Efficacy of Standardized Extract of Bacopa monnieri (Bacognize®) on Cognitive Functions of Medical Students: A Six-Week, Randomized Placebo-Controlled Trial.

Rationale. Bacopa monnieri, popularly known as Brahmi, has been traditionally used in Ayurveda since ages for its memory enhancing properties. However, data on placebo-controlled trial of Bacopa monnieri on intellectual sample is scarce. Hence this study was planned to evaluate the effect of Bacopa monnieri on memory of medical students for six weeks. Objective. To evaluate the efficacy of Bacopa monnieri on memory of medical students with six weeks' administration. Method and Material. This was a randomized double blind placebo-controlled noncrossover, parallel trial. Sixty medical students of either gender from second year of medical school, third term, regular batch, were enrolled from Government Medical College, Nagpur, India. Baseline biochemical and memory tests were done. The participants were randomly divided in two groups to receive either 150 mg of standardized extract of Bacopa monnieri (Bacognize) or matching placebo twice daily for six weeks. All baseline investigations were repeated at the end of the trial. Students were followed up for 15 days after the intervention. Results. Statistically significant improvement was seen in the tests relating to the cognitive functions with use of Bacopa monnieri. Blood biochemistry also showed a significant increase in serum calcium levels (still within normal range).

A simple cold pressure technique for the evaluation of analgesic drugs in healthy subjects.

AIM: An experimental pain model which is sensitive and reproducible would be a useful pharmacological tool both for existing and new 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 analgesic agents. MATERIALS AND METHODS: The method was standardized by recording pain threshold and pain tolerance values in 24 healthy volunteers. Reproducibility of the test procedure was evaluated by recording the pain threshold and pain tolerance values by a single observer on two sessions (inter-day reproducibility), and second observer in one session (inter-observer reproducibility), separately. Validity of the model was further tested by evaluating the analgesic effect of tramadol in 12 healthy volunteers. RESULTS: Cold pain model was found to produce low variability with coefficient of variation less than 15%. Inter-observer and inter-day reproducibility was very good as shown by Bland - Altman plot with most of the values within ± 2SD. Analgesic activity by Tramadol was statistically different from placebo (P < 0.05). CONCLUSION: The newly developed pain model offers a stable and sensitive method for the early assessment of analgesic activity.

Effect of beta-1-blocker, nebivolol, on central aortic pressure and arterial stiffness in patients with essential hypertension.

INTRODUCTION: Blood pressure (BP) reduction is the major determinant of benefit provided by antihypertensive treatment. Although different drugs reduce peripheral BP to some extent, there may be a significant difference in their effect on central BP reduction. It has been shown that beta-blockers are efficient in reducing peripheral, but not central BP. This study was done to assess the effect of beta-1-blocker, nebivolol, in patients with essential hypertension on central aortic pressures and arterial stiffness. MATERIALS AND METHODS: In this single arm, open-labeled study, 13 patients were given nebivolol, 5 mg orally once daily for 15 days. Primary outcome was change in central aortic pressure, and other measures of efficacy included changes in brachial BP, augmentation index (AIx%), AIx%@75 HR, augmentation pressure (AP), heart rate (HR), and carotid femoral pulse wave velocity (PWVcf). RESULTS: Nebivolol 5 mg significantly reduced central aortic pressures [systolic BP, 131.5-111.6 mmHg; diastolic BP, 96.3-81.7 mmHg; Mean Arterial Pressure (MAP), 111.3-94.0 mmHg (all P<0.0001), and Pulse Pressure (PP), 35.2-29.7 mmHg (P<0.01)]. AIx%@75 HR reduced from 29 to 21.6 (P<0.001) and PWVcf reduced from 8.6 to 7.2 m/s (P<0.001). One subject was lost to followup. CONCLUSION: Nebivolol 5 mg demonstrated antihypertensive efficacy in patients with essential hypertension by reducing not only peripheral brachial pressures, but also significantly reducing central aortic pressures, augmentation index, and carotid femoral pulse wave velocity, which is the marker of arterial stiffness.

