Analgesic efficacy and pharmacokinetics of topical nimesulide gel in healthy human volunteers: double-blind comparison with piroxicam, diclofenac and placebo

Objective: The present study was conducted to compare the analgesic efficacy of a new topical gel formulation of nimesulide (10 mg of pure drug) with that of placebo, diclofenac and piroxicam gels (10 mg of pure drug) in three parallel groups in a double-blinded, randomized fashion with vehicle placebo. The analgesic activity of nimesulide was subsequently correlated with its pharmacokinetic profile. Methods: The drugs were applied on a fixed marked area on the skin of the right forearm. Pain stimulus was administered using a modification of the Hollander method, before and at 15, 30, 60, 120 min and 240 min post-treatment. The pain experienced by the subjects was ranked separately on the visual analogue scale (VAS) and the ten-point category scale. Antinociception induced by the treatments was evaluated through the placebo-related ratings (PRR) and total pain relief (TOTPAR) analysis. The plasma concentration of nimesulide was estimated using high-performance liquid chromatography (HPLC). Results: Nimesulide exhibited better efficacy than diclofenac, piroxicam and placebo. It demonstrated faster onset of action in concordance with earlier studies. Peak analgesic effect was observed at 120 min post-treatment, which correlated with the pharmacokinetic profile of the drug in gel formulation. In this study, diclofenac was found to be superior to piroxicam though both drugs exhibited peak analgesic effect at 60 min post-treatment. In the modified Hollander method, a good correlation was found between the ten point category scale and the VAS, indicating that it may serve as a sensitive and reliable method for the screening of analgesic drugs. Conclusion: The superior analgesic activity of nimesulide (as gel formulation), correlating with its pharmacokinetic profile, indicates that the topical route of administration may be a safe and effective alternative to the presently used oral and rectal routes. Received: 20 October 1997 / Accepted in revised form: 22 April 1998     

Acinetobacter bacteremia in patients with diarrhoeal disease.

In 1994, 171 (27%) of all positive blood cultures in our hospital were due to Acinetobacter species. Of these, 138 cultures were considered significant, 91 (66%) were community-acquired and 47 (34%) were nosocomial. Most acinetobacter bacteraemia in children < or = 1 year old was community-acquired, while nosocomial infection was more common in children > 1 year old (P = 0.01). Most children < or = 5 years old were severely malnourished. The incidence of bacteraemia was lowest during the post-monsoon to early winter months. Acinetobacter bacteraemia associated mortality was twice (16%) that of all other patients (7.7%, P < 0.0005) and accounted for 4.5% of all hospital deaths during the study period. Bacteraemia caused by Acinetobacter species is an important cause of morbidity and mortality among our patient population with diarrhoeal disease.     

Chronic opioid antagonist treatment: assessment of receptor upregulation

Changes in specific brain opioid binding and opioid pharmacodynamics were determined in mice treated with the opioid antagonist naltrexone (subcutaneously implanted pellets) for 8 days. Chronic opioid antagonist treatment increased the number of binding sites (upregulation) for [³H]naloxone (+55%) and [³H][D-Ala²,D-Leu⁵]enkephalin (+41%) but did not alter the affinity of the ligands, as determined in saturation studies. Displacement studies of [³H]naloxone by morphine also indicated that there was no change in morphine's affinity. In vivo estimation of naloxone affinity (pA₂), agreed with the in vitro results indicating that chronic naltrexone treatment did not alter naloxone affinity. Chronic naltrexone treatment (0.5, 1.0, 15.0 mg pellets) increased the analgesic potency of morphine (supersensitivity) in a dose-dependent manner, up to a maximal increase in relative potency of 1.8. However, in mice tested with the naltrexone pellets still implanted, the 15 mg naltrexone pellet was able to shift the dose-response function for morphine analgesia more than 300-fold. The lowest dose naltrexone pellet (0.5 mg), produced significant antagonism of morphine analgesia, but did not produce significant supersensitivity. Thus, supersensitivity and upregulation are not proportional to the degree of antagonism of opioid effects; and supersensitivity in the mouse is related to increased binding sites and not to changes in receptor affinity as determined by in vivo and in vitro methods.     

