Biomedical subjects

S Quasthoff

Publications and source records attributed to S Quasthoff.

At least 19 recordsLinked to original sources

PubMed2002

[Prevention of oxaliplatin-induced neuropathy by carbamazepine. A pilot study].

INTRODUCTION: Oxaliplatin has been proven antitumoral activity in numerous clinical trials. Peripheral sensory neuropathy with predominantly hyperpathic symptoms induced by cold is the most severe and dose-limiting toxicity resulting from oxaliplatin therapy. We demonstrated that oxaliplatin alters sodium channel kinetics on sensory neurons. This effect could be antagonized in vitro by the sodium channel blocker carbamazepine. Therefore a pilot study was initiated to investigate if carbamazepine prevents oxaliplatin-induced neuropathy in patients with colorectal cancer. PATIENTS AND METHODS: Ten patients (six males, four females, mean age 56 +/- 12 years) refractory to 5-fluorouracil were treated with oxaliplatin, 5-fluorouracil, and folinic acid. The patients additionally received carbamazepine. Doses were adapted to a serum level of 3 - 6 mg/l. Patients were questioned about side-effects weekly and treatment-related toxicities were documented using the modified WHO scale. Results were compared with 30 historic controls treated with the same chemotherapy without carbamazepine. RESULTS: The cumulative oxaliplatin dose was higher in the carbamazepine group (median 722 mg/m(2) and 510 mg/m(2), respectively, p = 0.020). Carbamazepine levels were 4.5 +/- 1.5 mg/l. In contrast to the control group no neuropathy higher than grade 1 occurred in the carbamazepine group. Rate of carbamazepine-induced side effects was low. CONCLUSIONS: These observations demonstrate that oxaliplatin-induced sensory neuropathy more than grade 1 may be prevented by carbamazepine. Prevention of oxaliplatin-induced neurotoxicity by carbamazepine would possibly enable chemotherapy with considerable higher doses of oxapliplatin and thus enhance activity. A multicenter trial will elucidate if more serious distal neurotoxicities, which occur after application of higher cumulative doses of oxaliplatin, can also be prevented by carbamazepine.

Antimetabolites, Antineoplastic↗

PubMed2001

[Nerve growth factor (NGF) in treatment of diabetic polyneuropathy. One hope less?].

Diabetic polyneuropathy (DPN) is by far the most common neuropathy in the western world. In Germany, some 3-4 million patients are afflicted. In the U.S., a large-scale multicenter trial was initiated to evaluate the efficacy and safety of recombinant human nerve growth factor (rhNGF) in the treatment of DPN. A total of 1019 patients were randomly assigned in this double-blind study to receive either rhNGF or placebo over a 48-week period. The rhNGF had no significant side effects apart from mild hyperalgesia at the injection site. However, the substance failed to show significant benefit on global assessment, neuropathic sypmtoms and signs or neurophysiological parameters of nerve function when compared to the placebo group. Possible reasons for the negative outcome of this trial are the small dosis of rhNGF used, choice of a study population different from those enrolled in earlier promising studies, and the multifactorial etiology of DPN, which poses significant difficulties to the design and evaluation of therapeutic trials.

Diabetic Neuropathies↗

PubMed2000

The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons.

The chemotherapeutic oxaliplatin causes a sensory-motor neuropathy with predominantly hyperpathic symptoms. The mechanism underlying this hyperexcitability was investigated using rat sensory nerve preparations, dorsal root ganglia and hippocampal neurons. Oxaliplatin resulted in an increase of the amplitude and duration of compound action potentials. It lengthened the refractory period of peripheral nerves suggesting an interaction with voltage-gated Na(+) channels. Application of oxaliplatin to dorsal root ganglion neurons resulted in an increase of the Na(+) current, a block of the maximal amplitude and a shift of the voltage-response relationship towards more negative membrane potentials. The effect was detectable on 13 of 18 tested cells. This observation, together with the absence of any effect on Na(+) currents of hippocampal neurons, suggests that the interaction of oxaliplatin is restricted to one or more channel subtypes. The effect of oxaliplatin could be antagonised by the Na(+) channel blocker carbamazepine which could be used to reduce side effects of oxaliplatin therapy in patients.

