P. Usha Rani

A randomized, double blind, placebo controlled, cross over study to evaluate the analgesic activity of Boswellia serrata in healthy volunteers using mechanical pain model

Objective: Experimental pain models in human healthy volunteers are advantageous for early evaluation of analgesics. All efforts to develop nonsteroidal anti-inflammatory drugs (NSAIDs) which are devoid of gastrointestinal and cardiovascular system effects are still far from achieving a breakthrough. Hence we evaluated the analgesic activity of an ayurvedic drug, Boswellia serrata by using validated human pain models which has shown its analgesic activity both in-vitro and preclinical studies to evaluate the analgesic activity of single oral dose (125 mg, 2 capsules) of Boswellia serrata compared to placebo using mechanical pain model in healthy human subjects. Materials and Methods: After taking written informed consent, twelve healthy subjects were randomized (1:1) to receive single oral dose of Boswellia serrata (Shallaki®) 125 mg, 2 capsules or identical placebo in a crossover design. Mechanical pain was assessed using Ugo basile analgesymeter (by Randall Selitto test) at baseline and at 1 hr, 2 hrs and 3 hrs after test drug administration. Pain Threshold force and time and Pain Tolerance force and time were evaluated. Statistical analysis was done by paired t-test. Results: Twelve healthy volunteers have completed the study. Mean percentage change from baseline in Pain Threshold force and time with Boswellia serrata when compared to placebo had significantly increased [Force: 9.7 ± 11.0 vs 2.9 ± 3.4 (P = 0.05) and time: 9.7 ± 10.7 vs 2.8 ± 3.4 (P = 0.04)] at third hr. Mean Percentage change from baseline in Pain Tolerance force and time with Boswellia serrata when compared to placebo had significantly (P ≤ 0.01) increased at 1 hr, 2 hrs and 3 hrs. Conclusion: In the present study, Boswellia serrata significantly increased the Pain Threshold and Pain Tolerance force and time compared to placebo. Both study medications were well tolerated. Further multiple dose studies may be needed to establish the analgesic efficacy of the drug.

Phase 0 - Microdosing strategy in clinical trials

Drug development is an activity that is long, complex and expensive. In 2004, attrition in the drug development paradigm prompted the US Food and Drug Administration (FDA) to introduce its ‘Critical Path’ document, which highlighted the serious discordance between major scientific advances and limited drug development process. One issue addressed was that of microdosing. The concept of microdosing involves the use of extremely low, nonpharmacologically active doses of a drug to define the pharmacokinetic profile of the medication in human subjects. Microdosing, thus, appears as a new viable concept in the ‘toolbox’ of the drug development activity. It appears that microdosing strategy could complement standard animal-to-human scaling, redefining the existing concept of phase I clinical research. In future, when research methods and technology involved in Phase 0 studies become more sophisticated, human microdosing may be applied to a number of drugs developed subsequently.

A randomised, double-blind, parallel, placebo-controlled study to evaluate the efficacy of MF 5232 (Mucotrol), a concentrated oral gel wafer, in the treatment of oral mucositis.

AbstractObjective: Oral mucositis is a major complication of cytotoxic chemotherapy and radiotherapy associated with significant morbidity, pain, odynophagia, dysgeusia and subsequent dehydration and malnutrition, and effective prophylaxis and/or treatment of this condition is essential. The currently available palliative treatment shows improvement only in patients with mild to moderate mucositis. The primary aim of this study was to compare the clinical efficacy of MF 5232 (Mucotrol™), a concentrated oral polyherbal gel wafer formulation, with placebo in the management of chemoradiation-induced mucositis in cancer patients. Patients and design: In this randomised, double-blind, pilot study a total of 30 patients of either sex with chemoradiation-induced oral mucositis were randomised to receive MF 5232 (n = 15) or a matching placebo (n = 15) after food three times a day for 7–10 days. Patients were evaluated using validated and standardised scoring systems at baseline and after 7–10 days of treatment. Results: There were 11 evaluable patients in each treatment group. There was a significant reduction in mean mucositis scores with MF 5232 as follows: WHO (from 3.0 to 1.8), Radiation Therapy Oncology Group (gross score: from 2.8 to 1.8; functional score: from 2.9 to 1.0), and Objective Scoring System (ulceration score: from 7.4 to 4.4; erythema score: from 13.7 to 7.0). There were no significant changes in scores for placebo recipients. The treatments were well tolerated, with the exception of two patients in the treatment group who reported a burning sensation in the mouth after dissolving the wafer. Conclusion: This pilot study provided positive evidence for the efficacy of MF 5232 therapy in chemoradiation-induced mucositis. This was probably a result of its local analgesic, antioxidant and immunomodulatory activity and wound-healing properties. Further in-depth analysis in a larger number of patients is required to confirm these positive results.

