Electrochemistry of anticonvulsants: electron transfer as a possible mode of action.

Reduction potentials were determined for various anticonvulsants, including progabide, SL 75.102, CGS 9896, pyridazines, zonisamide, 1,2,3-triazoles, and copper complexes. The values generally were in the range of about -0.1 to -0.6 V for the protonated drugs and the metal complexes. Reduction potentials provide information on the feasibility of electron transfer (ET) in vivo. If the value is relatively positive (greater than about -0.6 V), the agent can act catalytically as an electron acceptor from an appropriate cellular donor. A concomitant favorable influence on abnormal neuronal processes associated with epilepsy could occur. We describe ET as a possible mode of action of anticonvulsants as well as some antiepileptic agents with no electrochemical data based on this hypothetical ET approach.

Electrochemical reduction of arylethenylpyridinium salts: relation to structure and anthelmintic activity.

Cyclic voltammetry data were obtained for a series of 1(1-)- and 1(2-arylethenyl)pyridinium salts. The 1(1-arylvinyl) salts exhibited more negative reduction potentials than their N-beta-styryl counterparts. Rationalizations of the reduction values are provided. Differences in reduction potentials within a series are discussed utilizing substituent constant effects. Correlations exist for the electrochemical data and anthelmintic activity.

Reduction potentials of anthelmintic drugs: possible relationship to activity.

Electrochemical data were acquired for several categories of anthelmintic agents, namely, iminium-type ions, metal derivatives and chelators, quinones and iminoquinones, and nitroheterocycles. Reductions usually were in the favorable range of +0.2 to -0.7 V versus normal hydrogen electrode. The drug effect is believed to result in part from either the catalytic production of oxidative stress or disruption of helminth electron transport systems. Relevant literature results are discussed.

Minimum essential structural requirements for lactam antibiotic action.

A mechanism of action encompassing mono- and bicyclic beta-lactams has been proposed previously, which stresses the importance of formation of an electron transfer (ET) entity (conjugated iminium) as a requirement for antibiotic activity, in association with enzyme inactivation. Additional evidence in support of this contention is now provided. Reduction potentials for several cephalosporins and pyrazolidinones, all of which contain an oximino functionality in the side chain, were observed in the range of -0.6 to -0.7 V. Comparison is made with related compounds lacking imine. Agents containing side chain hydrazone, oxamazins (mono beta-lactams), and lactivicin are discussed based on the ET approach.

Anti-cancer action of metal complexes: electron transfer and oxidative stress?

Evidence is presented in support of an electron transfer mechanism for various metal complexes possessing anti-neoplastic properties. Cyclic voltammetry was performed on several metallocenes, bis(acetato)bis(imidazole)Cu(II), and coordination compounds (Cu or Fe) of the antitumor agents, bipyridine, phenanthroline, hydroxyurea, diethyldithiocarbamate, and alpha, alpha'-bis(8-hydroxyquinolin-7-yl)-4-methoxytoluene. The favorable reduction potentials ranged from +0.5 to -0.5 Electrochemical behavior is correlated in some cases with structure and physiological activity. Relevant literature data are discussed.

Electrochemistry of the anticancer agents methotrexate and alpha-difluoromethylornithine in iminium form.

The electrochemical characteristics of the antitumor agents methotrexate and alpha-difluoromethylornithine were determined as their iminium derivatives. Iminium formation from methotrexate is accomplished in vivo via protonation by enzyme. The requisite imine precursor is generated from alpha-difluoromethylornithine by condensation with enzyme containing pyridoxal phosphate. Electroreduction occurs in the range of -0.2 to -0.6 V. The relationship of reduction to structure is discussed. A possible mode of anticancer action involving electron transfer is presented.

Mode of action of antiprotozoan agents. Electron transfer and oxy radicals.

Cyclic voltammetry data were obtained for most of the main classes of antiprotozoan agents, specifically, nitroheterocycles, quinones, metal complexes and derivatives, iminium-type ions, and azo compounds. The reductions were generally reversible in the range of -0.3 to -0.9 V. Catalytic production of oxidative pressure from redox cycling involving oxygen is believed to be an important mode of action by the medicinal agents. Literature data contribute support.

Electron transfer-oxy radical mechanism for anti-cancer agents: 9-anilinoacridines.

A possible mode of action involving electron transfer is advanced for the 9-anilinoacridines. The mechanism entails formation of toxic oxy radicals which destroy the neoplasm. Cyclic voltammetry was performed on iminium type ions derived by protonation of the acridines. Reductions were generally reversible with potentials of about -0.60 V. Involvement of quinoidal metabolites is also a possibility. The relationship of electrochemical behavior to structure and physiological activity is addressed.

An integrated concept of amebicidal action: electron transfer and oxy radicals.

Cyclic voltammetry data were obtained for most of the main categories of antiamebic agents, specifically, quinones, heterocyclic nitro compounds, metal derivatives and chelators, and iminium-type ions. The reductions (our data and literature values) were for the most part reversible, with potentials usually in the favorable range of +0.10 to -0.56 V. The drug effect is believed to result generally from the catalytic production of oxidative stress usually arising from the formation of superoxide via electron transfer. In addition, relevant literature data are provided.

