Scientific evaluation of Ayurvedic drugs - the use of N-of-1 clinical trials.

Despite its ancient roots and prominence in India as an accepted alternative to modern medicine, Ayurveda's growth has been hampered by an inability to carry out clinical studies of its effectiveness and safety using modern scientific methods - while preserving the core of Ayurveda, which is personalised medicine. In this comment, we propose that the N-of-1 trial be used as a practical method to evaluate Ayurvedic treatments, which is simultaneously consistent with the canons of modern medicine and of Ayurveda. We emphasise the importance of doing this as a practical alternative that will benefit patients. We need not wait to resolve the epistemic inconsistency between Ayurveda and modern medicine to take steps in this direction.

Present status of Catharanthus roseus monoterpenoid indole alkaloids engineering in homo- and hetero-logous systems.

Catharanthus roseus synthesizes one of the most structurally, chemically and biologically active phytomolecules monoterpenoids indole alkaloids (MIAs) with having a wide range of pharmaceutical activities. Being the sole source of antineoplastic MIAs vinblastine and vincristine C. roseus has become one of the most valued plant. The low in planta availability of these MIAs and unavailability of alternative chemical synthesis system has enhanced their demand and equally let to the exorbitant market cost. To bridge this gap alternative production systems have been investigated using MIAs metabolic engineering (ME) in the homologous and heterologous systems. The availability of improved recombinant technologies along with genomics and metabolomics tools has opened the door of tremendous new potentials of ME. To encash these potentials of ME for MIAs pathway, efforts were made by expressing constitutive structure biosynthesis enzymes, transporters, and transcription factors of C. roseus MIAs biosynthesis in both homologous and heterologous systems. Here we review the knowledge of C. roseus MIAs pathway metabolic engineering in homologous and heterologous systems, gained in the past 35 years of C. roseus research.

Recent advancements in supporting materials for immobilised photocatalytic applications in waste water treatment.

The aim of this paper is to provide a review on the usage of different anchoring media (supports) for immobilising commonly employed photocatalysts for degradation of organic pollutants. The immobilisation of nano-sized photocatalysts can eliminate costly and impractical post-treatment recovery of spent photocatalysts in largescale operations. Some commonly employed immobilisation aids such as glass, carbonaceous substances, zeolites, clay and ceramics, polymers, cellulosic materials and metallic agents that have been previously discussed by various research groups have been reviewed. The study revealed that factors such as high durability, ease of availability, low density, chemical inertness and mechanical stability are primary factors responsible for the selection of suitable supports for catalysts. Common techniques for immobilisation namely, dip coating, cold plasma discharge, polymer assisted hydrothermal decomposition, RF magnetron sputtering, photoetching, solvent casting, electrophoretic deposition and spray pyrolysis have been discussed in detail. Finally, some common techniques adopted for the characterisation of the catalyst particles and their uses are also discussed.

Pharmacokinetics, toxicity, and functional studies of the selective Kv1.3 channel blocker 5-(4-phenoxybutoxy)psoralen in rhesus macaques.

The small molecule 5-(4-phenoxybutoxy)psoralen (PAP-1) is a selective blocker of the voltage-gated potassium channel Kv1.3 that is highly expressed in cell membranes of activated effector memory T cells (TEMs). The blockade of Kv1.3 results in membrane depolarization and inhibition of TEM proliferation and function. In this study, the in vitro effects of PAP-1 on T cells and the in vivo toxicity and pharmacokinetics (PK) were examined in rhesus macaques (RM) with the ultimate aim of utilizing PAP-1 to define the role of TEMs in RM infected with simian immunodeficiency virus (SIV). Electrophysiologic studies on T cells in RM revealed a Kv1.3 expression pattern similar to that in human T cells. Thus, PAP-1 effectively suppressed TEM proliferation in RM. When administered intravenously, PAP-1 showed a half-life of 6.4 hrs; the volume of distribution suggested extensive distribution into extravascular compartments. When orally administered, PAP-1 was efficiently absorbed. Plasma concentrations in RM undergoing a 30-day, chronic dosing study indicated that PAP-1 levels suppressive to TEMs in vitro can be achieved and maintained in vivo at a non-toxic dose. PAP-1 selectively inhibited the TEM function in vivo, as indicated by a modest reactivation of cytomegalovirus (CMV) replication. Immunization of these chronically treated RM with the live influenza A/PR8 (flu) virus suggested that the development of an in vivo, flu-specific, central memory response was unaffected by PAP-1. These RM remained disease-free during the entire course of the PAP-1 study. Collectively, these data provide a rational basis for future studies with PAP-1 in SIV-infected RM.