Non-invasive measurement of aortic pressure in patients: Comparing pulse wave analysis and applanation tonometry.

OBJECTIVE: The aim of the present study was to validate and compare novel methods to determine aortic blood pressure non-invasively based on Oscillometric Pulse Wave Velocity (PWV) measurement using four limb-cuff pressure waveforms and two lead Electrocardiogram (ECG) with a validated tonometric pulse wave analysis system in patients. MATERIALS AND METHODS: After receiving the consent, in 49 patients with hypertension, coronary artery disease, diabetes mellitus, PWV, and central blood pressures were recorded in a randomised manner using both the oscillometric and tonometric devices. All recordings were performed 10 minutes after the patient lying comfortably in a noise-free temperature-controlled room. The test was performed between 09 am and 10 am after overnight fast. A minimum of three measurements were performed by the same skilled and trained operator. From the raw data obtained with two devices, software calculated the final vascular parameters. RESULTS: A total of 49 patients (8 women and 41 men), of mean age 40.5 years (range: 19-81 years) participated in the present study. After transforming the brachial pressures into aortic pressures, the correlation coefficient between the Aortic Systolic Pressure (ASP) values obtained with two methods was 0.9796 (P<0.0001). The mean difference between ASP with two methods was 0.3 mm Hg. Similarly, Aortic Diastolic Pressure (ADP) values obtained with two methods also correlated significantly with correlation coefficient of 0.9769 (P<0.0001). The mean difference of ADP was 0.2 mm Hg. In case of Aortic Pulse Pressure (APP), the mean difference was 0.1 mm Hg. All parameters of central aortic pressures obtained with two methods correlated significantly. CONCLUSION: The new method of transforming the Carotid Femoral PWV (cfPWV) and brachial blood pressure values into aortic blood pressure values seems to be reasonably good. The significant correlation between the values obtained by tonometric device and oscillometric PWV method shows that the latter can be used non-invasively in patients to find the aortic pressure.

The effect of L-arginine on arterial stiffness and oxidative stress in chronic kidney disease.

Chronic kidney disease (CKD) is a growing problem worldwide. The disproportionate increase in the burden of cardiovascular disease in patients with CKD may be significantly contributed by nontraditional risk factors. Increased arterial stiffness has been recognized as an important player in contributing to this morbidity and mortality. The aim of this study was to report the effect of L-arginine on arterial stiffness and oxidative stress in patients with CKD. Thirty patients with stage II to IV CKD were administered 9 g of L- arginine per day orally for a period of 12 weeks. The parameters evaluated at baseline, at 8 weeks, and at the end of 12 weeks were serum nitric oxide (NO), carotid.femoral pulse wave velocity (cf PWV), and radial artery pulse wave analysis which included aortic augmentation pressure (AP), aortic augmentation index (AIx), aortic augmentation index at heart rate of 75 bpm, subendocardial viability ratio, radial pressures, and central aortic pressure. Serum levels of NO and malondialdehyde (MDA) were estimated at baseline and at the end of 12 weeks. The control group was composed of age- and sex-matched healthy individuals. Twenty-five patients completed the study. Two patients were lost to follow.up; three patients developed adverse events and were excluded. Baseline NO levels were low (13.55 ± 7.49 µM/L) in all the subjects. Administration of L-arginine resulted in improvement in the carotid-radial PWV (m/s) (10.08 ± 1.72 at baseline to 8.56 ± 1.16 by 12 weeks; P < 0.001), cf PWV (m/s) (13.06 ± 2.65 at baseline to 10.62 ± 1.93 at 12 weeks; P < 0.001), Aortic Augmentation Index (%) (32 ± 10.34 at baseline to 17.84 ± 8.05 at 12 weeks; P < 0.001), aortic augmentation pressure (mm of Hg) (14.03 ± 6.53 at baseline to 7.12 ± 3.85 at 12 weeks; P < 0.001), and NO (µM/L) (13.55 ± 7.49 at baseline to 30.22 ± 9.8 at 12 weeks; P < 0.001). There was no significant change in the levels of MDA (nanomol/ml) (20.0 ± 10.14 at baseline and 19.16 ± 9.36 at 12 weeks; P = ns). In conclusion, PWV, an indicator of arterial stiffness, is greatly increased even in the early stages of CKD. Supplementation of L-arginine is a safe, well-tolerated, and effective way of improving endothelial dysfunction in patients with CKD.

