Physical Stability of Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols

The effect of storage on the physical stability of solid dispersions of triamterene or temazepam in polyethylene glycols was studied using differential scanning calorimetry (DSC), particle-size analysis and dissolution methods. The enthalpies of fusion of the carriers, without included drug and previously fused and crystallized, increased on storage. Analysis of similarly treated solid dispersions, containing either 10% temazepam or 10% triamterene, showed that each drug influenced the morphology of the polyethylene glycol (PEG). The enthalpies and melting points of the solidus components of the dispersions' carriers were initially reduced after preparation, but on storage these increased. The particle sizes of the drugs dispersed in the PEGs increased on storage. The changes in dissolution after storage of triamterene or temazepam dispersions were smaller for dispersions in PEG 1500 than for dispersions in PEGs of higher molecular weight (PEG 2000, PEG 4000 or PEG 6000) in which the reduction in dissolution was particularly marked during the first month of storage. The rank order of changes in dissolution were PEG 1500 ? PEG 2000 < PEG 4000 ～ PEG 6000.     

The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole

1 Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine.
2 Ten healthy male volunteers were given co-trimoxazole (800  mg sulphamethoxazole and 160  mg trimethoprim) alone or 1  h after either fluconazole (150  mg) or ketoconazole (200  mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24  h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N₄-acetyl sulphamethoxazole, or sulphamethoxazole N₁-glucuronide excreted in urine.
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points.     

Medical Kits For Business Travellers

A survey of occupational physicians of the Food Industry MedicalOfficers Group was undertaken to establish details of medicalkits supplied by their organizations to business travellers.The most common approach was an in-house medical kit with instructionsemphasizing self treatment of the common ailments of travellerssuch as motion sickness, sleeplessness, diarrhoea, indigestionand headaches. The majority of kits included a small supplyof needles, syringes, IV cannulae etc either in a commercial‘;Aids Kit’ or as inhouse supplies. Antimalarialswere provided either as a standard kit item or as required.About half provided antibiotics for the self treatment of infections.Very few provided a telephone number for use in the event ofmedical emergencies. A standard medical kit specification isproposed. Requests for reprints should be addressed to: Dr S.P. Deacon, Corporate Health and Safety, Kellogg Company of GB Ltd, Stretford, Manchester M32 8RA. U.K.     

Preservation of All Chordae Tendineae and Papillary Muscle During Mitral Valve Replacement with a Tilting Disc Valve

Mitral valve replacement was performed in 21 patients using a surgical technique that preserves the entire papillary muscle and chordal apparatus. With this technique, the anterior mitral leaflet is split from the center of the free edge toward the annulus. Bilateral incisions are made from the proximal end of this split to the two mitral commissures, detaching the anterior leaflet from the annulus. These two halves of the leaflet, with all chordae intact (corresponding to the anterolateral and posteromedial papillary muscles), are judiciously trimmed to remove areas of leaflet untethered by chordae tendineae and (when necessary) fibrous thickening; then swung posteriorly and sutured to the posterior mitral annulus using mattress sutures with pledgets. This surgical technique is expected to favor the preservation of left ventricular function and avoid occurrence of irreversible left ventricular dilation/dysfunction, and has been used successfully for calcific and degenerative etiologies, using both tilting disc valves and porcine bioprostheses. It is especially useful in the implantation of tilting disc and bileaflet mechanical prostheses because anterior subvalvular chordae tissue may interfere with the disc excursion and relocated to the posterior leaflet annulus.     

Platelet and Thrombin Inhibitors as Adjuncts to Thrombolytic Therapy and Percutaneous Coronary Interventions: A Review

A large body of evidence supports the critical role of thrombus formation in the pathogenesis of acute MI as well as the early ischemic complications after percutaneous coronary interventions. Both platelets and the plasma proteins involved in fibrin formation are intimately involved in the thrombotic process. Recently, pharmacological agents that hinder fibrin formation and platelet activation or aggregation have been developed. These drugs are being tested in patients with acute MI, in conjunction with thrombolytic agents, and in patients undergoing percutaneous coronary interventions. So far, the antiplatelet agents appear very promising in the area of percutaneous coronary intervention. Information on their role in acute myocardial infarction is still too preliminary to draw conclusions. Results with antithrombin agents have been less promising. This article will briefly describe the mechanisms of thrombus formation, detail the mechanism of action of available antithrombotic pharmacological agents, and review recent clinical trials of these agents.