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M Fiege

Publications and source records attributed to M Fiege.

At least 19 recordsLinked to original sources
PubMed2005

Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine.

BACKGROUND AND OBJECTIVE: The phosphodiesterase-III (PDE-III) inhibitor enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of enoximone or caused by inhibition of PDE-III remained unclear. Therefore, the effects of the PDE-III inhibitor amrinone in porcine MH normal (MHN) and MHS skeletal muscles were investigated. METHODS: MH-trigger-free general anaesthesia was performed in eight MHS and eight MHN swine. The MH status of the swine was determined by detection of the Arg615-Cys point mutation on chromosome 6 indicating MH susceptibility. Skeletal muscle specimens were excised for the in vitro contracture tests with amrinone. Amrinone was added cumulatively every 5 min to muscle specimens in order to obtain organ bath concentrations between 20 and 400 micromol L(-1). The in vitro effects of amrinone on muscle contractures and twitches were measured. RESULTS: Amrinone-induced contractures in all skeletal muscle preparations. MHS muscles developed contractures at significantly lower bath concentrations of amrinone than MHN muscles. Contractures of MHS compared to MHN muscles were significantly larger at bath concentrations of 80, 100, 150, 200 and 400 micromol L(-1) amrinone. Muscle twitches remained unchanged up to and including 200 micromol L(-1) amrinone. CONCLUSIONS: Inhibition of PDE-III in general elicited higher contractures in MHS than in MHN muscles. Therefore, a contribution of PDE-III and the cyclic adenosine monophosphate (cAMP) system in the pathophysiology of MH must be suspected.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

[Theophylline induces contractures in porcine skeletal muscle preparations with the disposition to malignant hyperthermia].

OBJECTIVE: Theophylline, a methylxanthine, leads to an increase of the cytoplasmic Ca(2+)-concentration in the muscle cell. Since the in-vitro contracture test (IVCT) with halothane and caffeine does not distinguish a 100% between malignant hyperthermia susceptible (MHS) and non-susceptible (MHN), we examined the in-vitro effects of theophylline in porcine skeletal muscle preparations. METHODS: After approval by the local animal care committee ten MHS- and nine MHN-swine were anaesthetized and muscle biopsies taken. For IVCT, muscle specimens were exposed to bolus administrations of theophylline in concentrations of 3.0 respectively 5.0 mmol/l. Muscle contracture development and twitch amplitudes were recorded over a period of 30 minutes. Data are expressed as medians and ranges. RESULTS: After both theophylline bolus administrations MHS-muscles developed significantly higher contractures compared to the MHN-specimens. The MHS-muscles reached a maximum contracture of 17.0 mN (7.2-59.6 mN) after administration of 3.0 mmol/l theophylline. In comparison, two MHN-specimens showed weak contractures with a maximum of 1.4 mN. The 5.0 mmol/l theophylline IVCT resulted in maximum contractures of 19.1 mN (2.1-39.2 mN) for the MHS-preparations. Just in three MHN-muscles weak contractures of 0.0 mN (0.0-0.8 mN) were recorded. Thus, a significant difference without overlap was revealed for the maximum contracture. CONCLUSION: Theophylline in concentrations of 3.0 and 5.0 mmol/l revealed a clear difference between MHS- and MHN-porcine muscle preparations. Further examinations on human skeletal muscles are needed to demonstrate the value of theophylline in the IVCT MH-diagnosis.

Animals↗
PubMed2004

[Is a presymptomatic malignant hyperthermia in-vitro diagnosis with 4-chloro-3-ethyl phenol possible? A study using porcine skeletal preparations].

