ABSTRACT
Abstract Ph1 is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Ph1 to treat chronic pain reverted opioid tolerance with a safer profile than -conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Ph1 (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Ph1 antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.
ABSTRACT
Abstract Background: Phoneutria nigriventer venom contains Ph1. This toxin and its recombinant form have a remarkable analgesic potential that is associated with blockage of voltage-gated calcium channels and TRPA1 receptors. Although morphine is a mainstay drug to treat moderate and severe pain related to cancer, it has serious and dose-limiting side effects. Combining recombinant Ph1 and morphine to treat pain is an interesting approach that has been gaining attention. Therefore, a quantitative and reliable method to establish the strength of the antinociceptive interaction between these two substances is necessary. The present study was designed to investigate the nature of the functional antinociceptive (analgesic) interaction between Ph1 recombinant toxin and morphine in a model of cancer pain. Methods: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw of C57BL/6J mice. Von Frey filaments measured the paw-withdrawal threshold after intrathecal administration of morphine, recombinant Ph1, and their combination. Thermal hyperalgesia was assessed using Hargreaves apparatus. The degree of interaction was evaluated using isobolographic analysis. Spontaneous and forced motor performance was assessed with the open-field and rotarod tests, respectively. Results: Co-administration of recombinant Ph1 and morphine synergistically reverses the melanoma-induced mechanical hyperalgesia. The potency of the mixture, measured as the effective dose to reach 50% of maximum possible effect (MPE) in ameliorating mechanical hyperalgesia, was about twice fold higher than expected if the interaction between morphine and recombinant Ph1 was merely additive. Treatment with the combination at doses necessary to reach 50% of MPE caused no spontaneous nor forced motor alterations. Conclusion: The combinatorial use of recombinant Ph1 and morphine allows significant and effective dose reduction of both agents, which has translational potential for opioid-sparing approaches in pain management related to cancer.
ABSTRACT
Objective:To analyze the feasibility of detecting Ph1 in leukemia patients in the Kinshasa University Clinics in the Democratic Republic of Congo,at KU Leuven,Belgium.Methods:Bone marrow and peripheral blood samples with chronic myeloid leukemia,acute myeloid leukemia or acute leukocytes leukemia were obtained from 32 patients in Kinshasa University clinics in the Democratic Republic of Congo and transferred to KU Leuven in Belgium for iFISH feasibility.Ph1 was detected by using a remote analysis of interphase fluorescence in situ hybridization (iFISH).Results:Out of the 32 patients involved in this study,65.6％ (n =21) of the cases were successfully tested,of which 52.4％ (n =11) were iFISH positives for the variant t(9;22)(presence of Ph1) in chronic myeloid leukemia samples and 47.6％ (n =10) negatives in all subtypes of hematological malignancies.However,there was a female predominance in chronic myeloid leukemia samples Phi-positives by iFISH,whereas no sexual influence was observed on acute subtypes of leukemia.Conclusions:iFISH analysis is feasible on samples obtained from remote sites in the Democratic Republic of Congo.However,the optimization of the sample storage is necessary to further improve iFISH's performance.
ABSTRACT
Chronic myeloid leukemia (CML) is characterized by a Ph 1 chromosome that derives through a translocation between chromosomes 9 and 22, i.e., t (9;22). Identifying the Ph 1 chromosome through cytogenetic analysis is an important aspect of CML diagnosis. The aim of this study was to determine the significance of cytogenetic analysis in the diagnosis of CML as well as to find out a relationship between chromosomal abnormalities and CML patients in different stages of treatment. Six CML patients were investigated for this study. The presence of Ph 1 chromosome was detected at different times of treatment using GTG banding on peripheral blood or bone marrow aspirations, and the results were analyzed using cytovision workstation. Hematological features were compared between newly diagnosed patients and patients under treatment. The Ph 1 chromosome was strongly associated with all cases of CML. The regression of Ph 1 chromosomes differed for each patient depending on the treatments and individual response to specific treatments.
ABSTRACT
BACKGROUND: Chronic Myelogenous Leukemia (CML) is the first proven disease in which gene abnormality, t(9;22)(q34;q11) can cause the disease to occur in humans. Recently, targeted therapy with STI571 (GleevecTM), signal transduction inhibitor for BCR-ABL kinase was developed and can induce cytogenetic remission in patients with CML. Hypermetaphase-FISH (HMF)/Interphase-FISH (I-FISH, Fluorescence in situ hybridization) aiming specific chromosomal abnormalities are unambiguous quantitative molecular genetic methods for individual Philadelphia (Ph1) chromosome positive cells. We evaluated the change of Ph1 chromosome in CML patients during STI571 therapy using HMF/I- FISH. METHODS: Twenty one patients with CML were treated with STI571 which was provided from Norvatis pharmaceutical company as Expanded Access Program for Compassionate Use from May 2001 at the doses of 200-600 mg/day orally. Median age of this cohort was 37 years old and median follow up duration was 113 days (48~165 days). HMF or I-FISH using bone marrow or peripheral blood were performed on the sample at baseline, day 14, day 28 and then monthly. RESULTS: Complete cytogenetic responses which were assessed by HMF/I-FISH counting several hundreds cells were found in 8 of 21 patients. Among them, 4 of 10 chronic phase, 2 of 2 accelerate phase and 2 of 8 blastic crisis patients achieved cytogenetic complete response. One patient with blastic crisis was relapsed after achieving cytogenetic complete response. Grade III-IV thrombocytopenia and neutropenia were noticed in 8 and in 7 patients respectively, but there were no major bleeding episodes nor neutropenic fever. CONCLUSION: BCR-ABL tyrosine kinase inhibitor, STI571 was tolerable for patients with CML. The majority of patients achieved hematologic remission and 8 out of 21 patients achieved complete cytogenetic response regardless of their disease stage. Cytogenetic response of Ph1 chromosome can be quantified accurately with HMF/I-FISH.