Human experimental pain models: A review of standardized methods in drug development.

Human experimental pain models are essential in understanding the pain mechanisms and appear to be ideally suited to test analgesic compounds. The challenge that confronts both the clinician and the scientist is to match specific treatments to different pain-generating mechanisms and hence reach a pain treatment tailored to each individual patient. Experimental pain models offer the possibility to explore the pain system under controlled settings. Standardized stimuli of different modalities (i.e., mechanical, thermal, electrical, or chemical) can be applied to the skin, muscles, and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using a multimodel-multistructure testing, the nociception arising from different body structures can be explored and modulation of specific biomarkers by new and existing analgesic drugs can be profiled. The value of human experimental pain models is to link animal and clinical pain studies, providing new possibilities for designing successful clinical trials. Spontaneous pain, the main compliant of the neuropathic patients, but currently there is no human model available that would mimic chronic pain. Therefore, current human pain models cannot replace patient studies for studying efficacy of analgesic compounds, although being helpful for proof-of-concept studies and dose finding.

Development of a simple radiant heat induced experimental pain model for evaluation of analgesics in normal healthy human volunteers.

OBJECTIVE: Human experimental pain models help to understand the mechanism of the painful conditions and can also be adopted to test analgesic efficacy of drugs. In early phases, the clinical development of new analgesics is hindered due to the lack of reliable tests for the experimental pain models. In the present study, we have developed and validated a simple radiant heat pain model which can be used for future screening of various analgesic agents. MATERIALS AND METHODS: We have standardized the thermal pain model by recording pain threshold and pain tolerance time in seconds at three different intensities and levels in 24 healthy subjects. Reproducibility of the test procedure was evaluated by recording the pain parameters by two observers on three consecutive days. Validity of model was further tested by evaluating the analgesic effect of tramadol. RESULTS AND CONCLUSIONS: Use of radiant heat pain model with high intensity and short level was found to produce low variability with coefficient of variation less than 5%. Interobserver and interperiod reproducibility was very good as shown by Bland - Altman plot; with most of the values within ± 2SD. Tramadol produced statistically significant increase in pain threshold time. The newly developed pain model produces a type of experimental pain which is responsive to analgesic effects of tramadol at clinically relevant doses.

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.

Antitumor activity of NRC-AN-019 in a pre-clinical breast cancer model.

Breast cancer is the second most frequently diagnosed tumor in women. Overexpression of human epidermal growth factor receptors (EGFRs) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior and response to systemic therapy. In this study, we describe a novel compound (NRC-AN-019), which has better antitumor activity than Lapatinib. Here, we demonstrate that NRC-AN-019 is more effective in inhibiting angiogenic potential and proliferation of both MDAMB231 and HTB20/BT474 cells. FACS analysis shows that NRC-AN-019 treatment caused the accumulation of MDAMB231 and BT474 cells in the sub G0/1 phase in a dose-dependent manner and was accompanied by increased PARP cleavage, which is indicative of apoptosis. In addition, we observed inhibition of EGFR phosphorylation in both MDAMB231 and BT474 cells. From our animal studies using SCID mice implanted with BT474 cells, we observed dose-dependent inhibition of tumor growth in NRC-AN-019-treated animals compared to controls or Lapatinib-treated mice at comparable concentrations. The dose-dependent inhibition of EGFR phosphorylation was confirmed by immunohistochemical analysis of tumor sections. In vitro results demonstrate that NRC-AN-019 is superior to Lapatinib in EGFR-overexpressing cells and has strong anti-angiogenic, anti-proliferative and pro-apoptotic properties in an EGFR-overexpressing background (BT474). In vivo studies demonstrate that the antitumor activity of NRC-AN-019 is better over Lapatinib. These results suggest that NRC-AN-019 has greater therapeutic potential in the treatment of Her-2-positive breast cancer.

