplasia. The age and sex standardized overall HRQOL score of the adult patients (0.885 on a scale from 0 to 1) was significantly lower than that of normal controls (0.928) (P < 0.001). The difference in the HRQOL between the patients and the controls consisted mainly of the differences in dimensions of mobility, usual activities, sexual activity and discomfort, for which the patients reported a significantly lower status (more problems) than the controls (P < 0.001). Adolescent patients demonstrated HRQOL profiles similar to those of adults. However, age-specific problems occurred on the dimensions of school and hobbies, friends and physical appearance (P < 0.05). In a detailed examination of different patient groups, some clinically unexpected findings were observed, suggesting that denial is at least in part involved. Conclusion Subjective assessment of HRQOL of patients with chondrodysplasias is valuable for provision of optimal care. In treatment and management special attention should be paid to those dimensions on which the patients' perceived status is currently suboptimal, especially during adolescence which probably is the most critical period in the lives of these individuals. Received: 7 April 1997 / Accepted in revised form: 31 July 1997