According to recent findings, the immune system and brain speak a common biochemical language. Cytokines, peptide hormones and neurotransmitters, and their receptors are endogenous to the brain, endocrine and immune system. Cells of the immune system can regulate the brain and endocrine system through the actions of the cytokines on receptors in the brain and through the synthesis of peptide hormones. Neural regulation of the immune system occurs through autonomic nervous system activation and the release of hypothalamic and pituitary hormones. Complex neuroendocrine immune system interactions occur between the thymus gland and the gonadal hormones and between cytokines and corticosteroid hormones. The corticosteroids appear to provide negative feedback to inhibit the release of IL-1 and suppress immune system activity, thus preventing some autoimmune diseases. Opioid peptides, substance P, somatostatin and other neuropeptides also regulate the activity of immune system. Neuroendocrine immune system interactions are mediated through the hypothalamus and the paraventricular nucleus appears to play a central role in the integration of these three systems. The integration of neural, endocrine and immune system activity may occur through common receptors and second messenger system.

Tiagabine is a nipecotic acid derivative discovered through mechanistic-based drug design program for the treatment of epilepsy. Tiagabine is a specific and potent y-aminobutyric acid (GABA)-uptake inhibitor whose anticonvulsant activity has been demonstrated in several widely used animal experimental models including methyl-6,7-dimethoxy-4-ethyl-(-carboline-3-carboxylate induced clonic convulsions, pentylene tetrazol (PTZ)-induced tonic convulsions, sound-induced convulsions in DBA/2 mice, genetically epilepsy-prone rats, electrically induced convulsions in kindled rats and status epilepticus in cobalt-lesioned rats. However, tiagabine is weakly efficacious in intravenous PTZ seizure threshold test, bicuculline-induced seizure test, and maximal electroshock seizure test. Ln vivo microdialysis shows that tiagabine increases the extracellular GABA overflow in a dose-dependent manner. Four GABA transporter molecules known as GAT-1 to GAT-4 have been cloned and sequenced in brain. Tiagabine is a selective inhibitor of GAT-1, which is predominantly localized in presynaptic terminals of neurons, with little or no affinity for other three transporters. The drug has shown potent antiepileptic activity when given orally thrice daily at a dose of 24-54 mg/day with a half-life of 5-8 h. Tiagabine was clinically evaluated using a novel enrichment (Amery) design which rapidly established the efficacy of tiagabine in adjunctive partial seizures. The tiagabine monotherapy may provide a new approach to the treatment of patients with partial seizures refractory to other antiepileptic drugs. The results of numerous multicentre add-on, open label, placebo-controlled long-term clinical trials established the efficacy of tiagabine as add-on therapy in patients with epilepsy difficult-to-control. Efficacy of the drug is also sustained with long-term treatment without any tolerance to anticonvulsant activity.The drug was well tolerated in an integrated safety analysis of several double-blind, add on therapy trials in patients with epilepsy with difficult-to-control seizures. Tiagabine does not induce or inhibit metabolic processes of other antiepileptic agents.The adverse events reported include dizziness, asthenia, nervousness, tremor and mild depression. Further clinical experience will not only confirm efficacy but also optimize the dosage of tiagabine for monotherapy and add-on therapy in seizure control. These data suggest that tiagabine is a potent and broad spectrum anticonvulsant with a novel mode of action but without causing tolerance to the anticonvulsant effect.

0bjective:To study the effect of S-allyl cysteine sulphoxide (SACS) in antagonising deleterious metabolic effects of monosodium glutamate in rats on atherogenic diet. Methods: Rats on atherogenic diet with monosodium glutamate at two doses received SACS for thirty days. At the end of thirty days, blood pressure, heart rate, serum lipid levels and activities of some serum, liver, heart and intestinal enzymes were assessed. Results: SACS significantly decreased the concentration of serum lipids except HDL cholesterol and enzyme activities in serum, liver, heart and intestine in rats treated with MSG at both doses. There was no significant effect of SACS on phosphatases in rats treated with MSG (1 g/kg). SACS did not have any significant effect on blood pressure and heart rate. SACS significantly decreased pentobarbitone induced sleeping time in rats on MSG with atherogenic diet. Conclusions: Our data suggests that SACS significantly antagonises the metabolic aberrations caused by MSG in rats on atherogenic diet.

