Treatment of severe metformin-associated lactic acidosis with renal replacement therapy and tris-hydroxymethyl aminomethane: a case report.

BACKGROUND: Type B lactic acidosis is a rare but serious side effect of metformin use. The risk of metformin-associated lactic acidosis is elevated in renal or liver impairment, heart failure and in metformin overdose. Metformin-associated lactic acidosis is treated with renal replacement therapy although this can be limited by metformin's large volume of distribution and a patient's hemodynamic instability. Tris-hydroxymethyl aminomethane is a buffer that rapidly equilibrates in liver cells and increases the intracellular pH of hepatocytes. Intracellular alkalosis increases lactate uptake by the liver and can promote gluconeogenesis which results in increased lactate metabolism and decreased lactate production. Unlike intravenous bicarbonate which can worsen acidosis due to carbon dioxide retention and hypocalcemia, tris-hydroxymethyl aminomethane does not generate large amounts of carbon dioxide and can improve cardiac contractility in experimental models. CASE PRESENTATION: We present a case of a 43-year-old African American male who intentionally ingested 480,000 g of metformin. He developed severe metformin-associated lactic acidosis that was refractory to 21 hours of high flux hemodialysis. This was followed by an additional 12 hours of high flux hemodialysis augmented by continuous intravenous infusion of tris-hydroxymethyl aminomethane. After initiating tris-hydroxymethyl aminomethane, the patient had rapid reversal of lactic acidosis and was weaned off vasopressors and mechanical ventilation. CONCLUSIONS: While metformin-associated lactic acidosis can be treated with renal replacement therapy, severe cases of lactic acidosis may not be amenable to renal replacement therapy alone. Through its unique buffer mechanisms, tris-hydroxymethyl aminomethane can be used in conjunction with dialysis to rapidly improve acidosis associated with metformin.

Ortho-Cyclization in Asymmetrically Substituted Arylnitroso Oxides.

The mechanism of the photooxidation of a number of asymmetrically substituted phenyl azides in acetonitrile was studied. The key intermediates of this reaction are the corresponding nitroso oxides, the unimolecular consumption of which occurs via the cis form when the terminal oxygen atom of the NOO moiety reacts with the ortho position of the aromatic ring. As a result, it is opened to form a nitrile oxide. In the case of 3-methylphenyl azide, the reaction proceeds via the cis/syn form of nitroso oxide with a regioselectivity of 91%. The methoxy substituent at the para position changes the direction of the ortho-cyclization so that it occurs via the cis/anti form of nitroso oxide independently on the nature of a meta substituent. Nitrile oxides, which are formed as a result of these transformations of nitroso oxides, are stabilized by [3 + 2] cycloaddition with acetonitrile to give 1,2,4-oxadiazoles. The observed regioselectivity of the ortho-cyclization of nitroso oxides was explained using theoretical methods. Its cause consists in the extra-stabilization of the transition state of the reaction of the cis/anti form due to a stereoelectronic effect of the para-methoxy substituent.

Synthesis of new N,N'-Pd(Pt) complexes based on sulfanyl pyrazoles, and investigation of their in vitro anticancer activity.

The synthesis of new N,N'-mononuclear bi-ligand Pd(ii) and tri-ligand Pt(ii)complexes bearing sulfanyl(phenyl, benzyl, cyclohexyl, 4-hydroxyphenyl)3,5-dimethyl-1H-pyrazole ligands has been carried out. The obtained compounds were studied for apoptosis-inducing activity and effect on the cell cycle for Jurkat, K562, and U937 neoplastic cell cultures and conditionally normal human embryonic kidney HEK293 cells. The cells showed the highest sensitivity to platinum and palladium complexes in comparison with ligands and cisplatin. The cytotoxic properties are enhanced for compounds with cyclohexyl substituents at the S-atom in sulfanyl pyrazoles and complexes.

Interplay of Conformational and Chemical Transformations of Ortho-Substituted Aromatic Nitroso Oxides: Experimental and Theoretical Study.

The mechanism of the photooxidation of aromatic azides containing a substituent at one of the ortho positions (2,4-dimethoxyphenyl azide (1a) and 2-methyl-4-[(2E)-1-methylbut-2-en-1-yl]phenyl azide (1b)) was studied in acetonitrile. The electronic spectra and the kinetic regularities of the consumption of corresponding nitroso oxides, which are the reaction intermediates, were investigated by flash photolysis. Owing to the one-and-a-half order of the C-N and N-O bonds and asymmetric molecule structure these nitroso oxides exist as four conformers (cis/syn, cis/anti, trans/syn, and trans/anti). The conformers differ in the spectral properties and in the reactivity in various irreversible transformations. The only product, (2Z,4E)-4-methoxy-6-oxohepta-2,4-dienenitrile oxide (7a), was observed during photooxidation of 1a, whereas transformations of the nitroso oxide isomers derived from 1b led to a set of stable products: the cis/anti isomer was transformed into (3,4,7-trimethyl-3a,4-dihydro-2,1-benzisoxazol-5(3H)-ylidene)ethanal (10), the trans isomers recombined forming the corresponding nitro and nitroso compounds, and the most reactive cis/syn isomer was transformed into ortho-nitrosobenzyl alcohol 11. The last was oxidized slowly to the corresponding benzaldehyde 12. Interaction of 11 and 12 led to the formation of (Z)-1,2-bis(2-formyl-4-((2E)-1-methylbut-2-en-1-yl)phenyl)diazene-1-oxide (13). The DFT simulation and kinetic modeling of the nitroso oxide transformations as well as the product analysis allowed revealing the fine details of the mechanism of decay for these species.

A revised mechanism of thermal decay of arylnitroso oxides.

The electronic spectra were measured and the unimolecular decay kinetics of the isomeric forms (cis and trans) of 4-methoxyphenylnitroso oxide in acetonitrile, benzene, and hexane was studied using flash photolysis. The cis form absorbed in a shorter wavelength region and was more labile than the trans form. The difference between the reactivity of the two species increased on going from hexane to acetonitrile. The temperature dependences of reaction rate constants were studied for both isomeric forms. The analysis of products of flash photolysis of 4-methoxyphenyl azide in the presence of oxygen allowed for understanding the mechanism of thermal decay of nitroso oxides. It was shown that the trans nitroso oxide is converted into cis nitroso oxide. The latter undergoes an unusual ring cleavage reaction to form 4-methoxy-6-oxohexa-2,4-dienenitrile N-oxide derivative. We conclude that the nitro- and nitrosobenzenes, which are the main products of the steady-state photolysis of aromatic azides in the presence of oxygen, are formed by the photochemical transformation of the nitroso oxides.