OBJECTIVE: The diagnosis of malignant hyperthermia is currently performed with the in-vitro contracture test (IVCT) with halothane and caffeine. This test has a sensitivity of 99.0 % but only a specificity of 93.6 %. A cumulative IVCT with 4-chloro-3-ethyl-phenole (CEP) has recently been shown to differentiate between MH susceptible (MHS) and MH normal (MHN) swine. The pur-pose of this study was to investigate the ability of bolus CEP-applications to distinguish between porcine MHS- and MHN-muscle specimens using the IVCT. METHODS: After approval by the local animal care committee 8 MHS- and 8 MHN-swine were anaesthetized and muscle biopsies taken. For IVCT, muscle specimens were exposed to bolus administration of CEP in concentrations of 75 resp. 100 micro mol l (-1). Predefined parameters were: (1) onset time of the contracture development, (2) time to the achievement of the 2, 5 and 10 mN contracture level and (3) maximum contracture level. Data are expressed as medians and ranges. RESULTS: After 75 micro mol l (-1) CEP administration all MHS-muscles showed contractures after 0.5 min (0.2 min/0.9 min). The 2 mN contracture level was reached by all MHS-, the 5 mN level by four MHS- and the 10 mN level by one MHS-specimen. The maximum contracture was 5.3 mN (2.4 mN/12.9 mN). The onset time after 100 micro mol l (-1) CEP was registered as 0.3 min (0.1 min/0.7 min) in the MHS-preparations. Again, the 2 mN level was achieved by all MHS-specimens, the 5 mN level by 5 and the 10 mN level by one MHS-bundle. The maximum contracture was measured as 5.9 mN (2.8 mN/13.9 mN). In 7 MHN-specimens no contracture development was measured. After 75 micro mol l (-1) CEP one MHN-muscle showed a maximum contracture of 1.0 mN, after 100 micro mol l (-1) CEP one MHN-bundle demonstrated a maximum contracture of 1.1 mN. Hence, a significant difference between MHS and MHN without overlap was revealed with both CEP-concentrations in the onset time of contracture, in the 2 mN contracture level and the maximum contracture. CONCLUSION: Since a clear differentiation between MHS and MHN porcine specimens was achieved after bolus application of 75 and 100 micro mol l (-1) CEP, MH-diagnosis might be possible with a CEP-IVCT. It seems worthwhile to examine this hypothesis in men.

Animals↗
PubMed2004

Dantrolene--a review of its pharmacology, therapeutic use and new developments.

Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.

Dantrolene↗
PubMed2003

[Dantrolene. Pharmacological and therapeutic aspects].

Malignant hyperthermia (MH) is a genetic, potentially life-threatening disorder of the skeletal muscle presenting during or following general anaesthesia. Trigger agents are volatile anaesthetics and depolarising muscle relaxants. Dantrolene is the only available drug for effective and specific MH therapy, which reduces significantly the mortality rate. Dantrolene is a skeletal muscle relaxant that depresses the excitation-contraction coupling,however, the specificity of action remains unknown. Recent studies identified the ryanodine receptor, the calcium release channel of the sarcoplasmic reticulum, as the direct molecular target of dantrolene. In addition to its use for MH, dantrolene is used in other disorders such as neuroleptic malignant syndrome and spasticity. Since dantrolene is weakly water soluble, the clinical preparation is time and manpower consuming. New agents have been synthesized, but because of economic considerations no registration for clinical usage has been realised.

Dantrolene↗
PubMed2003

Multicentre evaluation of in vitro contracture testing with bolus administration of 4-chloro-m-cresol for diagnosis of malignant hyperthermia susceptibility.

BACKGROUND AND OBJECTIVE: The in vitro contracture test with halothane and caffeine is the gold standard for the diagnosis of susceptibility to malignant hyperthermia (MH). However, the sensitivity of the in vitro contracture test is between 97 and 99% and its specificity is 78-94% with the consequence that false-negative as well as false-positive test results are possible. 4-Chloro-m-cresol is potentially a more specific test drug for the in vitro contracture test than halothane or caffeine. This multicentre study was designed to investigate whether an in vitro contracture test with bolus administration of 4-chloro-m-cresol can improve the accuracy of the diagnosis of susceptibility to MH. METHODS: Three hundred and fifty-two patients from 11 European MH laboratories participated in the study. The patients were first classified as MH susceptible, MH normal or MH equivocal by the in vitro contracture test according to the European MH protocol. Muscle specimens surplus to diagnostic requirements were used in this study (MH susceptible = 103 viable samples; MH equivocal = 51; MH normal = 204). 4-Chloro-m-cresol was added to achieve a concentration of 75 micromol L(-1) in the tissue bath. The in vitro effects on contracture development and muscle twitch were observed for 60 min. RESULTS: After bolus administration of 4-chloro-m-cresol, 75 micromol L(-1), 99 of 103 MH-susceptible specimens developed marked muscle contractures. In contrast, only two of 204 MH-normal specimens showed an insignificant contracture development following 4-chloro-m-cresol. From these results, a sensitivity rate of 96.1% and a specificity rate of 99.0% can be calculated for the in vitro contracture test with bolus administration of 4-chloro-m-cresol 75 micromol L(-1). Forty-three patients were diagnosed as MH equivocal, but only specimens from 16 patients developed contractures in response to 4-chloro-m-cresol, indicating susceptibility to MH. CONCLUSIONS: The in vitro contracture test with halothane and caffeine is well standardized in the European and North American test protocols. However, this conventional test method is associated with the risk of false test results. Therefore, an improvement in the diagnosis of MH is needed. Regarding the results from this multicentre study, the use of 4-chloro-m-cresol could increase the reliability of in vitro contracture testing.