Oxidative stress in hemodialysis patients receiving intravenous iron therapy and the role of N-acetylcysteine in preventing oxidative stress.

To determine the contribution of injectable iron administered to hemodialysis (HD) patients in causing oxidative stress and the beneficial effect of N-acetylcysteine (NAC) in reducing it, we studied in a prospective, double blinded, randomized controlled, cross over trial 14 adult HD patients who were randomized into two groups; one group received NAC in a dose of 600 mgs twice daily for 10 days prior to intravenous iron therapy and the other group received placebo. Both the groups were subjected to intravenous iron therapy, 100 mg of iron sucrose in 100 mL of normal saline given over a period of one hour. Blood samples for the markers of oxidative stress were taken before and after iron therapy. After the allowance of a week of wash out period for the effect of N-acetylcysteine we crossed over the patients to the opposite regimen. We measured the lipid peroxidation marker, malondiaaldehyde (MDA), to evaluate the oxidative stress and total anti-oxidant capacity (TAC) for the antioxidant level in addition to the highly sensitive C-reactive protein (HsCRP). Non-invasive assessment of endothelial dysfunction was measured by digital plethysmography before and after intravenous iron therapy. There was an increase of MDA (21.97 + 3.65% vs 7.06 + 3.65%) and highly sensitive C-reactive protein (HsCRP) (11.19 + 24.63% vs 13.19 + 7.7%) after iron administration both in the placebo and the NAC groups. NAC reduced the baseline acute systemic generation of oxidative stress when compared to placebo, which was statistically significant with MDA (12.76 + 4.4% vs 9.37 + 4.40%: P = 0.032) but not with HsCRP though there was a declining trend (2.85 + 22.75 % vs 8.93 + 5.19%: P = 0.112). Pre-treatment with NAC reduced the endothelial dysfunction when compared to placebo, but it was not statistically significant, except for reflection index (RI). We conclude that in our HD patients NAC reduced the oxidative stress before and after the administration of intravenous iron therapy in addition to the endothelial dysfunction induced by this treatment.

Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study.

BACKGROUND AND OBJECTIVE: Hyperglycaemia leads to increased oxidative stress resulting in endothelial dysfunction. ACE inhibitors, antioxidants and HMG-CoA reductase inhibitors (statins) have been shown to improve endothelial function. The aim of this study was to compare the effects of NCB-02 (a standardized preparation of curcuminoids), atorvastatin and placebo on endothelial function and its biomarkers in patients with type 2 diabetes mellitus. METHODS: A total of 72 patients with type 2 diabetes were randomized to receive NCB-02 (two capsules containing curcumin 150 mg twice daily), atorvastatin 10 mg once daily or placebo for 8 weeks. Endothelial function assessment was performed at baseline and post-treatment using digital volume plethysmography (salbutamol [albuterol] challenge test) to measure change in reflective index, an indicator of arterial vascular tone. Blood samples were similarly collected at baseline and post-treatment for estimations of malondialdehyde, endothelin-1 (ET-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFalpha). Pre-and post-treatment safety assessments were also conducted. ANOVA and paired t-test evaluations were used for comparison. RESULTS: A total of 67 patients completed the study. At baseline, there was no significant difference in the various parameters tested. In all three groups, the change in reflective index at baseline was <6% as assessed by the salbutamol challenge test, indicating the presence of endothelial dysfunction. Compared with baseline, there was a significant improvement in endothelial function after treatment with atorvastatin (mean +/- SD: -3.63 +/- 3.17% vs -8.95 +/- 6.80%, respectively) and NCB-02 (-2.69 +/- 3.02% vs -8.19 +/- 5.73%, respectively). Similarly, patients receiving atorvastatin or NCB-02 showed significant reductions in the levels of malondialdehyde, ET-1, IL-6 and TNFalpha. No significant improvements were obtained in patients administered placebo. CONCLUSION: NCB-02 had a favourable effect, comparable to that of atorvastatin, on endothelial dysfunction in association with reductions in inflammatory cytokines and markers of oxidative stress. Further studies are needed to evaluate the potential long-term effects of NCB-02 and its combination with other herbal antioxidants.