Objective: To evaluate the immunopotentiating and immunoprophylactic effects of Immue-21 (l-21) a polyherbal Ayurvedic product. Methods: Effect of l-21 (50 mg/kg, p.o), on morphometric and functional changes of mouse peritoneal macrophage was evaluated. Its effect on chemotaxis assay for leucocytes and on heamatological parameters were also studied. Adjuvant effect of l-21 was studied in rabbits. lmmunopotenttating effect of l-21 was studied against UV rays,cyclophosphamide and cyclosporine induced immunosuppression in mice and rats. lmmunoprophylactic effect of l-21 was studied in E.coli induced peritonitis in mice. Results: l-21 exhibited a significant increase in both morphometric and functional changes of macrophage in mice. It also significantly increased in vitro chemotaxis of leucocytes and in vivo total WBC and RBC counts in albino mice. l-21 significantly potentiated humoral immunity in rabbits and showed significant protection against UV rays, cyclophosphamide and cyclosporine A induced immunosuppression. l-21 provided 50% protection against E. coli induced abdominal peritonitis in albino mice. Conclusion: l-21 may have immunopotentiattng and immunoprophylactfc activity.

Objectives: The aim of this study was to investigate the effect of A. booneistem bark extracts on immune system in vitro using complement system and polymorphonuclear (PMN) leucocytes as immunological parameters. Methods: Pulverized stem bark of A. boonei was defatted with petroleum ether and extracted with diethylether (DE), ethylacetate (EA), ethanol (EtOH) and water (AQ). Their anticomplementary activity was investigated on classical (CP) and alternative (AP) pathways of complement-mediated haemolysis using human serum and antibody-sensitized sheep erythrocytes (CP) or rabbit erythrocytes (AP). Their effects on phagocytic activity of PMN was assessed by using PMNs isolated from venous blood of healthy volunteers, serum treated zymosan, and luminol solution. Chemiluinescence was induced by zymosan. Results: DE and EA extracts showed strong inhibition in the CP-mediated haemolysis whereas EtOH and AQ extracts showed little inhibition. None of the extracts inhibited AP-mediated haemolysis. The anticomplementary action of the active extracts increased with increase in temperature and time of preincubation. None of the extracts inhibited the chemiluminescence generated by stimulated PMNs. Conclusion: Some extracts of A. boonei stem bark (ABSB) have in vitro anticomplementary activity which is mediated through the classical pathway.The anticomplementary action may be the reason for its beneficial effect in rheumatoid arthritis.

Objective: To find out the prescribing practices in the B.P.Koirala Institute of Health Sciences with special emphasis on the utilization pattern of antimicrobial agents (AMA) and to compare with the drug prescribing practice of physicians in developed countries. Methods: A prospective cross sectional study was conducted in the month of October 1996. Prescriptions were collected from all the 94 in-patient case records and usingWHO basic drug indicators, the prescribing pattern was analysed. Results: Prescription analysis showed that the bed occupancy rate, out of 200 beds, was 47%. The average number of drugs per prescription was 5.26. 84% of all prescriptions contained AMA. It was the most commonly prescribed (42.8%) group of drugs followed by anti-inflammatory and analgesics (13.1%). Cloxacillin was the most commonly prescribed AMA followed by ampicillin. Ciprofloxacin plus metronidazole combination was the most frequently used. Prophylactic use of AMA was more in surgical departments. Therapeutic and prophylactic uses of AMA were appropriate only in 30.2% and 55.6% of cases respectively. The use of injections was frequent as evidenced by a mean of 2.12 injections per prescription. The duration of treatment was not mentioned for 45.6% of all the drugs prescribed. Conclusion: The results indicate that there is a scope for improving prescribing habits and minimizing the use of AMA. This could be facilitated by periodic prescribers education.

Objective: To investigate the effect of acetone soluble fraction of petroleum ether extract of Lawsonia inermis leaves on memory, anxiety and behaviour mediated via monoamine neurotransmitters. Methods: The effect of acetone soluble fraction of pet. ether extract of Lawsonia inermis on memory was assessed using elevated plus maze and passive shock avoidance paradigms.The effects on clonidine induced hypothermia.lithium induced head twitches and haloperidol induced catalepsy were observed to study the effect on noradrenaline, serotonin and dopamine mediated behaviour respectively Results: The acetone fraction of pet.ether extract of L. inermis exhibited prominent nootropic activity, potenttated clonidine induoed hypothermia and decreased lithium induced head twitches. However, the haloperidol induced catalepsy was not modified. Conclusion: The acetone soluble fraction of pet. ether extract exhibited prominent nootropic activity.The fraction modified 5-HT and NA mediated behaviour. It is concluded that the leaves of L. inermis possess a potential for exploring a nootropic principle.