4-Aminopyridine↗

PubMed2000

Expression of messenger RNA of the cardiac isoforms of troponin T and I in myopathic skeletal muscle.

In the absence of clinical signs, elevated values of the cardiac isoforms of troponin T (cTnT) and I (cTnI) can be found in the serum samples of some patients with skeletal muscle myopathies; the cause is unclear. We studied the messenger RNA (mRNA) expression of cTnT and cTnI in the skeletal muscles of 24 patients with histologically proven myopathies and in 18 patients in whom a myopathy could be excluded. For cTnT- and cTnI-mRNA determination, we designed specific primer pairs for nested polymerase chain reaction. After amplification, the products were digested with 2 restriction enzymes and visualized. We found cTnT mRNA in 7 skeletal muscle biopsy specimens (6 patients with Duchenne muscular dystrophy, 1 patient with a primary sarcoglycanopathy) and cTnI mRNA in 6 (5 with Duchenne muscular dystrophy, 1 patient with a histologically negative biopsy). The mRNA of the cardiac isoforms, cTnT and cTnI, is expressed in the skeletal muscles of patients with Duchenne muscular dystrophy, but also in some other myopathies. Further studies are needed to show whether the mRNA is translated into the protein, but serum levels of cTnT and cTnI in patients with Duchenne muscular dystrophy would seem to indicate this.

Biomarkers↗

PubMed1999

X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1).

The sensorimotor neuropathy of the Charcot-Marie-Tooth type (CMT) is the most common hereditary disorder of the peripheral nervous system. The X-linked dominant form of CMT (CMTX) is associated with mutations in the gene for the gap junction protein connexin32. We examined four CMTX pedigrees two of which had potentially novel mutations in the only coding exon of connexin32. One previously unreported missense mutation, Ala39Val, was found in a family displaying a CMT phenotype with additional upper limb postural tremor reminiscent of a Roussy-Lévy syndrome. A novel single base insertion, 679insT, is among the first mutations found in the fourth transmembrane domain of connexin32. Frameshift and premature stop of translation are supposed to result in a non-functional carboxy-terminus. Two further families had the known missense mutations Arg15Trp and Arg22Gln. Several female carriers were found normal on clinical presentation, however, the genotype was paralleled by decreased nerve conduction velocities (NCV) and slowed central conduction of brain stem auditory evoked responses (BAER). Median motor NCVs showed mild (in women) to intermediate (in males) reduction, indicating a peripheral neuropathy with a predominating axonal component. Nerve biopsy findings were consistent with the electrophysiological data showing a marked loss of large myelinated fibres and clusters of regenerating axons. Electron microscopy revealed various alterations of the axoglial attachment zone. This suggests defective axon-Schwann cell interactions which may induce the axonopathy in CMTX.

Adolescent↗

PubMed1998

The role of axonal ion conductances in diabetic neuropathy: a review.

Diabetic neuropathy is a common complication in diabetes mellitus. Diabetic neuropathy is accompanied by alterations in axonal excitability, which can lead to either "positive" (paresthesia, dysesthesia, pain) and/or "negative" (hypesthesia, anesthesia) symptoms. The mechanisms underlying these alterations in axonal excitability are not well understood. Clinical tests reveal reduced nerve conduction velocity and axonal loss, but fail to explain nerve excitability. Many different factors have been suggested in relation to the pathophysiology of diabetic neuropathy. There are probably as many factors as there are different clinical pictures in diabetic neuropathy. Nevertheless, it seems that hyperglycemic hypoxia is mainly responsible for the electrophysiological changes seen in damaged diabetic nerves. This article summarizes experimental data indicating that a dysfunction of ion conductances, especially voltage-gated ion channels, could contribute to abnormalities in the generation and/or conduction of action potentials in diabetic neuropathy.

Animals↗

PubMed1998

Differences in the sensitivity to purinergic stimulation of myelinating and non-myelinating Schwann cells in peripheral human and rat nerve.