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.

Influence of piperine on the pharmacokinetics of nevirapine under fasting conditions: a randomised, crossover, placebo-controlled study.

BACKGROUND: Nevirapine is a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase and is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. Piperine (1-piperoylpiperidine) is an alkaloid and the main pungency principle in both black and long pepper. There are indications that piperine inhibits, rather than stimulates, drug metabolism in most cases, thus increasing the bioavailability and effect of some drugs. METHODS: This was a crossover, placebo-controlled pilot study conducted in a total of eight healthy adult males aged 20-40 years. Subjects were randomly assigned to receive piperine 20mg or placebo each morning for 6 days, and on day 7, nevirapine 200mg plus piperine 20mg or nevirapine plus placebo in a crossover fashion. Blood samples were collected from 1 to 144 hours post-dose for pharmacokinetic analysis. RESULTS: Mean maximum plasma concentration (C(max)), area under the plasma concentration-time curve from 0 hours to the last measurable concentration (C(last)) [AUC(t)], AUC extrapolated to infinity (AUC(infinity)) and C(last) values of nevirapine were increased by approximately 120%, 167%, 170% and 146%, respectively, when co-administered with piperine. The treatments were well tolerated, indicating few or no clinical adverse effects. CONCLUSION: This pilot study provided evidence for enhanced bioavailability of nevirapine when administered with piperine. Further in-depth studies in a large number of patients receiving different dosage regimens are required to confirm these results and further our understanding of a possible clinical advantage arising from the bioenhancement capabilities of piperine in the treatment of HIV infection.

Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects.

AIMS: Ginkgo biloba is available as an over-the-counter drug and reported to cause haemorrhage when coadministered with other antiplatelet agents. We set out to study the interactions of G. biloba with cilostazol and clopidogrel. METHODS: A randomized, open-label, crossover study of 10 healthy male volunteers. The dosage schedules were 120 mg G. biloba, 240 mg G. biloba, 100 mg cilostazol, 200 mg cilostazol, 75 mg clopidogrel, 150 mg clopidogrel, 120 mg G. biloba+ 100 mg cilostazol and 120 mg G. biloba+ 75 mg clopidogrel. Platelet aggregation, platelet count, bleeding time and clotting time were measured 0 and 6 h after drug administration. Platelet aggregation was performed using a dual channel aggregometer, by the turbimetric technique using adenosine diphosphate 5 micromol and 10 micromol, and collagen 1 microg ml(-1). RESULTS: Platelet inhibition with the combination of G. biloba and clopidogrel or cilostazol was not statistically significant compared with individual doses of drugs, with all the three aggregants. There was significant (P < 0.05) potentiation of prolongation of bleeding time with the combination of cilostazol and G. biloba compared with individual doses of both the drugs. There was no significant change in clotting time and platelet count. CONCLUSIONS: Coadministration of G. biloba either with cilostazol or clopidogrel did not enhance antiplatelet activity compared with individual agents. Ginkgo biloba potentiated the bleeding time prolongation effect of cilostazol. There was no significant correlation between prolongation of bleeding time and inhibition of platelet aggregation.