A bioequivalence study of two brands of sumatriptan tablets

Abstract In this double-masked, randomized, crossover, bioequivalence study, two 100-mg tablet preparations of sumatriptan (Suminat ® and Imigran ® ) were compared in 12 healthy male subjects (mean ± SD age, 25 ± 6 years). Pharmacokinetic variables—mean maximum plasma concentration, time to reach mean maximum plasma concentration, and the mean area under the plasma concentration-time curve—were not statistically significantly different for the two treatment groups. Vital variables, such as blood pressure and heart rate, also did not show any significant between-group differences. Statistical analysis revealed no difference in the two formulations. In can be concluded that the two tablet preparations of sumatriptan are likely to be bioequivalent.

Sumatriptan Delays Paracetamol Absorption in Migraine Patients

SummaryThe effect of sumatriptan 100mg orally on paracetamol absorption was evaluated in 9 migraine patients. Sumatriptan pretreatment significantly lowered the peak paracetamol concentration and also delayed the time to reach peak concentration. The paracetamol peak concentration decreased significantly from 36.28 ± 10.85 mg/L to 18.26 ± 6.7 mg/L, and the time to reach the peak was significantly delayed from 1.36 ± 0.38 hours to 2.72 ± 1.0 hours after sumatriptan treatment. The rate of absorption of paracetamol up to 3 hours was significantly reduced after sumatriptan administration. At 2 hours after sumatriptan administration, only 67% of total paracetamol was absorbed, while the absorption was 97% without sumatriptan. The total absorption of paracetamol at the end of the 8th hour was, however, not affected. These results suggest that in migraine patients there is a delay in gastric emptying time with sumatriptan. Further studies are warranted during the acute attack to elucidate the clinical significance of the present study findings.

Recent trends in the nitrergic nervous system

The late 20th century witnessed the novel discovery of Nitrergic or Nitroxidergic innervation of the vascular smooth muscles, their role as a vasodilator in cerebral, ocular and penile vasculature, as well as their reciprocal action to adrenergic vasoconstriction. The identification of this nerve as a postganglionic parasympathetic nerve, the discovery of autonomic efferent nerves where Nitric oxide (NO) is the neurotransmitter (NTM) to blood vessels, its physiological role in the control of smooth muscle tone, and the pharmacological implications of NO have been reviewed. This will aid an in-depth analysis of vascular dysfunctions and the development of strategic pharmacotherapeutic interventions with time.

A simple thermal pain model for the evaluation of analgesic activity in healthy subjects

Objective: Assessment of the analgesic effect of an agent in an experimental pain model permits a level of control not possible in a clinical pain setting and is an ideal approach for evaluation of analgesic drugs. The aim of the present study was to establish a simple and reliable method of producing experimental pain, which can be used for screening of various analgesic agents. Materials and Methods: The standardized method was followed in all cases, by recording thermal pain threshold in seconds in 24 healthy volunteers using hot air source at two different speeds, which is equipped in an acrylic-made chamber adjustable to three different levels. Reproducibility of the test procedure was evaluated by recording the thermal threshold parameter by a single observer on two sessions (interday reproducibility) and second observer on one session (interobserver reproducibility) separately. Validity of model was further tested by evaluating the analgesic effect of tramadol on 12 healthy volunteers. Results: Thermal pain model was found to produce low variability with coefficient of variation (CV) less than 10%. Interobserver and interday reproducibility were very good, as shown by Bland–Altman plot, with most of the values within ± 2SD. There was a significant increase in pain threshold time with use of tramadol as compared to placebo which was statistically significant (P < 0.05). Conclusion: The newly developed pain model offers a stable and sensitive method for the early assessment of analgesic activity.