Charge transfer-oxy radical mechanism for anti-cancer agents.

The proposal is advanced that anti-cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochemical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants.

Conjugated and cross-conjugated mesomeric betaines. Correlation of electroreduction with structure and physiological activity.

Electroreduction studies were performed on several cross-conjugated mesomeric betaines containing the fused pyrazolium (2) and fused imidazolium (3) ring systems. Studies at acidic pH were of principal interest. Substituent effects for 2 were in line with prior findings, and reduction potentials were comparatively negative (-0.96 to -1.34 V). Reduction potentials fit the modified Hammett equation. Compound 3 was more readily reduced (-0.88 V). The related psi-oxatriazoles (6) gave values in the range of -0.85 to -1.22 V. The electrochemical characteristics are compared with those of the mesoionic sydnones (4) and sydnoneimines (5). These mesoionic compounds were generally reduced at more positive potentials than 2 and 3. A relationship between electroreduction and physiological activity is proposed. The overall results are in keeping with the hypothesis of widespread participation of iminium-type species in biological systems.

Mechanism of antibacterial action: electron transfer and oxy radicals.

Most of the main categories of bactericidal agents, namely, aliphatic and heterocyclic nitro compounds, metal derivatives and chelators, quinones, azo dyes, and iminium-type ions, are proposed to exert their action by a unified mechanism. The toxic effect is believed to result generally from the catalytic production of reactive oxygen radicals that usually arise via electron transfer. Cyclic voltammetry was performed on a number of these agents. Reductions were for the most part reversible, with potentials in the favorable range of -0.20 to -0.58 V.

Oxidative ionic metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): correlation of electroreduction with physiological behavior.

Electrochemical studies (reduction potential and reversibility) were performed on 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+). MPP+ gave reduction potentials in the range of -1.09 to -1.11 V in organic solvents in a process which was reversible. The reduction potential of MPDP+ was -0.64 V (irreversible). Possible relationships involving the electrochemical properties, oxy radical formation, and biological activity of these and related iminium species are discussed.

Charge transfer and oxy radicals in antimalarial action. Quinones, dapsone metabolites, metal complexes, iminium ions, and peroxides.

A mechanism of action is proposed that encompasses almost all of the main categories of antimalarial agents: quinones and precursors, dapsone metabolites, metal complexes of thiosemicarbazones and biguanides, iminium-type ions from acridines and quinolines, and peroxides. The toxic effect of the drugs is believed to result from the generation of reactive oxygen radicals that usually arise via charge transfer. Electrochemical studies (reduction potential and reversibility) were performed on a number of these agents. Reduction potentials range from -0.23 to -1.52 V. It is likely that the in vivo values are appreciably more positive in certain cases.

The use of hyperbaric oxygen therapy in bony reconstruction of the irradiated and tissue-deficient patient.

Eighteen bony reconstructions of the mandible or maxilla using a newly defined and specific hyperbaric oxygen protocol are reported. Eleven of 12 grafts in irradiated tissue met six rigid criteria for a 91.6% rate of success. All six grafts into scarred and deficient tissue beds also met the same criteria, for an overall success rate of 94%. The rationale for emphasizing preoperative tissue preparation using hyperbaric oxygen is discussed, as are the mechanisms of action of hyperbaric oxygen on a biochemical, cellular, and tissue level. Neovascularity and neocellularity are demonstrated histologically by human biopsy specimens, and this is suggested as being the reason for the excellent results of reconstruction in irradiated and/or deficient tissue beds.

Computerized tomography in oral and maxillofacial surgery.

Computerized tomography has revolutionized the art of diagnosis by noninvasive techniques. Until recently, its use in oral and maxillofacial surgery has been limited. Basic principles include the production of a two-dimensional image representing an anatomically accurate slice of tissue. Advantages of computerized tomography are lack of image superimposition, preservation of detail of soft tissue, enhancement of vascular tumors, selective enlargement of areas of interest, tomographic capability, and the future possibility of the production of three-dimensional images. However, the presence of any metallic restoration produces artifacts, which limits the use of computerized tomography to areas excluding the dentition where restorations are present. Clinical application at our institution has been to use computerized tomography in the differential diagnosis of infections, midfacial trauma, vascular lesions, and lesions involving the mandibular ramus and maxilla.

Radionuclide bone imaging in the differential diagnosis of head and neck lesions. A preliminary report.

The use of technetium 99m pyrophosphate (99mTcPP) imaging in the evaluation of benign and malignant tumors of the head and neck has been limited. In a clinical prospective study, twenty-one patients with suspected benign or malignant lesions of the temporomandibular joint, temporal bone, maxilla, or mandible were evaluated with regard to clinical presentation, radiographic findings, preoperative 99mTcPP bone scan, and final pathologic diagnosis. Eleven of twenty-one patients had positive scans at the site of biopsy-proven disease. In three cases, a bone scan was the single positive diagnostic test prior to surgical intervention. 99mTcPP imaging offers an additional noninvasive technique in the preoperative evaluation of patients with lesions of the osseous structures of the head and neck.