Biopsy↗
PubMed2003

Effects of a 5HT(2) receptor agonist on anaesthetized pigs susceptible to malignant hyperthermia.

BACKGROUND: The pathophysiology of the serotoninergic system in malignant hyperthermia (MH) is not completely understood. The serotonin-2 (5HT(2A)) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) induces typical MH symptoms, including skeletal muscle rigidity, an increase in body temperature, hyperventilation and acidosis in conscious MH-susceptible (MHS) pigs. Whether these symptoms are directly generated in skeletal muscle, result from central serotonergic overstimulation or from a porcine stress syndrome remains unresolved. In this study the in vivo effects of DOI on anaesthetized (and thus stress-protected) MHS and MH-normal (MHN) pigs were investigated. METHODS: and results. DOI 1 mg kg(-1) was administered three times at 40-min intervals to five MHS and five MHN anaesthetized pigs. Body temperature, heart rate, muscle tone, arterial carbon dioxide pressure (Pa(CO(2))), pH and creatine kinase concentrations were measured. The clinical occurrence of MH was defined by Pa(CO(2)) above 70 mm Hg and an increase in body temperature of more than 2 degrees C. Intragroup differences were analysed with the Friedman test as an overall non-parametric ANOVA and, in case of significance, with the Wilcoxon test. Intergroup comparisons were performed with the Mann-Whitney U-test (statistical significance P<0.05). MHS and MHN pigs developed muscle fasciculations, significant increases in body temperature and Pa(CO(2)) and a significant decrease in pH after the administration of DOI. These changes were comparable in both groups until the third dose of DOI, when in MHS pigs heart rate and Pa(CO(2)) rose significantly and pH fell significantly compared with MHN pigs. All MHS pigs fulfilled the MH criteria. Body temperature increased by more than 2 degrees C in all MHN pigs and Pa(CO(2)) exceeded 70 mm Hg in two. Thus, two MHN pigs fulfilled the criteria of MH. CONCLUSIONS: The comparability of the clinical presentation following DOI administration in MHS and MHN animals and the order of the development of MH-like symptoms favour the hypothesis of a central serotonergic overstimulation, leading to a serotonin syndrome.

Amphetamines↗
PubMed2002

In vitro effects of 4-chloro-3-ethylphenol in skeletal muscle preparations from malignant hyperthermia susceptible and normal swine.

BACKGROUND AND OBJECTIVE: The in vitro contracture test with halothane and caffeine is the current gold standard for diagnosis of malignant hyperthermia. This test has a sensitivity of 99.0% but a specificity of only 93.6%. Therefore, an alternative drug is desirable which distinguishes between malignant hyperthermia-susceptible and malignant hyperthermia-normal subjects with a higher specificity and sensitivity. METHODS: 4-chloro-3-ethylphenol has recently been shown to trigger Ca2+-induced Ca2+-release in skeletal muscle terminal cisternae and to increase the myoplasmic free Ca2+ concentration in skeletal muscle fibres. The purpose of this study was to investigate the ability of 4-chloro-3-ethylphenol to distinguish between malignant hyperthermia-susceptible and malignant hyperthermia-normal porcine muscle specimen in the in vitro contracture test. Ten malignant hyperthermia-susceptible and 14 malignant hyperthermia-normal swine were anaesthetized and muscle biopsies were taken. For the in vitro contracture test muscle specimens were exposed to cumulative concentrations of 4-chloro-3-ethylphenol (12.5 to 200 micromol L(-1)). RESULTS: 4-chloro-3-ethylphenol produced contractures in a concentration-dependent manner in the malignant hyperthermia-susceptible muscle bundles. In contrast, cumulative 4-chloro-3-ethylphenol did not generate contractures in malignant hyperthermia-normal specimens. Contractures were significantly greater (P < 0.05) in the malignant hyperthermia-susceptible compared to the malignant hyperthermia-normal preparations in all 4-chloro-3-ethylphenol concentration steps from 50 micromol L(-1) to 200 micromol L(-1). There was no overlap between the two groups above a concentration of 75 micromol L(-1) in cumulative 4-chloro-3-ethylphenol in vitro contracture tests. CONCLUSIONS: It remains to be verified whether an in vitro contracture test with 4-chloro-3-ethylphenol can also discriminate between malignant hyperthermia-susceptible and malignant hyperthermia-normal humans. Since no prior tested agent revealed a clear differentiation in contracture development without overlap, the 4-chloro-3-ethylphenol test might be a promising new approach to the diagnosis of malignant hyperthermia.