Protective effect of CardiPro against doxorubicin-induced cardiotoxicity in mice.

The effect of CardiPro, a polyherbal formulation, with an antioxidant property, has been studied on doxorubicin (DXR)-induced cardiotoxicity in mice. CardiPro (150 mg/kg b.w., twice daily was administered orally for 7 weeks along with four equal injections (each containing 4.0 mg/kg b.w., DXR) intraperitoneally, once weekly (cumulative dose 16 mg/kg). After a 3-week post DXR treatment period, cardiotoxicity was assessed by noting mortality, volume of ascites, liver congestion, changes in heart weight, myocardial lipid peroxidation, antioxidant enzymes and histology of heart. DXR-treated animals showed higher mortality (50%) and more ascites. Myocardial SOD and glutathione peroxidase activity were decreased and lipid peroxidation was increased. Histology of heart of DXR-treated animals showed loss of myofibrils and focal cytoplasmic vacuolization. CardiPro significantly protected the mice from DXR-induced cardiotoxic effects as evidenced by lower mortality (25%), less ascites, myocardial lipid peroxidation, normalization of antioxidant enzymes and minimal damage to the heart histologically. Our data confirm the earlier reports that DXR cardiotoxicity is associated with the free radical-induced tissue damage. Administration of CardiPro, with an antioxidant property, protected the DXR-induced cardiotoxicity in mice.

Efficacy and tolerability of trandolapril in mild to moderate hypertension--a double blind comparative clinical trial with enalapril in Indian population.

Several large scale clinical trials have demonstrated that angiotensin converting enzyme inhibitors offer cardiovascular and renal protection independent of their effects on systolic BP. Trandolapril is a new angiotensin converting enzyme inhibitor approved for the treatment of hypertension. The potential advantages of this drug are long duration of action and better tolerability. The objective of the study was to compare the efficacy and tolerability of trandolapril with that of enalapril in mild to moderate hypertension in Indian population. In this double blind, multicentric, parallel comparative clinical study, 120 patients with mild to moderate hypertension were randomly assigned to receive trandolapril 2 mg or enalapril 5 mg once daily for 8 weeks. The attainment of sitting diastolic blood pressure <90 mmHg at the end of 8th week was considered as primary outcome measure and attainment of diastolic blood pressure <90 mmHg or reduction of at least 10 mmHg diastolic blood pressure compared to baseline at any visit was considered as secondary outcome measures. 98.4% patients treated with trandolapril and 92.6% patients treated with enalapril fulfilled the primary outcome measure. 54, 72 and 62% patients on trandolapril and 52, 61 & 64% patients on enalapril fulfilled secondary outcome measure at the end of 2nd, 4th and 8th week respectively. Also trandolapril was better tolerated than enalapril with no significant abnormality in lab parameters.

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.

OBJECTIVE: 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.

Randomised, Double-Blind, Parallel, Placebo-Controlled Study of Oral Glucosamine, Methylsulfonylmethane and their Combination in Osteoarthritis.

