Biomedical subjects

Stefan Quasthoff

Publications and source records attributed to Stefan Quasthoff.

9 recordsLinked to original sources

PubMed2006

Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study.

BACKGROUND: Oxaliplatin-induced neurotoxicity is a growing, relevant clinical problem. In this study we evaluated the efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer. METHODS: Chemotherapeutic treatment consisted of oxaliplatin 85 mg/m(2) given biweekly and weekly folinic acid 500 mg/m(2) followed by a 24-h infusion of 5-FU 2000 mg/m(2) (FUFOX). One cycle consisted of six consecutive weeks of treatment followed by two weeks of rest (=Treatment B). For Treatment A carbamazepine was added in a dosage for targeted plasma levels of 4-6 mg/L. Neurotoxicity was regularly assessed using a specific scale. Moreover, an evaluation of chronic sensory symptoms and a neurologic examination including tests for vibrational sense, strength and deep tendon reflexes were added creating a peripheral neuropathy (PNP) score. RESULTS: The prospectively defined adequate number of patients needed to provide power for the primary outcome could not be achieved. 19 patients were assigned to Treatment A and 17 to Treatment B. At baseline, the distribution of all clinicopathologic variables was comparable between the two groups. Overall response rates were 16% and 24% and overall survival 15.1 months and 17.4 months for Treatment A and Treatment B, respectively. Between Treatment A and Treatment B there were no major differences when considering worst neurotoxicity during the study period (p=0.46). Grade 3/4 neurotoxicity occured in 4 patients with Treatment A vs. 6 patients with Treatment B. There were no major differences between both groups in each category of the PNP score. CONCLUSIONS: Based on the small number of patients and low statistical power of our study definite conclusions regarding efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer cannot be drawn.

Adult↗

PubMed2006

A comparative study of the action of tolperisone on seven different voltage dependent sodium channel isoforms.

The specific, acute interaction of tolperisone, an agent used as a muscle relaxant and for the treatment of chronic pain conditions, with the Na(v1.2), Na(v1.3), Na(v1.4), Na(v1.5), Na(v1.6), Na(v1.7), and Na(v1.8) isoforms of voltage dependent sodium channels was investigated and compared to that of lidocaine. Voltage dependent sodium channels were expressed in the Xenopus laevis oocyte expression system and sodium currents were recorded with the two electrode voltage clamp technique. Cumulative dose response relations revealed marked differences in IC(50) values between the two drugs on identical isoforms, as well as between isoforms. A detailed kinetic analysis uncovered that tolperisone as well as lidocaine exhibited their blocking action not only via state dependent association/dissociation with voltage dependent sodium channels, but a considerable fraction of inhibition is tonic, i.e. permanent and basic in nature. Voltage dependent activation was affected to a minor extent only. A shift in steady-state inactivation to more negative potentials could be observed for most drug/isoform combinations. The contribution of this shift to overall block was, however, small at drug concentrations resulting in considerable overall block. Recovery from inactivation was affected notably by both drugs. Lidocaine application led to a pronounced prolongation of the time constant of the fast recovery process for the Na(v1.3), Na(v1.5), and Na(v1.7) isoforms, indicating common structural properties in the local anesthetic receptor site of these three proteins. Interestingly, this characteristic drug action was not observed for tolperisone.

Amino Acid Sequence↗

PubMed2005

[Evidence-based therapy of painful neuropathies in the primary care practice].

In the future, a growing number of polyneuropathies is to be expected since metabolic diseases are increasing and those falling ill are becoming older. The therapy must meet rising standards in the midst of ever tightening financial resources. In the process, the treatment must inevitably undergo an assessment based on the evidence of its effectiveness. A number of traditional, empirical treatment methods will no longer fit into this picture. The therapy of neuropathic pain is an example of a fundamental knowledge and cause-oriented treatment strategy. Here, a great number of therapeutic options were established that comply with the criteria of an evidence-based medicine.

Diagnosis, Differential↗

PubMed2004

Morvan's syndrome: clinical, laboratory, and in vitro electrophysiological studies.

Morvan's syndrome is a rare disorder characterized by neuromyotonia, hyperhidrosis, and central nervous system dysfunction. We report a patient with features of this syndrome, but who initially presented with breathing difficulties. Concentric needle electromyography showed an abundance of myokymic and neuromyotonic discharges. Exercise tests and repetitive nerve stimulation showed a decrement-increment response of compound muscle action potentials. Antibodies against voltage-gated potassium channels were not detected on repeated testing, but the presence of oligoclonal bands in the cerebrospinal fluid (CSF) suggested an autoimmune etiology. At follow-up over 3 years, no cancer was found. Electrophysiological in vitro studies of effects of patient serum and CSF on rat nerves provided no evidence of altered voltage-gated sodium or potassium conductances. We conclude that putative humoral factors do not block ion channels acutely but may cause channel dysfunction with chronic exposure.

Action Potentials↗

PubMed2003

No blocking effects of the pentapeptide QYNAD on Na+ channel subtypes expressed in Xenopus oocytes or action potential conduction in isolated rat sural nerve.