Allium sativum constituents: effect on free radical generation from rat neutrophils.

Reactive oxygen species formation or respiratory burst by the neutrophils helps to remove the invaded pathogens and thus constitute a major defense against pathogenic microorganisms. Production of these radicals by activated neutrophils at the site of inflammation however inflicts damage to the host tissue. Modulation of the neutrophil respiratory burst is therefore important in determining the balance between immune defense and host tissue injury during inflammatory conditions. Garlic extracts and various compounds isolated from garlic have been found to possess various activities, however no report is available on their effect on neutrophil free radical generation. The present study was therefore undertaken to evaluate the effect of garlic aqueous extract, alcoholic extract and various fractions on the free radical generation from neutrophils. Among the tested fractions, chloroform fraction of garlic seems to be very potent in attenuating the free radical generation from rat neutrophils, which could be beneficial in the inflammation associated pathological conditions.

Evaluation of antimuscarinic activity in human volunteers: a teaching aid in clinical pharmacology.

The antimuscarinic activity of oxyphenonium bromide, diphenhydramine hydrochloride and astemizole were evaluated in six volunteers. The parameters used were salivary secretion, heart rate and pupillary size. The results indicated that the changes in heart rate and pupillary size and measurements were not convenient parameters for class room demonstration. However, salivary secretion and dryness of mouth were found to be reliable parameters for measurement. It was concluded that simple procedures like evaluation of antimuscarinic activity could be introduced as teaching aids in clinical pharmacology for undergraduate students.

Possible mechanism of endosulfan-induced enhancement of memory acquisition and retention in mice.

The effects of pre-training and post-training administration of endosulfan on retention of a step-down passive avoidance task was studied in mice. Endosulfan at doses of 1.0 mg/kg(ip) and 2.0 mg/kg(ip) enhanced memory acquisition and retention. This effect of endosulfan was possibly mediated by interaction with cholinergic neurotransmission, as scopolamine (0.5 mg/kg, ip) significantly antagonized the memory enhancing effects of endosulfan. Clonidine (0.05 mg/kg, ip) did not have any effect on enhancement of memory produced by endosulfan, thus indicating possibly no role of noradrenergic system.

BRL 38227--a potassium channel opener, antagonizes digoxin-induced convulsions.

Experimental evidence suggests that potassium channel openers play an important role in convulsions. In this study, the anticonvulsant activity of BRL 38227, a new potassium channel opener against digoxin-induced convulsions, is reported. Intraventricular administration of digoxin (7.5 micrograms), included "popcorn-type" convulsions in rats. BRL 38227, injected centrally increased the onset time of convulsions and decreased the mortality rate in a dose-dependent manner. Pretreatment with 4-aminopyridine, a potassium channel blocker antagonized the protective effect of BRL 38227. These findings show the involvement of potassium channels in digoxin-induced convulsions. Further these results indicate that in the future potassium channels might be a target for new anticonvulsant drugs.

Effects of ranitidine alone and in combination with chlorpheniramine on histamine-induced wheal and flare and psychomotor performance.

Some reports suggest that addition of an H2 antagonist increases the efficacy of H1 antagonist but the influence on the side effect profile of antihistamines are largely unknown. The effects of ranitidine, chlorpheniramine, their combination and placebo on histamine induced wheal and flare, psychomotor performance and subjective symptoms were studied in 6 healthy male volunteers in a double blind randomized and cross-over (Latin square) study. Ranitidine significantly reduced the histamine induced wheal at 4 hrs (P < 0.05). Chlorpheniramine and the combination significantly reduced both histamine induced wheal and flare at 2 hrs and at 4 hrs (P < 0.05). Addition of ranitidine reduced the feeling of sleepiness produced by chlorpheniramine, though other subjective symptoms were not affected. None of the treatment schedules produced any consistent change in the psychomotor performance of the volunteers.

MK-801 antagonizes the lethal action of centrally and peripherally administered cypermethrin in mice and rats.

