Assessment of Clinical Pharmacokinetic Drug-Drug Interaction of Antimalarial Drugs α/ß-Arteether and Sulfadoxine-Pyrimethamine.

Antimalarial drug combination therapy is now being widely used for the treatment of uncomplicated malaria. The objective of the present study was to investigate the effects of coadministration of intramuscular α/ß-arteether (α/ß-AE) and oral sulfadoxine-pyrimethamine (SP) on the pharmacokinetic properties of each drug as a drug-drug interaction study to support the development of a fixed-dose combination therapy. A single-dose, open-label, crossover clinical trial was conducted in healthy adult Indian male volunteers (18 to 45 years, n = 13) who received a single dose of AE or SP or a combination dose of AE and SP. Blood samples were collected up to 21 days postadministration, and concentrations of α-AE, ß-AE, sulfadoxine, and pyrimethamine were determined by using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and statistically analyzed to calculate the geometric mean ratio and confidence interval. Following single-dose coadministration of intramuscular AE and oral SP, the pharmacokinetic properties of α/ß-AE were not significantly affected, and α/ß-AE had no significant effect on the pharmacokinetic properties of SP in these selected groups of healthy volunteers. However, more investigations are needed to explore this further. (This study has been registered in the clinical trial registry of India under approval no. CTRI/2011/11/002155.).

Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug.

Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T 1/2, MRT, and AUC0-∞ of the active metabolite 97/63 were 11.85 ± 1.94 h, 13.77 ± 2.05 h, and 878.74 ± 133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials.

Predictive value of routine hematological and biochemical parameters on 30-day fatality in acute stroke.

OBJECTIVE: This prospective study was planned to study the prognostic value of routine clinical, hematological and biochemical parameters, including platelet aggregation in patients of acute stroke, on fatality occurring during the first 30 days. MATERIAL AND METHODS: In this study 116 consecutive patients (77 males and 39 females) of stroke (within 72 hours of onset) were included. After clinical evaluation and neuroimaging, blood investigations, hemoglobin, total leukocyte count, platelet count, platelet aggregation, erythrocyte sedimentation rate (ESR), blood sugar, urea, creatinine, sodium, potassium, serum cholesterol, serum bilirubin, aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT), albumin, and globulin estimations were performed. The patients were followed up for a maximum period of 30 days from the onset of stroke, and patients who expired were grouped as 'expired' and the rest as 'survivors'. Logistic regression analysis was carried out among the significant parameters to identify independent predictors of 30-day fatality. RESULTS: Univariate analysis demonstrated that among hematological parameters, high total leukocyte count and ESR, at admission, correlated significantly with an undesirable outcome during the initial 30 days. Among biochemical parameters, elevated urea, creatinine, serum transaminases (SGOT and SGPT) and globulin levels correlated significantly with death. Logistic regression analysis demonstrated that a low Glasgow Coma Scale (GCS) score along with biochemical parameters such as high serum creatinine, SGPT, ESR and total leukocyte count correlated with death. CONCLUSION: Impaired consciousness, high total leukocyte count, raised ESR, elevated creatinine and SGPT levels, estimated within 24 hours of hospitalization, are the most important indicators of 30-day mortality in patients with first-time ischemic stroke.

Response of Mycobacterium habana vaccine in patients with lepromatous leprosy and their household contacts. A pilot clinical study.

