org-2766 and Nervous-System-Diseases

Topics: Adrenocorticotropic Hormone; Animals; Anticonvulsants; Cells, Cultured; Diabetic Neuropathies; Disease Models, Animal; Humans; Melanocyte-Stimulating Hormones; Nerve Regeneration; Nervous System Diseases; Neurons; Peptide Fragments; Pro-Opiomelanocortin; RNA, Messenger

Topics: Adrenocorticotropic Hormone; Amifostine; Cisplatin; Ditiocarb; Fluid Therapy; Glutathione; Hematologic Diseases; Humans; Kidney Diseases; Nervous System Diseases; Peptide Fragments; Thiosulfates

This randomized, double-blind, placebo-controlled study evaluates the effect of the corticotropin (4-9) analogue Org 2766 on the neuropathy-free interval in patients receiving vincristine (VCR) containing chemotherapy for Hodgkin's or non-Hodgkin's lymphoma.. In a longitudinal design, 150 patients were evaluated by interview, neurological examination, and neurophysiological techniques. Patients with an expected cumulative VCR dose of at least 8 mg received a single dose of Org 2766 or placebo before and after each intravenous VCR injection and 3-4 weeks after cessation of VCR. The final patient assessment was performed 1 month after discontinuation of study medication. The neuropathy-free interval as the major end point of this study was defined as the first occurrence of bilateral paresthesias and expressed as the administered cumulative VCR dose. This bi-center study represents the largest cohort of patients monitored for the effect of an ACTH-analogue on VCR neurotoxicity.. A total of 147 patients were included in the final analysis. No significant differences were observed between the placebo and actively treated group for the major and secondary endpoints.. Contrary to a single previous pilot study in patients receiving VCR-based chemotherapy, in our study the ACTH (4-9) analogue Org 2766 did not provide protection from VCR-induced neuropathy.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Double-Blind Method; Female; Hodgkin Disease; Humans; Interviews as Topic; Longitudinal Studies; Lymphoma, Non-Hodgkin; Male; Middle Aged; Nervous System Diseases; Peptide Fragments; Placebos; Vincristine

It is uncertain whether intensive dosing schedules of cisplatin, intended to attain a higher anti-tumour efficacy, alter the severity of cisplatin-induced neuropathy. We assessed the development of neuropathy in three groups of patients treated with cisplatin in different dosing schedules. The severity of neuropathy was determined by measurement of the vibration perception threshold (VPT) before treatment and during follow-up for 2-12 months after the last cycle. 66 patients were treated with an intensive weekly regimen of doses varying from 70 to 85 mg/m2 in 1 day (trial A), 21 patients with a 3-weekly combination chemotherapy containing cisplatin 75 mg/m2 in 1 day (trial B) and 20 patients with a 3-weekly regimen containing cisplatin 20 mg/m2 for 5 consecutive days (trial C). The mean dose intensity achieved was 59 mg/m2/week in trial A, 21 mg/m2/week in trial B and 33 mg/m2/week in trial C. The maximum post-treatment VPT correlated significantly with pretreatment VPT (P < 0.001) and with the cumulative dose of cisplatin (P < 0.001). Following correction for these two variables, the maximum posttreatment VPT did not show a statistically significant association with dose intensity. These results suggest that neuropathy is not related to dose intensity of cisplatin. This implies that treatment with more intensive dosing schedules, employing equal cumulative doses of cisplatin, does not result in a concomitant increase in neurotoxicity within a cumulative dose range of 280-675 mg/m2.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Anticonvulsants; Cisplatin; Clinical Trials, Phase II as Topic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Nervous System; Nervous System Diseases; Peptide Fragments; Perception; Vibration