The present study investigated the effect of MK-801, an N-methyl-D-aspartate antagonist, on the convulsant lethal action of cypermethrin administered centrally or peripherally. Cypermethrin produced severe convulsions and death in a dose-dependent manner. MK-801 (0.5, 1 and 2 mg kg-1, intraperitoneally) significantly increased the onset time of convulsions and decreased the mortality in the peripherally treated cypermethrin group. MK-801 (1.0 and 2.0 mg kg-1) attenuated the convulsant action of cypermethrin (50 micrograms, intracerebroventricularly) significantly. Survival rate was also increased significantly. However, MK-801 (0.5 mg kg-1) did not produce any significant protective effect against centrally administered cypermethrin. These results suggest excitatory amino acids to be a target for pyrethroid-induced neurotoxicity.

Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in diazepam-dependent rats.

The effects of two calcium channel blockers (verapamil and cinnarizine) were evaluated on diazepam withdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg IP for 3 weeks. On abrupt termination of the drug, animals showed withdrawal hyperactivity that was assessed by autonomic, behavioural and motor signs. The peak effect was seen 3 days after the withdrawal of diazepam. On IP administration, verapamil and cinnarizine (10, 20 and 40 mg/kg) given on eight occasions at an interval of 12 h reversed the withdrawal-induced increase in spontaneous motor activity. Cinnarizine in higher doses (20 and 40 mg/kg) was found to be effective in suppressing the behavioural signs but verapamil did not show any protective effect against startle response and irritability. These results suggest that modulation of the calcium influx in the CNS might influence withdrawal.

A comparative study of intravesical instillation of 15(s) 15 Me alpha and alum in the management of persistent hematuria of vesical origin.

A prospective randomized, controlled study was done to compare the efficacy and safety of 15(s) 15 Me PGF2 alpha intravesical instillation and 1% alum vesical irrigation in the control of vesical hematuria which persisted even after continuous bladder irrigation with normal saline for 24 hours. Ten patients were treated with 15(s) 15 Me PGF2 alpha intravesical instillation in a dose of 1 mg daily for a maximum of 5 days. Six patients had complete cessation of macroscopic hematuria and partial control was seen in another 2 patients. Failure of control was seen in 2 patients. Nine patients were treated with 1% alum irrigation of bladder at a rate of 5 ml/min for a maximum period of 72 hours. Complete cessation of hematuria occurred in 6 patients and partial control in the other 3 patients. Bladder spasms was a common side effect of both drugs (19/19). Frequent catheter blockade (7/9) and recurrence of bleeding (3/9) were also seen with alum therapy. No systemic side effects occurred during therapy with both drugs. Alum, due to its safety and efficacy remains the drug of first choice for persistent vesical hematuria. High cost, low availability and stringent storage conditions are drawbacks for routine use of 15(s) 15 Me PGF2 alpha, however, PGF2 alpha promises to be a safe and effective alternative method and might be of great value in cases of alum failure as observed in two of our cases (9 and 10).

Memory enhancing effects of granisetron (BRL 43694) in a passive avoidance task.

Recent evidence suggests that serotonin plays an important role in learning and memory processes in animals. The present study examined the effect of the 5-HT3 receptor antagonist, granisetron (BRL 43694), on acquisition, retention and retrieval of a passive avoidance response in mice. Granisetron (1 and 10 micrograms/kg) administered 30 min before presentation of footshock increased the step-down latency when tested 24 h after footshock. The acquisition process was not affected by a dose of 100 micrograms/kg. Granisetron (10 and 100 micrograms/kg) produced a significant increase in latency to step out of the safety zone, when administered immediately after or 23.5 h after footshock. However, at 1 microgram/kg, granisetron had no effect. These results confirm the important role played by 5-HT in the process of learning and memory, and also suggest that memory enhancement may be possible with non-cholinergic treatments.

The effect of diclofenac sodium on urinary concentration of calcium, uric acid and glycosaminoglycans in traumatic paraplegics.

Non-steroidal anti-inflammatory drugs (NSAID) have been shown to decrease calcium excretion in the experimental animal, in human volunteers and in calcium stone formers. Paraplegics tend to be hypercalciuric during the first 2 years after their injury and this is said to be a predisposing factor for stone formation in these patients. The effect of the NSAID diclofenac sodium was studied in 12 traumatic paraplegics who had sustained their injury 1 to 6 months previously; 24-h urine samples collected before and 2 weeks and 4 weeks after oral diclofenac sodium 50 mg tds were analysed for calcium, uric acid, glycosaminoglycans (GAGs) and volume. There were no significant changes in urinary volume, uric acid and GAGs excretion. However, urinary calcium concentration and 24-h calcium excretion decreased significantly following 2 weeks' and 4 weeks' treatment with diclofenac sodium.