Schwann cells of the peripheral nervous system are distinguished by morphological and functional criteria in myelinating and non-myelinating subtypes. We and others have previously reported that Schwann cells in isolated peripheral human and rat nerve respond to extracellular application of ATP with a rise in the intracellular free calcium concentration [Ca2+]i. In the present study, the receptors mediating these Ca2+ transients have been investigated in myelinating and non-myelinating Schwann cells of intact fascicles of isolated human sural nerves, rat ventral roots, and rat vagus nerves. Microfluorometry and confocal laser scanning was used on preparations stained with the Ca2+-sensitive dyes Calcium Green-1 and Fura Red. In myelinating Schwann cells of human and rat nerves, the ATP-induced rise of [Ca2+]i resulted from the activation of a P2Y2 purinoceptor subtype (rank order of potency: UTP > or = ATP >> 2-MeSATP = ADP). In contrast, in non-myelinating Schwann cells, Ca2+ transients were produced by activation of a P2Y1 purinoceptor subtype (rank order of potency: 2-MeSATP > ATP > ADP >> UTP). The P1 agonist adenosine and alpha,alpha-meATP did not evoke Ca2+ signals. Ca2+ transients in both types of Schwann cells were found to be due to Ca2+ release from cyclopiazonic acid-sensitive intracellular stores. However, inhibition by suramin was only found in non-myelinating Schwann cells. These findings indicate that mammalian Schwann cells express phenotype-specific P2Y receptor subtypes.

Adenosine Triphosphate↗

PubMed1998

X-linked dominant Charcot-Marie-Tooth disease: nerve biopsies allow morphological evaluation and detection of connexin32 mutations (Arg15Trp, Arg22Gln).

X-linked Charcot-Marie-Tooth neuropathy (CMTX) is caused by mutations in the connexin32 gene on Xq13. Because of overlapping morphological and clinical data, CMTX patients often meet the criteria of autosomal-dominant CMT2, the neuronal type of CMT. Hence, it might be useful to analyse the connexin32 gene in suspected CMT2 patients when there is no male-to-male transmission. We selected a cohort of 30 patients who were considered having CMT2 on the basis of previous clinical and histopathological evaluation. DNA was extracted from paraffin-embedded sural nerve biopsy samples and screened for connexin32 mutations to verify the possible diagnosis of CMTX. In 2 patients mutations were found corresponding to amino acid substitutions of arginine for tryptophan in codon 15 and arginine for glutamine in codon 22 of connexin32. This study illustrates that archival material allows genetic classification of suspected CMT cases. Furthermore, there is additional proof that connexin32 mutations represent the underlying genetic defect in some cases of predominantly neuronal CMT.

Adolescent↗

PubMed1998

A special blocker reveals the presence and function of the hyperpolarization-activated cation current IH in peripheral mammalian nerve fibres.

Electrotonic responses recorded extra- or intracellularly from peripheral nerve preparations show a "sag" to hyperpolarizing current pulses. The biophysical nature of this "inward rectification" is still under discussion since the phenomenon has not been noted at voltage-clamped single nerve fibres, and since Cs+, which reduces inward rectification, is not a specific ion channel blocker. In this study, we found that low micromolar concentrations of ZD 7288, a specific blocker of the hyperpolarization-activated cationic current (Ih) in the soma of central mammalian neurons, result in a complete block of inward rectification in the electrotonic responses of isolated rat spinal dorsal roots. In addition, ZD 7288 enhanced the activity-dependent slowing of conduction seen in compound C fibre action potentials of isolated rat vagus nerves and augmented the post-tetanic hyperpolarization following trains of action potentials in unmyelinated and myelinated axons. The data suggest that ZD 7288 is a potent blocker and a useful research tool for the study of hyperpolarization-activated inward rectification (Ih) of peripheral nerve preparations.

