Chronic spinal infusion of loperamide alleviates postsurgical pain in rats.

Plantar incision in rat generates spontaneous pain behaviour. The opioid drug, morphine used to treat postsurgical pain produces tolerance after long-term administration. Loperamide, a potent mu-opioid agonist, has documented analgesic action in various pain conditions. However, loperamide analgesia and associated tolerance following continuous spinal administration in postsurgical pain has not been reported. Chronic spinal infusion of drugs was achieved using intrathecal catheters connected to osmotic minipump. Coinciding with the onset of spinal infusion of loperamide or morphine, rats were subjected to plantar incision. Pain-related behaviour was assessed by Hargreaves apparatus (thermal hyperalgesia) and von Frey filaments (mechanical allodynia). Morphine and loperamide (0.5, 1 and 2 µL/h) induced analgesia was observed until 7th day post-plantar incision in Sprague-Dawley rats. Morphine and loperamide produced dose-dependent analgesia. Loperamide, in the highest dose, produced analgesia till 7th day. However, the highest dose of morphine produced inhibition of thermal hyperalgesia till 5th day and mechanical allodynia only till 3rd day post-plantar incision. Morphine and loperamide produced analgesia in postsurgical pain, which may be mediated through different mechanisms. Longer duration of analgesia with loperamide could probably be due sustained blockade of calcium channels.

A pilot study on area under curve of mycophenolic acid as a guide for its optimal use in renal transplant recipients.

Background & objectives: The immunosuppressants administered to renal transplant subjects are usually monitored therapeutically to prevent graft rejection and drug toxicity. Mycophenolic acid (MPA) is an immunosuppressant. The present prospective study was undertaken to establish the utility of plasma level monitoring of MPA and to correlate it with clinical outcomes in renal transplant receipients. Methods: MPA plasma level at 2, 4 and 9 h and the area under concentration-time curve (AUC) were estimated using high performance liquid chromatography in 24 renal transplant recipients receiving immunosuppressant MPA plus tacrolimus and steroid. Results: There was wide inter-individual variation in MPA plasma level and the AUC. The incidences of gastrointestinal adverse drug events (diarrhoea and acidity) were significantly more in the high MPA AUC patients. Though biopsy proven acute rejection was not found, of the six subjects with lower MPA AUC (<30 mg.h/l), three were clinically diagnosed to develop tacrolimus nephrotoxicity. The Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) scores represented better health related quality of life in lower MPA AUC than in the higher MPA AUC (>60 mg.h/l). Interpretation & conclusions: The present findings suggest the MPA AUC of 30 - 60 mg.h/l in the maintenance stage of renal transplant patients to have optimum clinical benefit and relegated adverse events profile indicating the usefulness of AUC of MPA with limited sampling strategy in optimizing its use.

Gaso-transmitter hydrogen sulphide: Potential new target in pharmacotherapy.

Research in the last two decades has transformed the way hydrogen sulphide (H2S) is perceived from a noxious gas to a gaso-transmitter with a vast potential in pharmacotherapy. H2S is synthesized in various body-systems using the enzymes cystathionine beta-synthase and cystathionine gamma-lyase; either of these being the predominat enzyme in a particular system. H2S may be one of the physiological modulators of blood pressure in humans. The gas relaxes the vascular smooth muscle cells by opening up KATP channels. Moreover, it suppresses the proliferation of vascular smooth muscle cells. H2S may also be contributing in the protection afforded by ischaemia-preconditioning. Testosterone is thought to be responsible for the higher central nervous system level of H2S in males. In the central nervous system, H2S is implicated in Alzheimer’s disease, epilepsy, stroke and Down’s syndrome. Insulin secretion is associated with a decrease in the H2S levels. Raised H2S is detrimental in acute pancreatitis as well as in septic shock. Recently, H2S-releasing derivatives of certain drugs have shown promise in protection against gastric ulcer and in inflammatory bowel disease. The beneficial effects of certain sulphur containing herbs like ginseng and garlic may be mediated via H2S. In future, development of specific drugs modulating H2S levels may prove beneficial in varied disorders.

Attenuation of the effect of lindane on immune responses and oxidative stress by Ocimum sanctum seed oil (OSSO) in rats.

Present study was done to evaluate the effect of Ocimum sanctum seed oil (OSSO) on the immunotoxicity and oxidative activity of lindane in rats. Rats were divided into four groups (n = 8) and were treated with lindane (10 mg/kg, po) and/or OSSO (1 mg/kg, po) during the study period. Humoral immunity was assessed by measuring haemagglutination titre to sheep red blood cells (SRBC) and delayed type hypersensitivity (DTH) was assessed by measuring foot pad thickness. Lindane showed significant decrease in anti-SRBC antibody titre and also decreased percentage change in foot pad thickness in DTH response as compared to control group. OSSO per se produced significant increase in anti-SRBC antibody titre, but did not produce significant change in the foot pad thickness as compared to control group. However, it significantly antagonized the effect of lindane on the anti-SRBC antibody titre and foot pad thickness parameters. Lindane produced oxidative stress as indicated by increase in the levels of MDA and decrease in GSH levels. Treatment with OSSO per se showed antioxidant activity and also reversed the oxidative stress produced by lindane. The results suggest that OSSO can attenuate the immunotoxicity and oxidative stress produced by lindane.

Effect of minocycline and tetracycline on immunological responses in experimental animals.

In recent years, there has been an increase in the use of antibiotics, primarily tetracycline anlogues, like minocy cline to treat rheumatoid arthritis. However, the mechanism of action of these analogues is not clearly defined. The present study investigates the effects of minocycline and tetracycline on some immunological parameters in Wistar rats and Swiss albino mice. Haemagglutination (HA) titre was employed as parameter of humoral immune response and % leukocyte migration inhibition (% LMI) and footpad thickness tests were used as measures of cell mediated immune response. Both minocycline and tetracycline significantly improved humoral immune response in rats as indicated by an increase in anti-SRBC antibody titre. In the LMI test, depending on the time period of drug administration, there was an increase or a decrease in the % LMI. When drugs were administered on days 1-7 after sensitization, both the compounds caused a significant increase in % LMI. However, the % LMI was significantly decreased when the drugs were administered on days 7-13 of sensitization, indicating variable effects of these agents on the Immune mechanism depending on the time of administration in relation to the development of immune responsiveness. Both minocycline as well as tetracycline produced a significant decrease in the paw volume in the footpad-thickness test which indicates a decrease in lymphokine production/release. The present study thus shows that minocycline and tetracycline exhibit immunomodulatory properties, which may contribute significantly to their beneficial effects in rheumatoid arthritis.