Animals↗
PubMed2002

[In-vitro-effects of cocaine in skeletal muscle specimens of patients susceptible to malignant hyperthermia].

OBJECTIVE: The abuse of cocaine can cause serious medical complications like tachycardia, rhabdomyolysis, and hyperthermia. Because of the clinical similarities, it has been suggested that cocaine might be a trigger of malignant hyperthermia (MH). Therefore, aim of this study was to investigate the in-vitro effects of cocaine in skeletal muscle specimens of MH susceptible (MHS) and normal (MHN) patients. METHODS: 62 patients undergoing the in-vitro contracture test (IVCT) according to the protocol of the European MH Group (EMHG) for diagnosis of MH susceptibility were included in this study. In muscle specimens surplus to diagnostic requirements cocaine was added in order to achieve tissue bath concentrations of 0.01, 0.1 and 1.0 mM. The contracture development and twitch response have been registered. RESULTS: 21 patients were diagnosed as MHS and 36 patients as MHN. 5 patients tested as MH-equivocal (MHE) were excluded from the study. Following bolus administration of cocaine, no contracture development was observed in MHS, as well as MHN specimens. The muscle twitch decreased after cocaine administration significantly in both diagnostic groups. CONCLUSION: In contrast to the established MH trigger substances like volatile anaesthetics, cocaine produced no contracture development in MHS muscle specimens. Furthermore, cocaine produced a negative inotropic effect in all skeletal muscle preparations, which might be explained by local anaesthetic effects. Regarding these results, cocaine seems not to be a MH trigger agent.

Anesthetics, Local↗
PubMed2001

[Malignant neuroleptic syndrome after haloperidol administration].

The neuroleptic malignant syndrome (NMS) is a rare complication of antipsychotic therapy. We report on a 65-year-old patient who was treated with haloperidol, diazepam and mirtazapin because of a severe depressive episode with psychotic symptoms. He exhibited most of the signs and symptoms characteristic of NMS, e.g.: hyperthermia, rigidity, elevated creatine phosphokinase, leukocytosis, elevated liver enzymes, reduced consciousness and autonomic nervous system disturbances. A secondary pneumonia was diagnosed 2 days after the onset of the NMS, which might have been due to chest wall rigidity. Intensive care treatment consisted of immediate discontinuation of the offending agent, supportive therapy with rehydratation and catecholamines as well as application of dantrolen. After 23 days of intensive therapy all pathological parameters were normalised and the patient was transferred to an internal ward. Three main theories on the pathogenesis of NMS exist: 1. blockade of central receptors, 2. a skeletal muscle target model and 3. sympathoadrenal hyperactivity. The differential diagnosis includes among others malignant hyperthermia and serotonin syndrome.

Aged↗
PubMed2001

Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis.

BACKGROUND: Malignant hyperthermia (MH), heat stroke, and exercise-induced rhabdomyolysis (ER) were suspected to be related syndromes. However, it is not known whether individuals with history of ER have an increased incidence of susceptibility to MH. To establish an association between ER and susceptibility to MH, the authors determined the MH status in patients with a history of MH-like episodes induced by physical stress. METHODS: Twelve unrelated patients with ER, 18 patients with anesthesia-induced MH, and 28 controls were investigated with the in vitro contracture test (IVCT) according to the European MH Group protocol and the ryanodine contracture test. In addition, all patients were screened for genetic mutations, and histology was performed on muscle specimens. RESULTS: Ten ER patients had positive IVCT results, one patient had a negative test result, and one patient showed equivocal responses. Samples from patients with positive IVCT results showed pronounced contractures after exposition to ryanodine, as opposed to specimens from patients with negative IVCT results, which developed contractures slowly. Three ER patients had mutations at the ryanodine receptor gene. All anesthesia-induced MH patients had positive IVCT results, two of them presented the C1840T mutation. The control patients had normal contracture test results and no typical MH mutations. Histologic examination determined no specific myopathies in any patient. CONCLUSIONS: Regarding these results, the authors recommend performing muscle biopsies for histologic examination and IVCT in patients with ER. In addition, the patient should be seen by a neurologist and screened for genetic abnormalities to shed light on the genetics of MH.