Animals↗

PubMed1998

Clinical phase II evaluation of paclitaxel in combination with cisplatin in metastatic or recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: Paclitaxel as single agent has shown marked activity in several malignancies. The aim of the present phase II trial was to determine the activity of paclitaxel/cisplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: 200 mg/m2 paclitaxel was administered over three hours followed by cisplatin (100 mg/m2), repeated every 22 days. Twenty-eight patients were entered and received a total of 99 cycles (median 2, range 1-6). All patients were evaluable for toxicity, and 25 for response. RESULTS: Hematologic toxicities included leukopenia CTC grade 3 in 13 patients, and grade 4 in five patients, neutropenia grade 3 in nine patients, and grade 4 in eight patients, grade 3 anemia and grade 2 thrombocytopenia in one patient each. Non-hematologic toxicities included hypotension grade 2 (six patients), grade 3 (four patients), and grade 4 (two patients). A decline in renal function was observed in 15 courses and 10 patients, leading to a median delay of 2.5 days. Neurosensory and neuromotor toxicity grade 1 were observed in 13 patients (grade 2: 12 patients; grade 3: one patient), myalgia grade 3 in one patient, asthenia grade 3 in two and grade 4 in one patient. Partial responses were observed in 12 patients for an overall response rate of 48% (95% CI: 28%-68%) with a median response duration of 6.5 months (range 1-10 months). Stable disease was observed in seven patients, of who two also had clinical benefit. CONCLUSIONS: Paclitaxel 200 mg/m2 administered over three hours combined with cisplatin 100 mg/m2 is an active regimen warranting further evaluation.

Adult↗

PubMed1998

[Regional distribution of predisposition to maligant hyperthermia in Germany: tate in 1997].

Malignant hyperthermia (MH) is a rare autosomally dominantly hereditary and potentially life-threatening disease. The prevalence of the genetic MH predisposition is estimated as 1:10,000 to 1:20,000. In Germany no data on the regional distribution are available. Therefore, the purpose of this investigation is to summarise and present the epidemiological data of all German MH laboratories. Nine German hospitals offer the specific in vitro contracture test to diagnose the MH predisposition. All German MH laboratories carry out the examination in accordance with the standardised protocol of the European Malignant Hyperthermia Group. The laboratories were asked to provide the number of all patients investigated, excluding those suffering from other neuromuscular diseases, separated according to diagnostic groups and their places of residence, the number of the identified MH-families as well as the number of the clinically suspected and investigated MH cases with their places of residence. Eight MH laboratories provided the requested data. Until September 1997 a total of 2620 patients were investigated. In 865 patients (34%) MH suspicion was confirmed (diagnosis: MHS). 1494 patients (56%) were released by investigation from MH-suspicion (diagnosis: MHN). In 261 patients (10%) the MH-predisposition remained unsolved (diagnosis: MHE). 580 MH families were identified. Among 2620 patients 757 were clinically suspected MH cases. 35% of these suspected MH cases were classified as MHS, 10% as MHE and 55% as MHN. The documentation of the patients places of residence classified as MHS and MHE into a map of Germany demonstrates an exhaustive distribution with an increased regional prevalence in the areas of the MH laboratories. This concentration in the area of the MH laboratories becomes even more evident, when the places of residence of the MH suspected cases are demonstrated. In conclusion, the distribution of the MH predisposition is uniform and exhaustive in Germany. The presented regional concentration of clinically suspected MH cases among the MH laboratories is mainly interpreted as an expression of effective regional education and information. Considering the overall incidence of the MH predisposition as described above only 15-20% of the MH patients have so far been identified. The MH laboratories have already released about 10,000 patients from the suspicion of MH predisposition. A preliminary prevalence of at least 1:60,000 to 1:80,000 in Germany can be estimated according to the presented data.

Epidemiologic Studies↗

PubMed1997

Function of the hyperpolarization-activated inward rectification in nonmyelinated peripheral rat and human axons.