In a randomized, double-blind, placebo-controlled pilot study, we examined the effect of Org 2766--a corticotropin (4-9) analogue--on neurotoxicity in 28 patients with lymphoma who were treated with combination chemotherapy containing Vinca alkaloids (vincristine and vinblastine). The patients received a total dose of 12 mg of vincristine in the case of non-Hodgkin's lymphoma and a total dose of 16 mg of vincristine in the case of Hodgkin's disease. Moreover, the patients with Hodgkin's disease received a mean total dose of 84 mg of vinblastine. Subcutaneous injections of 2 mg of Org 2766 or placebo were administered to patients with non-Hodgkin's lymphoma on days 1 and 10 of each chemotherapy course and to patients with Hodgkin's disease on days 1 and 8 of each chemotherapy course. The first injection was always given before the administration of vincristine. Assessment of neurologic symptoms and signs and measurement of sensory thresholds (vibration sense and temperature sense) were performed on day 1 of the first, fourth, and sixth (or eighth) courses and 6 weeks after cessation of chemotherapy. Thirteen patients (mean age, 44.7 years) received Org 2766 and 15 patients (mean age, 54.7 years) received placebo. More symptoms occurred in the placebo group, but only numbness and autonomic complaints occurred significantly more often in the placebo group. Motor deficit and sensory disturbances were more severe and also occurred significantly more often in the placebo group. There was no difference with respect to reflex examination findings and sensory thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Adult; Double-Blind Method; Female; Hodgkin Disease; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Nervous System Diseases; Peptide Fragments; Pilot Projects; Placebos; Sensation Disorders; Vinblastine; Vinca Alkaloids; Vincristine

Taxol is a novel and promising oncolytic agent the use of which is hampered by its neurotoxicity. We now describe a taxol-induced neuropathy in rats and its prevention by the adrenocorticotropic hormone-(4-9) (ACTH-(4-9)) analog, ORG 2766. A decrease in sensory nerve conduction velocity was seen in taxol-treated rats, both with daily injections of small amounts (6 mg/kg per week) and with weekly injections of higher amounts (9 mg/kg per week) of taxol. Concomitant administration of ORG 2766 completely prevented the occurrence of a neuropathy.

Topics: Adrenocorticotropic Hormone; Animals; Anticonvulsants; Male; Nervous System Diseases; Neural Conduction; Paclitaxel; Peptide Fragments; Rats; Rats, Wistar

A major side effect of cisplatin treatment is peripheral neuropathy. In the past few years we have provided evidence that the ACTH4-9 analogue ORG 2766 provides protection against this neuropathy in rats and man. In this study we investigated the development of a cisplatin-induced neuropathy and the protective and therapeutic actions of ORG 2766 in mature rats. We also studied the effects of the peptide and of growth impairment caused by food restriction on nerve conduction velocities in healthy young adult rats (not subjected to any other treatment). In the neuropathy experiment, cisplatin induced a significant decrease in sensory nerve conduction velocity (SNCV), which could be prevented by concomitant administration of ORG 2766. The SNCV of the neuropathic animals recovered to control values within 10 weeks of discontinuation of cisplatin treatment. ORG 2766 did not enhance the rate of recovery. In the young adult rats neither ORG 2766 administration nor restricted weight gain significantly influenced either the motor or the sensory nerve conduction velocity. These results validate the animal model of cisplatin-induced neuropathy.

Topics: Adrenocorticotropic Hormone; Analysis of Variance; Animals; Body Weight; Cisplatin; Disease Models, Animal; Electrophysiology; Food Deprivation; Humans; Nervous System Diseases; Neural Conduction; Neurons, Afferent; Peptide Fragments; Rats; Rats, Wistar

Topics: Adrenocorticotropic Hormone; Amifostine; Anticonvulsants; Cisplatin; Female; Glutathione; Humans; Nervous System Diseases; Ovarian Neoplasms; Peptide Fragments

Org 2766 is one of a series of melanocortins (ACTH and related peptides) that exert trophic influences on the central and peripheral nervous system of the rat. We used acrylamide neuropathy in rats as an experimental model of peripheral neuropathies of the dying-back type in order to assess the potential therapeutic efficacy of Org 2766 in this type of nerve damage. The peptide reversed the delayed persistent deficit in sensory conduction velocity without preventing the initial loss of motor coordination. The recovery of apparently normal coordination was unaffected by the peptide, but resistance to a second toxic challenge suggested that recovery was more complete in the peptide-treated rats. The finding that Org 2766 improved the quality of the repair following acrylamide neuropathy, together with previous studies showing beneficial effects in neuropathies caused by cisplatin or diabetes and after mechanical trauma, strongly suggests that Org 2766 may be beneficial in the treatment of various conditions in which the nervous system has sustained damage.

Topics: Acrylamides; Adrenocorticotropic Hormone; Animals; Anticonvulsants; Electrophysiology; Female; Motor Neurons; Nervous System Diseases; Peptide Fragments; Postural Balance; Psychomotor Performance; Rats; Rats, Inbred Strains; Synaptic Transmission