Single dose vaccination was carried out with Mycobacterium habana vaccine, 31 lepromatous leprosy cases receiving 1.5 mg (1.5 mg = 6.27 x 10(8) bacilli) and 36 household contacts randomly receiving 1.5, 2.0, 2.5 mg vaccine intradermally. Duration of study was 18 weeks. Vaccination induced lepromin conversion in 100% of lepromatous leprosy cases and lepromin negative household contacts and augmentation of lepromin reactivity in 100% of lepromin positive household contacts, which was stable for the 15 weeks duration of follow-up. The maximum augmentation in lepromin reactivity was obtained with 1.5 mg of vaccine, which is probably the supramaximal dose. Overall, post-vaccination, those without prior BCG vaccination scars showed higher mean values of lepromin augmentation. Local vaccination site changes included induration, ulceration, itching, pain and uncomplicated regional lymphadenopathy, all of which remitted spontaneously by 15 weeks. Systemic side-effects noted were pyrexia, ENL and jaundice, and were seen with no greater frequency than that reported in other vaccine trials. Overall, systemic side-effects were easily controlled and were not accompanied by clinically detectable nerve or ocular damage. The safety profile investigations revealed an increase in the mean values of Hb%, RBC count and PCV in household contacts and of PCV in lepromatous patients, post-vaccination. Alterations in the liver function tests were also observed in patients of lepromatous leprosy. Thus, M. habana vaccine appears to be useful in stimulating specific CMI against M. leprae as evidenced by increased lepromin reactivity.

Lipoprotein(a) and coronary heart disease in Indian population.

OBJECTIVE: Present study was undertaken to evaluate the role of lipoprotein(a) in coronary heart disease (CHD) patients and its relationship with other established risk factors. METHODS: Blood samples of 67 control patients (non-cardiovascular problems) and 222 CHD patients (> or = 4 weeks post myocardial infarction) were analyzed. Lipoprotein(a) was measured in serum samples by enzyme-linked immunosorbent assay utilizing rabbit polyclonal antibodies against purified human Lp(a). Step-wise linear discriminant analysis was used to find the important parameters to discriminate CHD and non-CHD subjects. RESULTS: The LDL to HDL cholesterol ratio (p < 0.01) and serum level of lipoprotein(a) (p < 0.01) were significantly higher in CHD patients. Levels of lipoprotein(a) were found to be higher in females compared to males (p < 0.01). Positive family history of CHD did not show significant difference in Lp(a) levels. Lp(a) level in CHD patients with positive family history of NIDDM and hypertension was higher than in with negative family history. CONCLUSION: Clinical significance of serum level of Lp(a) and albumin in determining the risk of CHD has been observed. Lp(a) alone could correctly discriminate a CHD individual from a control subjects by 95%. Estimating of Lp(a) together with albumin provided 99% correct discrimination between control and CHD patients. These results also suggest that Lp(a) together with malnutrition could be responsible for the increased incidence of CHD in Indians. It is also indicated that in females atherothrombogenic potential of lipoprotein(a) remains suppressed before menopause but after this stage women lose this advantage.

Oxidative stress and metabolic control in non-insulin dependent diabetes mellitus.

The aim of this study was to evaluate conjugated dienes in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and its metabolic control. To achieve good metabolic control in addition to dietary management oral hypoglycemic agents such as glibenclamide, gliclazide and metformin were given to patients. Human plasma low-density lipoproteins (LDL) were delipidised and triglycerides (LDL-TG) and cholesterol esters (LDL-CE) were separated. Conjugated dienes in LDL-TG and LDL-CE of subjects with NIDDM (n = 90) and normal glucose tolerance (NGT) (n = 30) were measured using second derivative of uv absorption spectrum. Hypoglycemic agents lowered substantially concentration of cis, trans (c, t) and trans, trans (t, t) conjugated dienes in LDL-CE and LDL-TG. The duration of NIDDM has shown significant correlation (p < 0.001) with conjugated dienes in LDL-TG. Concentration of c, t and t, t-conjugated dienes in LDL-CE and LDL-TG were found significantly higher in subjects with NIDDM than NGT (p < 0.001). In conclusion, NIDDM, status of metabolic control and duration of diabetes have strong positive relation with oxidative stress.

Platelet functions & lipid profile within 24 hours following an attack of TIA, thrombotic & haemorrhagic stroke.