The function of time-dependent, hyperpolarization-activated inward rectification was analyzed on compound potentials of nonmyelinated axons in the mammalian peripheral nervous system. Isolated rat vagus nerves and fascicles of biopsied human sural nerve were tested in a three-chambered, Vaseline-gap organ bath at 37 degrees C. Inward rectification was assessed by recording the effects of long-lasting hyperpolarizing currents on electrical excitability with the use of the method of threshold electrotonus (program QTRAC, copyright Institute of Neurology, London, UK) and by measuring activity-dependent changes in conduction velocity and membrane potential. Prominent time-dependent, cesium-sensitive inward rectification was revealed in rat vagus and human sural nerve by recording threshold electrotonus to 200-ms hyperpolarizing current pulses. A slowing of compound action potential conduction was observed during a gradual increase in the stimulation frequency from 0.1 to 3 Hz. Above a stimulation frequency of 0.3 Hz, this slowing of conduction was enhanced during bath application of 1 mM cesium. Cesium did not alter action potential waveforms during stimulation at frequencies < 1 Hz. Cesium-induced slowing in action potential conduction was correlated with membrane hyperpolarization. The hyperpolarization by cesium was stronger during higher stimulation frequencies and small in unstimulated nerves. These data show that a cesium-sensitive, time-dependent inward rectification in peripheral rat and human nonmyelinated nerve fibers limits the slowing in conduction seen in such axons at action potential frequencies higher than approximately 0.3 Hz.

Action Potentials↗

PubMed1996

Immunohistochemical and electrophysiological evidence for omega-conotoxin-sensitive calcium channels in unmyelinated C-fibres of biopsied human sural nerve.

In vitro electrophysiological measurements of Ca2+ potentials in human sural nerve fascicles revealed that Ca2+ conductances might be present on unmyelinated C-fibres. Furthermore, these Ca2+ potentials were partially blocked by omega-conotoxin, a calcium antagonist for the N-type Ca2+ channels. Therefore, immunohistochemical staining with indirect immunofluorescent omega-conotoxin GVIA was used to localize N-type Ca2+ channels in intact and in enzymatically dissociated human sural nerve fascicles. Densities of toxin binding sites were highly heterogeneous throughout the different nerve fascicles investigated and putative N-type Ca2+ channels were localized in about 20% of the unmyelinated C-fibres. Myelinating Schwann cells as well as enzymatically demyelinated axons displayed no specific binding indicating the absence of N-type Ca2+ channels.

Calcium Channel Blockers↗

PubMed1996

P2 purinoceptor-mediated intracellular Ca2+ transients in human sural nerve.

Segments of biopsied human sural nerve were stained with the Ca(2+)-sensitive fluorescent dyes Calcium Green-1 and Fura Red. The emission ratio was used to follow changes in the intracellular free Ca2+ concentration ([Ca2+]i). Application of ATP and analogues in concentrations between 0.3 and 300 microM via the bathing solution resulted in a transient rise in [Ca2+]i. The rank order of agonist potency, 2-methylthioATP > ATP > UTP, and the failure of adenosine, alpha,beta-MeATP and beta,gamma-MeATP to evoke rises in [Ca2+]i indicate the presence of P2Y/U subtypes of purinoceptors in this preparation. ATP-induced Ca2+ transients in biopsied human nerve preparations might serve as a diagnostic tool in neuropathies.

Adenosine Triphosphate↗

PubMed1996

Capsaicin blocks tetrodotoxin-resistant sodium potentials and calcium potentials in unmyelinated C fibres of biopsied human sural nerve in vitro.

Topical application of capsaicin has been tested recently for treatment of painful peripheral neuropathy. In the present study, effects of capsaicin were explored on compound action potentials of isolated fascicles from human sural nerve biopsies. Capsaicin reduced the C fibre component by 30-60%; the remaining C fibres were not sensitive to the drug. A good correlation was found between the sensitivity of C fibres to capsaicin and their resistance to tetrodotoxin (TTX), i.e. C fibre action potentials recorded in the presence of TTX were completely blocked by capsaicin. Calcium action potentials seen after inhibition of axonal potassium conductances were also completely suppressed. The data indicate that application of capsaicin nearby human peripheral nerves might prevent action potential conduction in specific subtypes of C fibres.

Action Potentials↗

PubMed1996

Abnormal axonal inward rectification in diabetic neuropathy.