OBJECTIVE: Glucosamine, classified as a slow-acting drug in osteoarthritis (SADOA), is an efficacious chondroprotective agent. Methylsulfonylmethane (MSM), the isoxidised form of dimethyl-sulfoxide (DSMO), is an effective natural analgesic and anti-inflammatory agent. The aim of this study was to compare the efficacy and safety of oral glucosamine (Glu), methylsulfonylmethane (MSM), their combination and placebo in osteoarthritis of the knee. PATIENTS AND DESIGN: A total of 118 patients of either sex with mild to moderate osteoarthritis were included in the study and randomised to receive either Glu 500mg, MSM 500mg, Glu and MSM or placebo capsules three times daily for 12 weeks. Patients were evaluated at 0 (before drug administration), 2, 4, 8 and 12 weeks post-treatment for efficacy and safety. The efficacy parameters studied were the pain index, the swelling index, visual analogue scale pain intensity, 15m walking time, the Lequesne index, and consumption of rescue medicine. RESULTS: Glu, MSM and their combination significantly improved signs and symptoms of osteoarthritis compared with placebo. There was a statistically significant decrease in mean (+/- SD) pain index from 1.74 +/- 0.47 at baseline to 0.65 +/- 0.71 at week 12 with Glu (p < 0.001). MSM significantly decreased the mean pain index from 1.53 +/- 0.51 to 0.74 +/- 0.65, and combination treatment resulted in a more significant decrease in the mean pain index (1.7 +/- 0.47 to 0.36 +/- 0.33; p < 0.001). After 12 weeks, the mean swelling index significantly decreased with Glu and MSM, while the decrease in swelling index with combination therapy was greater (1.43 +/- 0.63 to 0.14 +/- 0.35; p < 0.05) after 12 weeks. The combination produced a statistically significant decrease in the Lequesne index. All treatments were well tolerated. CONCLUSION: Glu, MSM and their combination produced an analgesic and anti-inflammatory effect in osteoarthritis. Combination therapy showed better efficacy in reducing pain and swelling and in improving the functional ability of joints than the individual agents. All the treatments were well tolerated. The onset of analgesic and anti-inflammatory activity was found to be more rapid with the combination than with Glu. It can be concluded that the combination of MSM with Glu provides better and more rapid improvement in patients with osteoarthritis.

Evaluation of the antiretroviral activity of a new polyherbal drug (Immu-25) in patients with HIV infection.

OBJECTIVE: To evaluate the clinical efficacy and safety of a new polyherbal preparation, Immu-25, in HIV-infected patients. METHODS: 36 patients (10 female, 26 male) with a mean age of 35 +/-10 years, with confirmed HIV infection with a CD4 count <500 cells/microL, received two capsules of the test drug twice daily for 18 months in this open-label pilot study. Patients were evaluated at monthly intervals for general signs and symptoms, development of opportunistic infections, and changes in weight and performance index. Lymphocyte phenotyping and routine haematological, biochemical, hepatic and renal parameters were recorded after every 6 months of drug therapy. Viral load was evaluated before and after every 6 months of treatment. RESULTS: The polyherbal test preparation produced good symptomatic improvement within 6 months. There was an increase in mean (95% CI) weight from 58 (53-64)kg to 63 (56-69)kg, 64 (58-72)kg and 68 (62-74)kg after 6, 12 and 18 months of treatment, respectively. The incidence and severity of symptoms such as diarrhoea, fatigue, anorexia, cough and fever decreased with drug treatment. There was a decrease in the mean (95% CI) viral load from 326 438 (428 600-186 420) copies/mL to 180 495 (258 300-124 000) copies/mL and 22 069 (42 100-16 000) copies/mL after 6 and 12 months of treatment, respectively. The decrease in viral load was associated with an increase in mean (95% CI) CD4 count from a baseline of 243 (203-388) cells/microL to 336 (263-486) cells/microL after 6 months of therapy, and this continued to rise to 527 (285-767) cells/microL (p < 0.001) and 618 (362-1012) cells/microL (p < 0.001) after 12 and 18 months of treatment, respectively. With the exception of mild gastrointestinal adverse effects, the drug was well tolerated. Both patients and investigators rated the treatment as good or very good. CONCLUSION: The polyherbal drug Immu-25 showed a favourable effect in patients with HIV infection. The test drug decreased the mean viral load, which was associated with good symptomatic improvement and an increase in the mean CD4 cell count. On the basis of these data, it can be concluded that this herbal drug may have a good immunomodulatory effect and has potential as a co-therapeutic agent in the management of HIV infection. Further studies are warranted to confirm its therapeutic potential.