The expression of a high level of morphine antinociceptive tolerance in mice involves both PKC and PKA

We have previously reported that intracerebroventricular (i.c.v.) injection of either a PKC or PKA inhibitor completely reversed the expression of 5- to 8-fold morphine antinociceptive tolerance. We developed a model of 45-fold morphine tolerance that included a 75-mg morphine pellet and twice daily morphine injections. PKC inhibitor doses of bisindolylmaleimide I and G?-7874 that completely reversed 8-fold tolerance only partly reversed the 45-fold level of antinociceptive tolerance. A component of tolerance was resistant to PKC inhibition, since even higher inhibitor doses failed to further reverse the high level of morphine tolerance. In addition, the 45-fold tolerance was only partly reversed by the PKA inhibitor KT-5720 at a dose previously cited by others to reverse 5-fold tolerance. Another PKA inhibitor 4-cyano-3-methylisoquinoline only partly reversed the morphine tolerance as well. In other experiments PKC and PKA inhibitors were co-administered together to determine their effectiveness for completely reversing the 45-fold level of morphine tolerance. Co-administering either bisindolylmaleimide I with KT-5720, or G?-7874 with KT-5720, completely reversed the high level of tolerance. The high level of morphine tolerance was also completely reversed by co-administering G?-7874 with 4-cyano-3-methylisoquinoline. Thus, high levels of morphine tolerance may reflect increases in protein phosphorylation by the terminal kinases of both the adenylyl cyclase and phosphatidylinositol cascades in brain and spinal cord areas critical to the expression of antinociception.     

Formulation and development of hydrodynamically balanced system for metformin: in vitro and in vivo evaluation.

The objective of the present study was to develop a hydrodynamically balanced system of metformin as a single unit floating capsule. Various grades of low-density polymers were used for the formulation of this system. They were prepared by physical blending of metformin and the polymers in varying ratios. The formulation was optimized on the basis of in vitro buoyancy and in vitro release in simulated fed state gastric fluid (citrate phosphate buffer pH 3.0). Effect of various release modifiers was studied to ensure the delivery of drug from the HBS capsules over a prolonged period. Capsules prepared with HPMC K4M and ethyl cellulose gave the best in vitro percentage release and were taken as the optimized formulation. By fitting the data into zero order, first order and Higuchi model it was concluded that the release followed zero order release, as the correlation coefficient (R(2) value) was higher for zero order release. It was concluded from R(2) values for Higuchi model that drug release followed fickian diffusion mechanism. In vivo studies were carried out in rabbits to assess the buoyancy, as well as the pharmacokinetic parameters of the formulation using gamma scintigraphy. The formulation remained buoyant during 5h of study in rabbits. The comparative pharmacokinetic study was performed by administration of the optimized HBS capsules and immediate release capsules, both with radiolabeled metformin, using gamma counter. There was an increase in AUC in optimized HBS capsules of metformin when compared with immediate release formulation.     

Long term intubation and successful weaning in two children with Guillain-Barre syndrome

No definite criteria exists in Guillian-Barre syndrome in children regarding prolonged ventilation through an endo-tracheal tube without tracheostomy and successful weaning using a T-piece. Here we report two such cases of Guillian-Barre syndrome requiring prolonged intubation for 56 days and ventilation for 30 days and ultimately successfully weaning them using the T-piece. Both the children eventually made a complete recovery, highlighting the point that in children prolonged intubation and ventilation using the portex tube is equally good, if not, better than tracheostomy with its attendant risks.     

Appendix vermiformis duplex — a lesson for the unwary

Appendix vermiformis duplex is a rare phenomenon. A case of a double appendix with one caecum and inflammation of one of the appendices is presented. The unusual presentations of the anomaly can cause diagnostic dilemmas. Awareness of a duplication is important, as failure to recognise the condition may lead to clinical problems and possible litigation.     

Fetal Intrahepatic Cholestasis Secondary to BO Hemolytic Disease

A rare occurrence of severe, direct hyperbilirubinemia in an infant with BO incompatibility was noted at four hours of age. Severe fetal hemolysis and markedly elevated indirect bilirubin levels might have caused induction of conjugating enzymes during fetal life in this case. Intrahepatic cholestasis was responsible for persistent conjugated hyperbilirubinemia after birth. This responded favorably to cholestyramine therapy.     

Advances in the treatment of chronic urticaria

There have been a number of exciting developments in the treatment of allergic diseases in recent years, but the development of new treatments for urticaria has lagged behind. The standard treatment for chronic urticaria (CU) involves the use of H1 antagonists. A number of small but promising studies have found potential benefit with medications that are used less often. This article reviews the established therapies for CU and the experimental evidence for the use of nonstandard and relatively unknown therapies. The potential usefulness of some of the new allergy medications for the treatment of CU also is discussed.     

Implications of patient and physician decision making: an illustration in treatment options for coronary artery disease

The objective of this study was to explore the extent to which patients and physicians desire patient participation in medical decision making. The cross-sectional pilot study involved 92 patients with coronary artery disease (CAD) and 50 physicians involved in treating patients with CAD. Desire to participate in making the decision between treatment options for CAD and factors that influence the decision were assessed. Physicians prefer to participate in shared decision making more often than do the patients (P = .016). When faced with clinical scenarios requiring a decision to be made between percutaneous transluminal coronary angioplasty and coronary artery bypass graft, patients and physicians tended to defer to one another to make the decision. Multinomial logistic regression models showed that the overriding factor influencing patient decision making was the physician's opinion (P < .0001) and the patient's preference was the overriding factor influencing physician decision making (P < .0001). Because patients tend to defer to physicians when making medical decisions, it is incumbent upon the physician to assure that the physician-patient dialogue reflects important information about the procedures (coronary artery bypass graft and percutaneous transluminal coronary angioplasty) and that preferences are acknowledged. This may impact greatly on achieving satisfactory health outcomes and patient satisfaction.