An abnormal axonal membrane conductance might contribute to human diabetic neuropathy. To test this idea, we have compared the threshold changes produced by long-lasting (100-200 ms) de- and hyperpolarizing currents applied to median motor and sensory axons at the wrist in 63 diabetic patients with those from 50 normal controls and 27 amyotrophic lateral sclerosis (ALS) patients. Averages of the threshold electrotonus plots for motor and sensory axons of diabetic patients showed more subexcitability during, and slower recovery following, the application of hyperpolarizing currents. Such alterations have been previously found in isolated rat nerves after inhibition of axonal inward rectification by means of cesium ions. The abnormalities in diabetics were positively correlated with the age of patients and the presence of neuropathy. Threshold electrotonus seen in diabetes differed strongly from the effects of acute ischemia and were unlike changes recorded in ALS. The data indicate that an abnormal inward rectification of peripheral axons is associated with diabetic neuropathy. A better understanding of the neurobiology of this conductance might provide information about the pathophysiology of this disease.

Adult↗

PubMed1995

Calcium potentials and tetrodotoxin-resistant sodium potentials in unmyelinated C fibres of biopsied human sural nerve.

Compound action potentials and electrotonic responses to 150 ms current pulses were recorded from isolated nerve fascicles of human sural nerve biopsies. Compound action potentials in normal bathing solution were characterized by previously described A beta, A delta and C fibre components. In addition, tetrodotoxin-resistant sodium- or calcium-dependent potential components were found when a mixture of tetrodotoxin and the potassium channel blockers 4-aminopyridine and tetraethylammonium was added to the bathing solution. In contrast to tetrodotoxin-sensitive action potentials, tetrodotoxin-resistant sodium- or calcium-dependent potentials could be recorded in the presence of high extracellular potassium concentrations (10-20 mM). Calcium action potentials were found to be sensitive to specific pharmacological antagonists or agonists of L-, N- and P-type calcium channels. Lidocaine, cadmium, verapamil and capsaicin showed unspecific blocking effects on calcium and tetrodotoxin-resistant potentials. Tetrodotoxin-resistant action potentials seem to originate from unmyelinated C fibres since a clear correlation was found between the number of C fibres and the amplitude of tetrodotoxin-resistant calcium and sodium spikes in preparations with different axon type composition. The evidence for tetrodotoxin-resistant Na+ and Ca2+ spikes in peripheral human axons offers new possibilities for a better understanding and/or treatment of abnormalities in the excitability of damaged or diseased peripheral nerves.

Action Potentials↗

PubMed1995

Differential diagnosis of periodic paralysis aided by in vitro myography.

In vitro twitch tests were performed on excised muscle bundles from 30 periodic paralysis (PP) patients in an attempt to verify the somatic origin of PP, and to differentiate between the hypokalemic (HypoPP) and the hyperkalemic forms (HyperPP). Seventeen PP patients with a definite diagnosis of familial HypoPP, familial HyperPP (subsequently confirmed by SCN4A mutations), or thyrotoxic PP entered the study, as well as 13 patients with a history of attacks of weakness but with negative clinical provocation tests and therefore ambiguous diagnosis; 15 normal subjects served as controls. In contrast to control, bundles from patients with clear diagnosis went into sustained paralysis on exposure to Cl-free solution. Exposure to K+ channel activators induced a large increase in force. Specifically for HypoPP muscle, low extracellular [K+] decreased twitch force which was further reduced by addition of insulin or adrenaline, whereas HyperPP bundles responded with an irreversible decrease in twitch force when extracellular [K+] was elevated. Out of the 13 patients with unclear diagnosis, the in vitro studies made it possible to classify 10 as HypoPP and one as HypePP (later confirmed by a M1592V mutation). In the remaining two patients who claimed to suffer from paralytic attacks, all in vitro tests were normal, questioning the occurrence of dyskalemic PP. The results demonstrate that in vitro tests can be used to ensure the proper diagnosis to a high percentage when clinical provocative tests have failed.

Adult↗