The present study was undertaken to evaluate comparatively the lipid profile and platelet functions within 24 h of the three most frequent types of stroke encountered in clinical practice. Twenty patients of transient ischaemic attacks, 22 of thrombotic stroke and 26 of haemorrhagic stroke (hypertensive putaminal haemorrhage), all within 24 h of the acute event, and 21 control subjects were studied. Spontaneous platelet aggregation, platelet aggregation induced with adenosine diphosphate (2.5, 3.75 and 5.0 microM) and lipid profile (serum cholesterol, triglycerides, high density lipoprotein, low density lipoprotein and very low density lipoprotein) estimations were performed in all the subjects. Mean platelet aggregation values were significantly lower in haemorrhagic stroke patients as compared to controls. Serum cholesterol, triglycerides and very low density lipoprotein levels in ischaemic groups i.e., transient ischaemic attacks and thrombotic stroke patients, were significantly elevated, more so in the former group. It appears that platelet hypofunction has a role in the pathogenesis of hypertensive putaminal haemorrhage while in patients of transient ischaemic attack and thrombotic stroke, lipids may be a contributing factor in cerebral atherogenesis.

Platelet functions and lipid profile in haemorrhagic and thrombotic stroke patients.

The present study was conducted in 17 patients of haemorrhagic stroke (HS), 19 patients of thrombotic stroke (TS) and 14 control subjects. In each subject platelet functions (spontaneous platelet aggregation (SPA), aggregation induced with 10, 5, 2.5 microM ADP and 10 micrograms/ml of collagen) and complete lipid profile (total cholesterol, triglycerides, high density lipoprotein [HDL], low density lipoprotein [LDL], very low density lipoprotein [VLDL] and LDL/HDL ratio) were performed within 7 days of onset of stroke. Platelet aggregation with 2.5 microM ADP was significantly lower (P < 0.05), in both the stroke groups in comparison to controls. No other changes were significant. Mean serum triglycerides and VLDL of TS group were significantly higher than that of controls. Mean LDL/HDL ratio of the same group was significantly lower than HS group. It can be concluded that alterations in platelet functions and lipid profile are induced by both types of strokes in acute stage.

Relevance of platelet serotonergic mechanisms in pregnancy induced hypertension.

Platelet functions are becoming the useful tool for delineating the etiology of pregnancy induced hypertension. Electronmicroscopic studies, efflux and content of 5-HT in platelets and platelet aggregation responses towards various aggregating agents have been measured in 25 normotensive pregnant subjects and 31 PIH subjects. Marked decrease changes have been noted in aggregation parameters with transformation from discoid to "spiny sphere" of platelets with long pseudopods along with prolonged time for spontaneous aggregation by platelets in PIH. Serotonin release from platelets was decreased and reserpine-induced release-reaction showed enhanced kinetics in PIH. Platelet serotonin content was raised and was inversely related to platelet count with severity of syndrome. Hence, a check and balance for platelet activation and aggregation in PIH might be crucial in the development of PIH.

Effect of anti-platelet therapy (aspirin + pentoxiphylline) on plasma lipids in patients of ischaemic stroke.

Twenty-one patients of ischaemic stroke were put on prolonged administration of antiplatelet drugs (aspirin 320 mg once daily with pentoxiphylline 400 mg thrice daily). The serum lipids along with other biochemical parameters were estimated before starting the treatment and after completion of 2 months of therapy. No significant changes were observed in any of the biochemical parameters including lipid profile except in serum high density lipoprotein (HDL) which increased significantly (< 0.05) after 2 months therapy. It is concluded that 2 months antiplatelet therapy has no adverse metabolic effect in patients of ischaemic stroke and the raised serum HDL may contribute to cerebral protective effect.

Clinical evaluation of chandonium iodide as a nondepolarising muscle relaxant.

The effect of chandonium iodide (as a non-depolarising muscle relaxant) was studied in 50 patients of ASA grade I or II who were scheduled for surgery. The patients were divided into 2 groups according to the dose of chandonium iodide (0.2 and 0.25 mg/kg respectively). The onset and duration of action was found to be dose dependent. Intubation characteristics were good to fair in all the patients, the reaction to intubation being either absent or mild. There was mild and transient rise in pulse and blood pressure. No allergic reaction was observed in any patient and reversal characteristics were good in all the cases.