Adolescent↗
PubMed2000

Spin-directed stereoselectivity of carbonyl-alkene photocycloadditions

The concentration dependence of the Paterno-Buchi photocycloaddition of the two cyclic enolethers 2,3-dihydrofuran and 2,3-dihydropyran, respectively, with aromatic as well as aliphatic aldehydes was studied. For aliphatic aldehydes, a sharp transition from low to high diastereostereoselectivity was observed, indicating a switch from singlet to triplet photocycloaddition with different selectivity controlling mechanisms.

Journal Article↗
PubMed2000

Effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible patients.

STUDY OBJECTIVES: To study the in vitro effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible (MHS) and normal (MHN) patients. DESIGN: Prospective study. SETTING: Malignant hyperthermia (MH) laboratory at a university hospital. PATIENTS: 47 patients with clinical suspicion for MH undergoing in vitro contracture test (IVCT) for diagnosis of MH susceptibility. INTERVENTIONS: Biopsies of M. quadriceps femoris were performed in adult patients with a 3-in-1 nerve block and in children with trigger-free general anesthesia. MEASUREMENTS AND MAIN RESULT: Patients were first classified as MHS or MHN by the IVCT according to the protocol of the European MH Group (EMHG). Patients with equivocal results (MHE) or with neuromuscular diseases were excluded from the study. Enoximone was added to the organ bath to surplus vital muscle specimens in single bolus concentrations of 0.4, 0.6, 0. 8, or 1.6 mmol/L. The in vitro effects of enoximone on muscle contractures and twitch were measured. Seventeen patients were classified as MHS and 30 as MHN by the EMHG criteria. Enoximone induced contractures in skeletal muscles in a dose-dependent manner. Contractures of MHS compared to MHN muscle specimens were significantly larger at all concentrations used in this study. No overlap in maximum contractures was seen between MHS and MHN muscles at a bath concentration of 0.6 mmol/L enoximone only. CONCLUSIONS: Diagnosis of MH by an IVCT test with a single bolus administration of enoximone seems to be possible using a concentration of 0.6 mmol/L. The findings of this study may indicate an involvement of the phosphodiesterase-III and cAMP system in pathogenesis of MH. Further in vivo investigation should determine the trigger potency of enoximone in MH susceptible individuals.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

A multicenter study of 4-chloro-m-cresol for diagnosing malignant hyperthermia susceptibility.

UNLABELLED: Standardization of the in vitro contracture test (IVCT) for malignant hyperthermia (MH) susceptibility has resulted in very rare false negative tests. However, false positive results stigmatizing the patient seem to be more frequent than false negative results and make supplementary tests desirable. This multicenter approach studied the usefulness of an IVCT with 4-chloro-m-cresol (4-CmC), a ryanodine receptor-specific agonist for a better definition of MH susceptibility. Diagnosis made by the standard IVCT was compared with the results of this 4-CmC test on muscle specimens of 202 individuals from 6 European MH centers. In the 4-CmC test, the results of the MH susceptible group differed significantly from both the MH normal and the MH equivocal group. 4-CmC revealed a qualitatively dose response-curve similar to caffeine. A correlation index of r = 0.79 for the concentration thresholds underlined the strong concordance of the caffeine and the 4-CmC effects. The optimal threshold concentration was determined to be 75 microM in the pooled data of all centers and is much lower than that of caffeine (2 mM), suggesting a more than 25-fold higher affinity of 4-CmC. The predictive value of 4-CmC is as high as that of caffeine and consequently higher than that of halothane. 4-CmC seems to be a suitable drug to refine diagnosis of MH susceptibility and could be used as an additional test substance. IMPLICATIONS: Although in vitro contracture testing for malignant hyperthermia diagnosis is well standardized, with a relatively high sensitivity and specificity, false test results cannot be excluded and may be associated with serious disabilities for the concerned individuals. In this multicenter study, 4-chloro-m-cresol was evaluated as a new test substance for the in vitro contracture testing. Its use improves the accuracy of in vitro diagnosis of malignant hyperthermia susceptibility.

Caffeine↗