Reversible block of Na(+) channels by endogenous pentapeptide QYNAD has been reported to account for the fast relapses and remissions seen in autoimmune demyelinating disorders. Here it is shown that, in contrast to previous reports, synthetic QYNAD (10-100 microM) applied to Na(+) channels (Na(v)1.6 and 1.8) expressed in Xenopus oocytes was unable to block the peak current or inhibit channel kinetics. Furthermore, QYNAD (100 microM) applied to five isolated rat sural nerve in vitro did not demonstrate any change in the amplitude of compound nerve action potential or latency. The reason for the ineffectiveness of QYNAD has not been elucidated; it was apparently not related to a problem in the synthesis of the pentapeptide. Our experiments raise significant concerns about the suggestion that QYNAD peptide is a Na(+) channel blocker or modulator. However, in a protein library search the amino acid sequence of QYNAD was found to be related to ankyrin-G, which plays a role in Na(+) channel clustering in the node of Ranvier.

Action Potentials↗

PubMed2002

Chemotherapy-induced peripheral neuropathy.

The induction of peripheral neuropathy is a common factor in limiting therapy with chemotherapeutic drugs. Little is known about the mechanisms responsible for the development of neuropathy. Depending on the substance used, a pure sensory and painful neuropathy (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (with vincristine, taxol, suramin) can ensue. Neurotoxicity depends on the total cumulative dose and the type of drug used. In individual cases neuropathy can evolve even after a single drug application. A general predisposition for developing a chemotherapy-induced neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol or inherited neuropathy. The recovery from symptoms is often incomplete and a long period of regeneration is required to restore function. Up to now, no drug is available to reliably prevent or cure chemotherapy-induced neuropathy.

Antineoplastic Agents↗

PubMed2002

Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures.

Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Acute neurotoxicity is characterized by the rapid onset of cold-induced distal dysesthesia and/or paresthesia. Sensory symptoms may also be accompanied by cold-dependent muscular contractions of the extremities or the jaw. The symptoms, often occurring during or shortly after infusion, are usually transient and mild. A persistent sensory peripheral neuropathy may also develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment. Studies have shown patients with acute sensory symptoms to display little or no axonal degeneration, suggesting a specific effect of oxaliplatin on sensory neurons and/or motor neurons or muscle cells that is not observed with other platinum agents. The similarity of the acute symptoms induced by oxaliplatin with those caused by several drugs or toxins acting on neuronal or muscular ion channels suggests that these symptoms may result from a specific interaction of oxaliplatin with ion channels located in the cellular membrane. Recent data indicate that oxaliplatin may act on specific isoforms of the voltage gated sodium (Na(+)) channel to increase the excitability of sensory neurons, an action inhibited by the Na(+) channel blocker carbamazepine. This contention is supported by recent clinical findings indicating that pharmacologic blockade of Na(+) channels may prevent and/or repress the acute neurotoxicity of oxaliplatin. Although there is no indication at the moment that a common cellular mechanism induces both the acute and the cumulative neurotoxicity of oxaliplatin, controlled clinical trials are currently underway to establish the value of Na(+) channel blockade against both acute and cumulative oxaliplatin neurotoxicities.

Animals↗

PubMed2002

Prevention of oxaliplatin-induced peripheral sensory neuropathy by carbamazepine in patients with advanced colorectal cancer.

Oxaliplatin plays a key role in the treatment of advanced colorectal cancer. The dose-limiting side effect of this platinum analogue is neurotoxicity. Significant efforts have been undertaken in an attempt to prevent and/or circumvent the development of neurotoxicity. Sodium channel inactivation kinetics on rat sensory sural nerve preparations are altered after exposure to oxaliplatin. Carbamazepine antagonizes this effect in vitro. Results from preliminary clinical studies indicate that the sodium channel blockers carbamazepine and gabapentin may be effective in preventing neurotoxicity. The role of amifostine is not yet clear. Randomized clinical studies are necessary to confirm the potential benefit of carbamazepine and other sodium channel blockers in preventing and/or overcoming the development of oxaliplatin-induced neurotoxicity.

Animals↗

PubMed1999

Confocal imaging reveals activity-dependent intracellular Ca2+ transients in nociceptive human C fibres.

Unmyelinated nociceptive fibres are a key element in the human nociceptive system, however, it is very difficult to investigate such fibres in vivo in more detail. An alternate approach are studies on isolated human nerves. Here we describe that confocal Ca2+ imaging reveals new information about the physiology of human nociceptive C fibres. Confocal images at two emission wavelengths were collected from regions with unmyelinated nerve fibres within segments of biopsied human sural nerves stained with the Ca2+-sensitive fluorescent dyes Calcium Green-1 and Fura Red. Short trains of supramaximal electrical stimuli applied to one end of the nerve as well as bath application of capsaicin resulted in an increase in the free intracellular Ca2+ concentration. Intracellular Ca2+ transients were seen at action potential frequencies above 1 Hz. They were absent in Ca2+-free bathing solution and reduced during bath application of cadmium. This indicates an extracellular source of the activity-dependent rise in [Ca2+]i. Furthermore, Ca2+ transients were also observed during elevation of the extracellular K+ concentration or during short trains of calcium action potentials. Such 'Ca2+ spikes' were elicited by a combination of tetrodotoxin and potassium channel blockers. These data suggest the presence of voltage-dependent Ca2+ channels in the membrane of nociceptive human nerve fibres.

Action Potentials↗