Sulphonamides combinations

Noli, C., Koeman, J.P., andWillemse, T., A retrospective evaluation of adverse reactions to trimethoprim-sulphonamide combinations in dogs and cats. Vet. Q., 17, 123-128, 1995. 

Proguardl (t) 17 h) inhibits dihydrofolate reductase which converts folic to folinic acid, deficiency of which inhibits plasmodial cell division. Plasmodia, like most bacteria and unlike humans, cannot make use of preformed foUc acid. Pyrimethamine and trimethoprim, which share this mode of action, are collectively known as the antifols. Their plasmod-icidal action is markedly enhanced by combination with sulphonamides or sulphones because there is inhibition of sequential steps in folate synthesis (see Sulphonamide combinations, p. 231). 

It is perhaps relevant to note here that in clinical use sulphonamide mixtures are preferred to single drugs, to minimize the formation of crystal deposition in the kidney. The use of mixtures of related sulphonamides results in enhanced mutual solubility [284]. This is perhaps a case of hydrotropy. Lehr [285] has determined the solubility of a number of sulphonamide combinations, and Frisk et al. [286] have reported on the solubility of the combination sulphadiazine, sulphamerazine, and sulphathiazole. The influence of sulphanilamide on the solubility of sulphathiazole indicated that a 1 1 molecular complex was formed [287]. 

The kinetics of the binding of anions and sulphonamides to carbonic anhydrase have been measured by the stopped-flow technique. The results are consistent with a mechanism involving a pH-dependent equilibrium between two co-ordination forms of the enzyme in which anions selectively combine with the low-pH form of the enzyme whereas sulphonamides combine with the high-pH form. The effect of pH on the anion affinity correlates with the pH dependence of the spectral change associated with the cobalt(n) form of the enzyme. Further evidence on the similarity of the conformations at the active sites of the zinc and cobalt(n) forms of carbonic anhydrase has been provided by spin-labelling. A nitroxide-substituted sulphonamide was used as the spin label and its e.s.r. spectrum was found to be almost identical in the two forms of the enzyme-inhibitor complex. 

The alkylating agent (0.11 mol) is added with stirring to the sulphonamide (0.05 mol), powdered KOH (7.0 g), K2C03 (7.0 g), and TBA-HS04 (1.7 g, 5 mmol) in PhH (60 ml) at room temperature. The mixture is stirred at ca. 50°C for 3-4 h and then cooled to room temperature and filtered. The solid residue is washed with PhH (3 x 20 ml) and the combined PhH solutions are washed with H20 until neutral, dried (MgS04), and evaporated to yield the alkylated sulphonamide. 

In experimental typhoid disease in mice treated with colimycin, the addition of pentoxyl prevents immunological disorders and stimulates an immunological reaction [294]. This compound potentiates the action of sulphonamides in mice infected with type II pneumococcus [295]. In combination with streptomycin, pentoxyl is beneficial in the treatment of experimental tuberculosis in guinea-pigs [296]. However, a single pharmacological report, relative to effects on the central nervous system, was unfavourable [297]. 

Fixed dose combinations of penicillin with sulphonamides. 

The HPLC-receptorgram assay combined the advantages of HPLC separation with the multiresidue detection of the Charm II tests. The procedure was tested for identification and quantitation of the most common veterinary drugs at regulatory levels or lower. It was validated for 40 individual drugs from seven antibiotic families 10 /3-lactams, 13 sulphonamides, 8 tetracyclines, 4 macrolides, 3 amphenicols, and other miscellaneous antimicrobials. This procedure combined a simple aqueous extraction and SPE with HPLC fractionation of individual drugs. Final identification and quantitation was achieved with the Charm II test. A drug contaminant could be identified in less then 3 hours (50). 

Sulphonamides are difficult to separate, but these systems are effective and may be used in combination. System TF, previously described, may also be used. 

Accordingly, the spectrum of applicability of these CSPs can be derived. It appears that cellulose- and amylose-carbamate CSPs are excellent for the enantioseparation of SAs with hydrogen donor and/or acceptor sites (amides, carbamates, sulphonamides, hydroxy groups) as well as aromatic moieties, advantageously in combination with bulky groups close to the interaction sites. Due to the broad range of applicability a more detailed list of resolvable SAs would extend this report. However, further information is available from the application guide [172], from review articles [47,99,1(X), and from recently published enantioseparations (Table 9.4). 

Sulphonamides, amongst the first successful chemotherapeutic agents, now have their place in medicine mainly in combination with trimethoprim. Because of the risks of adverse drug reactions associated with their use, this is generally restricted to specific indications where other therapeutic agents have clearly inferior efficacy. Many sulphonamide compounds have been withdrawn from the market. Their individual names are standardised in the UK to begin with sulfa-. ... 

Co-trimoxazole, at first, very largely replaced the use of a sulphonamide alone. In turn, trimethoprim on its own is now used in many conditions for which the combination was originally recommended, and it may cause fewer adverse reactions (see below). The combination is, however, retained for ... 

Adverse effects. Any sulphonamide-induced allergic reactions can be severe, e.g. erythema multiforme, Stevens-Johnson syndrome and foxic epidermal necrolysis. Because of its antifoT action the combination should not be used by pregnant women imless they take a folate supplement. 

Gruneberg RN. The microbiological rationale for the combination of sulphonamides with trimethoprim. J Antimicrob Chemother 1979 5(B) 27-36. 

Brumfitt W, Hamilton-Miller JM. Combinations of sulphonamides with diaminopyrimidines how, when and why J Chemother 1995 7(2) 136-9. 

Co-trimoxazole is a mixture of sulphamethoxazole (five parts) and trimethoprim (one part). The reason for using this combination is based upon the in vitro finding that there is a sequential blockade of folic acid synthesis, in which the sulphonamide is a competitive inhibitor of dihydropteroate synthetase and trimethoprim inhibits DHFR (see Chapter 12). The optimum ratio of the two components may not... 

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