Disease relevance of Isaxonine

• A study of the effects of isaxonine on vincristine-induced peripheral neuropathy in man and regeneration following peripheral nerve crush in the rat [1].
• Therapeutic trial of isaxonine in Duchenne muscular dystrophy [2].
• Paracetamol potentiates isaxonine toxicity in vitro [3].

High impact information on Isaxonine

• The reactive isaxonine metabolite became bound extensively to microsomal proteins, but not to plasma membrane proteins [4].
• In a second series of experiments, [2-14C] isaxonine (0.1 mM) was incubated with NADPH, hepatic microsomes and plasma membranes [4].
• Isaxonine and several other drugs transformed by cytochrome P-450 into reactive metabolites apparently lead to immunoallergic hepatitis in man [4].
• Presence of covalently bound metabolites on rat hepatocyte plasma membrane proteins after administration of isaxonine, a drug leading to immunoallergic hepatitis in man [4].
• Lymphocyte proliferation, assessed by measuring the increase in the number of cells in mitogen-stimulated cultures, was completely suppressed by both colchicine and taxol (100 nM) whereas significant inhibition by isaxonine required much higher concentrations (5 mM) [5].

Biological context of Isaxonine

• Electron microscopic studies confirmed that both taxol and colchicine (10 nM) arrested the responding lymphocytes in mitosis, and that isaxonine inhibited initial activation [5].
• Mechanism for isaxonine hepatitis. I. Metabolic activation by mouse and human cytochrome P-450 [6].
• In the presence of various concentrations of isaxonine (0.125-2 mM), binding followed Michaelis-Menten kinetics; the Vmax was increased by both phenobarbital and 3-methylcholanthrene pretreatments [6].
• Isaxonine is reported to have a favourable effect on nerve regeneration [7].
• Isaxonine is reported to accelerate the rate of peripheral nerve regeneration, stimulate axonal sprouting and promote motor and sensory function recovery [8].

Anatomical context of Isaxonine

• In vitro, addition of 4 mM glutathione decreased markedly the amount of [14C] isaxonine metabolite that bound to microsomal proteins during incubation of 1 mM [2-14C] isaxonine with hepatic microsomes and an NADPH-generating system [9].
• Administration of isaxonine (6 mg/kg powdered diet) had no effect on regeneration following sciatic nerve crush in the rat [1].
• Effects of isaxonine on skeletal muscle reinnervation in the rat: an electrophysiologic evaluation [10].
• The metabolism of isaxonine phosphate was compared in liver microsomes from rat, rabbit, dog, monkey and man and found to be qualitatively similar [11].
• Influence of isaxonine on the target phenomenon, muscle fibre size and neuromuscular junction in the tenotomized and denervated gastrocnemius muscle of the rat [8].

Associations of Isaxonine with other chemical compounds

• The effects of the neurotropic drug isaxonine on fully hydrated dipalmitoyl-phosphatidyl-choline (DPPC) bilayers has been studied in the temperature range 0 degree-60 degrees, using differential scanning calorimetry and electron spin resonance spectroscopy, with two stearic acid spin labels [12].
• 2. Putative neurotrophic compounds were tested on this functional recovery model: melanocortins (peptides derived from ACTH (corticotropin) and alpha-MSH (melanotropin], gangliosides and nimodipine were effective whereas isaxonine and TRH (thyrotropin releasing hormone) were not [13].
• Incubation, under air, of [2-14C] isaxonine (1 mM) with mouse liver microsomes and an NADPH-generating system resulted in the irreversible binding of a [14C] isaxonine metabolite to microsomal proteins; binding required active microsomes, NADPH and oxygen, it was inhibited by 4 mM piperonyl butoxide or by a CO-O2 (80:20) atmosphere [6].
• In order to search for compounds mimicking the neurotrophic activities, a series of substances possessing the guanidine group of isaxonine (2-isopropylamino-pyrimidine), were synthesized and tested for their ability to induce neurite outgrowth in cultures of explants of rat dorsal root ganglia [14].

Gene context of Isaxonine

• We conclude that isaxonine is activated by mouse and human cytochromes P-450 into a reactive metabolite [6].
• At low concentration (1% mol/mol), isaxonine is trapped in the polar interface and enhances the phospholipid multibilayers organization in the gel state [12].
• Inhibition in vitro of the polymerization of tubulin by uremic middle molecules: corrective effect of isaxonine [15].

Analytical, diagnostic and therapeutic context of Isaxonine

• In contrast, isaxonine (2-5 mM) suppressed blast transformation [5].
• Isaxonine base is a strong perturber of phospholipid bilayer order and fluidity--a differential scanning calorimetry and spin labeling study [12].
• Isaxonine has no direct effect on a diseased muscle with an intact nerve supply, nor in the early stages after complete denervation [8].
• In ten rats, treated with isaxonine, the qualitative and quantitative changes in the gastrocnemius muscle were compared with the control group over a period of 3 weeks [8].
• The compounds were more effective in cell cultures than isopropylaminopyrimidine (isaxonine) which had been previously developed and then withdrawn [16].

References