Assessment of preclinical vitamin A deficiency in children with persistent diarrhea.

To explore the relationship between vitamin A deficiency and persistent diarrhea among young children, we studied the vitamin A status of 23 children greater than 5 years of age with persistent diarrhea by performing conjunctival impression cytology (CIC) and the relative dose-response test (RDR) as a measure of liver reserve of vitamin A. The control group consisted of 23 age- and sex-matched children who were otherwise healthy in whom CIC was performed and fasting plasma retinol values were determined. The criteria for vitamin A deficiency in CIC were paucity of goblet cells and scanty, abnormal epithelial cells. None of these children had ocular manifestations of vitamin A deficiency. Among the children with persistent diarrhea, CIC characteristic of vitamin A deficiency was found in 17 (group 1) and CIC results were normal in six (group 2). In group 1, the serum retinol levels were 1 +/- 1 microgram/dl, and RDR was 88 +/- 14. In group 2, the serum retinol levels were 8 +/- 4 micrograms/dl (p less than 0.001) and the RDR was 16 +/- 12 (p less than 0.001). In the control group, the CIC results were normal in all the children and the plasma retinol levels in these children were 19 +/- 8 micrograms/dl. In conclusion, 17 of 23 children with persistent diarrhea had abnormal CIC results, significantly low serum retinol levels, and significantly high RDR results, although they had not yet manifested xerophthalmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Post-coital antifertility action of Ruta graveolens in female rats and hamsters.

Different preparations of Ruta graveolens were administered orally to female rats (Days 1-10 post coition) and female hamsters (Days 1-6 post coition). The powdered root (CDR), aerial parts (CDA) and the aerial parts aqueous extract (AEA) all showed potential anticonceptive activity in rats. Limited administration on selected days of CDA showed uniformly lesser activity than with 10-day treatment. Sequentially prepared petroleum ether and methanol extracts of CDA were as active as CDA itself. The benzene and chloroform extracts were toxic and inactive. Rutin, a known chemical constituent of the plant, was found to be inactive. None of the above preparations showed activity in hamsters.

Enhancement of memory retrieval and attenuation of scopolamine-induced amnesia following administration of 5-HT3 antagonist ICS 205-930.

Experimental evidence suggests an important role of serotonin in the process of learning and memory. The present study investigated the effect of 5HT3-receptor antagonist (ICS 205-930) on retrieval of a previously learned aversive habit in the mouse. The effect of ICS 205-930 on scopolamine (3 mg/kg) induced amnesia was also studied. ICS 205-930 (1, 10 & 100 micrograms/kg) produced a dose-dependent increase in latency to cross into the dark chamber. The scopolamine induced memory impairment was significantly attenuated by ICS 205-930 (10 micrograms/kg). These results suggest that memory deficits may be susceptible to attenuation with non-cholinergic treatments.

Possible mechanism of haloperidol-induced enhancement of memory retrieval.

The effects of pretest administration of haloperidol on retention of a step-through passive avoidance task was studied with a 3-day training and retention test interval. Haloperidol at doses of 0.3 mg/kg and 0.5 mg/kg i.p. enhanced memory retrieval. This effect of haloperidol is possibly mediated by interaction with alpha 2-adrenergic receptors, that results in increasing the noradrenergic transmission, or it could be due to direct interaction with dopamine receptors. Yohimbine (2.5 mg/kg) also enhanced memory retrieval, as shown by haloperidol. Clonidine (0.05 mg/kg) significantly antagonized the effect of haloperidol on memory retrieval. Scopolamine (0.5 mg/kg) did not have any effect on enhancement of memory produced by haloperidol.

Effect of subacute insecticide exposure on body weight, drug responses & electrical convulsions in mice.

Effect of subacute insecticide exposure was studied in male albino mice treated with phosphamidon, propoxur or aldrin at 1/40 LD50 dose intraperitoneally daily for 8 wk. The parameters studies included body weight, pentobarbitone (50 mg/kg) sleeping time, chlorpromazine (6 mg/kg) induced motor incoordination and convulsions induced by leptazol (100 mg/kg) and electrical stimulation (18 mA for 0.2 msec). While body weight and electrically induced convulsions were not affected, the effect of various drugs was significantly decreased. The observed changes may be due to the induction of hepatic drug metabolising enzymes by the insecticides. The study suggests that certain dose adjustment of drugs may be necessary in those exposed to insecticides over long periods.