Pharmacodynamic interaction study of Allium sativum (garlic) with cilostazol in patients with type II diabetes mellitus

Aim: Garlic is available as an over-the-counter herbal supplement and is known to have antiplatelet properties. Because of scarcity of clinical data regarding the safety of concomitant use of garlic supplements and anticoagulants, we tried to evaluate the effects of coadministration of single and multiple doses of garlic and cilostazol on platelet aggregation. Materials and Methods: The study was a randomized, open label, placebo-controlled, crossover study of type II diabetic patients, where 14 patients were enrolled and 10 completed the study. The patients were administered 600 mg aged garlic extract, 100 mg cilostazol, 600 mg aged garlic extract, and cilostazol or placebo for seven days as per prior randomization schedule. Blood samples for platelet aggregation and bleeding time and clotting time were collected before and 2, 4, and 6 hours after single-dose drug administration and after seven days of treatment. Results: After single- and multiple-dose administration of garlic, there was a significant inhibition of platelet aggregation at 2 hours, whereas with cilostazol, the inhibition was significant at all the three time points tested, with 4 hours showing maximum inhibition. Coadministration of garlic and cilostazol in single and multiple doses for seven days did not produce any significant change in the antiplatelet activity of the individual drugs. Conclusions: Coadministration of aged garlic extract and cilostazol did not enhance the antiplatelet activity compared with individual drugs. Large randomized trials are needed to further evaluate the possible interaction of garlic in higher doses and in combination with other antiplatelet activity drugs.

Subjective and polysomnographic evaluation of a herbal preparation in insomnia

In the present study a polyherbal preparatian was evaluated for clinical efficacy and safety in insomnia by subjective and Polysomnographic method. Thirtynine patients were included. After placebo run-in period, 2 tablets of the test formulation were given daily at bed time for 21 days. Sleep parameters - onset, duration, number of awakenings, quality and daytime hangover were recorded on a diary card. Before and after treatment with the test drug, computerised polysomnography was performed to record sleep parameters - total sleep time, sleep latency, efficiency and wake period. During the course of treatment with active drug, incidence of side effect was noted. The present herbal preparation produced significant improvement in sleep parameters. In most of the patients total sleep was significantly increased. Mean total sleep time was increased from 344 ±11.4 min to 403 ±11.2 min (p<0.001). There [was significant reduction in mean sleep latency from 40 ± 4.3 min to 29 ± 3.2 min (p<0.001) and similarly, mean number of nocturnal awakening decreased from 1.6 ± 0.12 to 1.03 ± 0.08 (p<0.001). The subjective improvement was correlated with Polysomnographie parameters. Total sleep time increased from 204 ± 31 min to 262 ± 38.6 min. Wake period during sleep reduced from 275 ± 23 min to 191 ± 38 min and the persistence sleep latency from 85 ± 23 to 24 ± 5.7 min. The sleep efficiency improved from 42 ± 5.7%, to 57 ± 6.6% with herbal formulation. The sleep period from stage I-IV increased from 43 ±2.8% to 54 ±4.1%. There was improvement in sleep quality score from 1.5 ± 0.04 to 1.8 ± 0.04. Test drug did not produce any feeling of hangover or day time sleeplessness, 11 patients complained mild epigastric distress after test drug. It can be concluded that the herbal formulation has good hypnotic activity and can be used in insominia.

Renal Effects of Oral Ketorolac in Patients with Mild to Moderate Pain

SummaryThe effect of oral ketorolac on renal parameters was investigated in 12 patients who were prescribed ketorolac 10mg 4 times daily for 1 week for the management of mild to moderate pain. No other medication was allowed during the study period. All patients had blood urea, serum creatinine and serum potassium concentrations estimated prior to and 5 days after ketorolac therapy. A statistically significant increase was seen in blood urea levels (23.01 ± 6.98 to 28.58 ± 5.63 mg/dl) and serum creatinine concentrations (0.93 ± 0.17 to 1.22 ± 0.39 mg/dl) after ketorolac therapy, compared with a nonsignificant increase in serum potassium concentrations (3.9 ± 0.52 to 4.39 ± 0.97 mEq/L). Thus, monitoring of renal parameters may be advisable during short term oral ketorolac therapy.