ABSTRACT
A novel method was designed involving the titration of alternating current titration in a cell where one electrode was shielded by a capillary enclosure restricting access to it by charge carriers. With this cell, charge transfer complex titration of several thiazines all with some antimicrobial properties was effected in acetonitrile, against the electron accepting molecule iodine. The maxima of the Job plots generated by these titrations exhibited displacement of their positions for the forward and reverse titrations with respect to electron donor-acceptor complexation conductivity and apparent stoichiometry. A plot of inverse conductivity maxima differences against literature-cited dipole moments squared yielded a straight line passing through the origin. The titration plot profiles are discussed in terms of the type, number, and mobility of charge carriers produced in the complexation interaction. This novel method may be used to determine dipole moments of bioactive homologues empirically. There was correlation between thiazine drug dipole moments and minimal inhibitory concentrations of these drugs for some bacterial and yeast species. Several new avenues of investigation of possible relevance to microbiology are suggested.
Subject(s)
Anti-Infective Agents/pharmacology , Bacteria/drug effects , Conductometry/methods , Yeasts/drug effects , Anti-Bacterial Agents , Antipsychotic Agents/pharmacology , Chlorpromazine/pharmacology , Conductometry/instrumentation , Electric Conductivity , Microbial Sensitivity Tests , Phenothiazines/pharmacologyABSTRACT
The charge transfer donor (D)-acceptor (A) complexes formed between three classes of vitamin K (all electron acceptors in this study) with several thiazine psychotropes, used also as antimicrobials, antimalarials, antibiotics, and anticoagulants, were studied by means of alternating current titrations. The monochloride thiazines formed 2:1 (D:A) complexes, interacting from 26 to 47.5%; the dihydrochloride formed a 3:1 (D:A) complex. The antimalarials quinine and its isomer quinidine yielded 2:1 (D:A) complexes, interacting 51 and 60%, respectively. Quinacrine did not complex with vitamin K. The antibiotics sulfisoxasole and sulfamethisole gave 1:1 complexes, respectively interacting 6.2 and 11.7%. The anticoagulants warfarin, coumarin and dicumarol, rather than forming complexes proceeded rapidly to chemical reaction. When the above thiazine antimicrobials, antimalarials and antibiotics are present in patients receiving vitamin K post-operatively the dosage of administered vitamin K should be increased to counteract the donor-acceptor interaction effect.
Subject(s)
Anti-Infective Agents/chemistry , Vitamin K/chemistry , Anti-Bacterial Agents/chemistry , Anticoagulants/chemistry , Antimalarials/chemistry , Antipsychotic Agents/chemistry , Conductometry , Drug Interactions , Molecular Structure , TemperatureABSTRACT
Drug resistance to chemotherapy is rapidly emerging. Resistance to one drug carries over resistance to unrelated anticancer drugs leading to multidrug resistance (MDR). A major factor of MDR is P-glycoprotein (P-gp) mediated ABC transport found in many eukaryotic cells. P-gp acts as a drug eMux pump. The mdr1 gene involved in P-gp 170 protein production is localized in the human chromosome 7 band p2 1.0-21.1. Point mutations after cross-resistance patterns. A variety of stimuli increase the expression of the mdr1 gene: lowered extracellular pH, heat shock, arsenite, cytotoxic agents, anticancer drugs, transfection with oncogenes, HIV-I, and UV-irradiation. An alternative hypothesis to the efflux pump claims that P-gp modifies the intracellular environment to reduce accumulation of anticancer drugs in cancer cells by creating ionic or proton gradients. Chemosensitizers that block P-gp drug extrusion are generally lipid-soluble at physiological pH, possess a basic nitrogen atom and at least two co-planar rings. P-gp blocking does not depend on drug chirality. This opens the way of treating P-gp related MDR with chiral versions of drugs relatively harmless in terms of side-effects. We believe that resistance modifiers combined with cytostatics will chemotherapeutically be more effective for cancer patients.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Drug Resistance, Multiple/physiology , Drug Resistance, Neoplasm/physiology , Genes, MDR/physiology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , ATP-Binding Cassette Transporters/physiology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antipsychotic Agents/pharmacology , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Glycosylation , Humans , Molecular Conformation , Phosphorylation , Tumor Cells, Cultured/drug effectsABSTRACT
1. Electron charge transfer interactions of some phenothiazine derivatives with aminoglycoside antibiotics, beta-lactams and penicillin-related antibiotics and bilirubin were investigated with alternating current titrations. 2. Neither the beta-lactams nor penicillin-related drugs interacted. 3. However, the aminoglycoside antibiotics formed complexes with the phenothiazines. 4. Tobramycin and gentamicin each formed 1:2 adducts with carbenicillin. 5. The phenothiazines interacted with bilirubin forming concentration-dependent micellar adducts which were exciplexes. This may explain the appearance of xanthomata in patients medicated with phenothiazines.