Objectives: To evaluate the relationship between centrally situated noradrenergic, adenosine-A, and GABAB receptors particularly because activation of each of them is known to inhibit gastric acid secretion. Methods: The total gastric acid output over a period of 4 h was investigated in pylorus ligated conscious rats who had received following i.c.v. treatments through a chronically implanted screw cannula in skull. In the first set of experiments rats were treated with an agonist i.e. either noradrenaline (NA,1 'g/rat) or balcofen (5'g/rat) or (-) N6 phenyl isopropyladenosine (L-PIA,10 'g/rat) just after the pylorus ligation. In the second set of experiments the rats received either prazosin ((-adrenergic blocker, 5 'g/rat) or 8 phenyltheophylline (8-PT, adenosine A, antagonist, 50'g/rat) or phaclofen (GABAB antagonist, 5 'g/ rat) 20 minutes prior to the administration of either NA (1 'g/rat) or baclofen (5 'g/rat) or L-PIA (10 'g/rat). Results : The i.c.v. administration of NA, L-PIA and baclofen significantly inhibited gastric acid output in pylorus ligated conscious rats. Prior treatment of rats with prazosin attenuated the antisecretory effect of NA as well as L-PIA, whereas the effect of baclofen remained unaffected. 8-PT and phaclofen, however, could only attenuate the antisecretory effect of L-PIA and baclofen respectively. Conclusion: The centrally situated adenosine-A, receptors operate through (-adrenergic receptors while inhibiting gastric acid secretion. The activation of centrally situated phaclofen sensitive GABAB receptors independently inhibit acid secretion and does not bear any relation with centrally situated (-adrenergic or adenosine-A, receptors.

Objectives: To evaluate the bioavailability of rectally administered diltiazem hydrochloride in rabbits Methods: Compressed rectal suppositories of diltiazem hydrochloride were formulated employing polyethylene glycol 4000 as base. The bioavailability of diltiazem hydrochloride from rectal suppositories was compared with that of oral administration of same dose of the drug. This study was carried out in a randomized cross over design and various pharmacokinetic parameters were calculated. Results: The maximum serum concentration (Cmax) and area under the curve (AUC0-() were significantly (p<0.05) higher in the case of rectal administration compared to oral administration. However, there was no significant difference in time for peak serum concentration (tmax) and elimination half-life (t1/2) for both rectal and oral route. Conclusions: The relative bioavailability of diltiazem hydrochloride was about 75% greater after rectal administration compared to oral route.This may be due to the avoidance of biotransformation of diltiazem by liver, intestine and lungs.

Objective: To develop mast cells in vitro from mouse bone marrow using concanavalin-A stimulated splenocyte supernatant. Methods: Bone marrow cells (BMCs) were cultured in 1:1 (vol/vol) mixture of enriched medium (RPMI-1640 with 10% fetal calf serum with L-glutamine, 2 mM HEPES buffer, NaHCO3 (2.0 gm/L) and gentamicin (40 mg/L) and conditioned medium (conmed) derived from concanavalin-A (Con-A; 2.5 'g/ml) stimulated mouse splenocyte. Results: After culturing mouse bone marrow cells for seven days approximately 1 O-l 5% of cells began to show metachromatic granules with toluidine blue which suggested that these were mast cells. After 14 days of culture around 74-80% cells were identified as mast cells and heterogenous with respect to density of metachromatic granules. Maximum differentiation of bone marrow cells into mast cells were observed when conditioned medium and fresh medium dilution was 1:1 (vol/vol). when dilution of conditioned medium was 16x, 32x. 64x and 128x, lesser conversion of BMCs into mast cells were observed. Conclusion:The development of mast cells from bone marrow precursor cells in the presence of Con-A stimulated splenocyte supernatant suggested that T-cell derived growth factor had differentiated bone marrow cells into mast cells in vitro when its optimal concentration was used.

0bjectives:To study the effect of size and charge of the liposome on the biodistribution of encapsulated 99m Tc-DTPA after intravenous injection into rats. Methods: Multilamellar (MLV) and small unilamellar (SUV) vesicles were prepared, each having positive, negative and neutral charge. 99mTc-DTPA was encapsulated into each of these liposomes as a marker of aqueous phase. Radioactivity at 3, 30 and 60 minutes in blood, liver, spleen, lungs and kidneys was measured. Results: MLVs were taken up to a greater extent as compared to SUVs in liver, spleen and lungs. Positively charged MLVs were taken up to a greater extent in liver as compared to neutral and negatively charged MLVs. In kidneys there was greater uptake of positively charged SUVs which was not significantly different from positively charged MLVs. Charge of MLV did not affect its uptake by kidney and spleen. Liposome encapsulated 99mTc-DTPA remained in circulation for a longer time as compared to free 99mTc-DTPA. Neutral MLVs were taken up to a greater extent by lungs at 1 h as compared to charged liposomes. Conclusions: Positively charged MLVs could be used to target drugs to liver. Positively charged SUVs could be more effective to target drugs to kidneys. MLVs could be used to target drug to spleen irrespective of charge.