Evaluation of the effect of Islamic fasting on lung volumes and capacities in the healthy persons

OBJECTIVE: To evaluate the changes in pulmonary volumes during and after Islamic fasting. METHODS: It is a cohort study conducted on 117 healthy subjects selected on a random basis from employees, professors and students of Iran University of Medical Sciences, Tehran, Iran, between December 1999 and January 2000. All of them underwent spirometry 10 days prior to Ramadan, 2 times during Ramadan, and one time 10 days post-Ramadan. In first visit, in addition to spirometry they underwent medical examination to make sure they are healthy. All of their spirometries and background information were collected. Repeated measurements analysis of variance method was used to compare the measurements. RESULTS: Approximately 69% of subjects were male and the mean age was 23.9 years. Mean fasting time was 27.8 days. The mean difference in forced expiratory volume in 1 second (FEV1%) was significant between the 4 visits (p=0.01). The mean FEV1% increased both during fasting and after Ramadan (p=0.017). The mean vital capacity and peak expiratory flow rate values increased during Ramadan significantly (p=0.043, p<0.001). Although the mean maximum mid-expiratory flow decreased in the beginning of Ramadan and significantly increased subsequently (p=0.02), MEF50% (p=0.004) and MEF75% (p=0.047) increased in the beginning of Ramadan and decreased subsequently. CONCLUSION: As a whole, fasting increases lung volumes and might improve pulmonary function. This finding seems to be relevant to the changes in weight during Ramadan.     

Temporal patterns in lung cancer death rates in Ireland

Background  Distinct temporal patterns can be identified through estimating annual-percent-changes (APC) in age-specific disease rates, but APCs in lung cancer rates among the youngest adults can also reflect the recent changing smoking habits of a population. Method  Lung cancer mortality rates from 1970 to 1999 were investigated in Ireland, using the Joinpoint regression modelling technique. Results  In the most recent decade (1989–1999) male lung cancer death rates showed a significant annual decline (−2.4%), but female annual rates have scarcely decelerated (0.1%). The combined gender youngest adults (30–39 year-olds) showed decreasing rates, but the annual decline in the youngest female rates were significant only from 1970 to 1990 and thereafter increased non-significantly. Conclusion  Unlike male lung cancer death rates, the overall female rates are increasing significantly. While the combined gender youngest adult rates are decreasing, the apparent reversal in trends among the youngest female rates from 1990 onwards is worrying.     

Prevalence of exclusive breastfeeding in Bangladesh and its association with diarrhoea and acute respiratory infection: results of the multiple indicator cluster survey 2003

The objective of this study was to investigate the association between the prevalence of exclusive breastfeeding and morbidity (diarrhoeal diseases and acute respiratory infection) in infants aged 0-3 month(s) using the Multiple Indicator Cluster Survey (MICS) 2003 data from Bangladesh. The study population included 1633 infants aged 0-3 month(s). The prevalence of diarrhoea and acute respiratory infection was compared using the chi-square tests between infants aged 0-3 month(s) who were exclusively breastfed and infants who were not exclusively breastfed. Logistic regression was used to adjust for confounders and for calculating adjusted odds ratios. To adjust for cluster sampling and reduced variability, the adjusted chi-square value was divided by the design effect, and a re-estimated p value was calculated. The prevalence of diarrhoea and acute respiratory infection in this sample of 0-3-month old infants in Bangladesh was 14.3% and 31.2% respectively. The prevalence of both illnesses was significantly associated with lack of exclusive breastfeeding. The adjusted odds ratio for diarrhoea was 0.69 (95% confidence interval [CI] 0.49-0.98, p = 0.039), and the adjusted odds ratio for acute respiratory infection was also 0.69 (95% CI 0.54-0.88, p = 0.003). Only 192 infants (11.7% of total sample) were exclusively breastfed at the time of interview, and 823 infants (50.3%) were never exclusively breastfed. The prevalence of prelacteal feeding was 66.6%. The results confirmed a protective effect of exclusive breastfeeding against infectious diseases-related morbidity in infancy and showed that frequently-collected cross-sectional datasets could be used for estimating effects. The low prevalence of exclusive breastfeeding in Bangladesh needs to be improved to decrease child morbidity.     

Safe-delivery practices in rural Bangladesh and its associated factors: evidence from Bangladesh demographic and health survey-2004

OBJECTIVES: This study examined the safe-delivery practices and its associated factors among rural Bangladeshi women. DESIGN: Cross-sectional survey data from Bangladesh Demographic and Health Survey (BDHS) 2004 were used. SETTING: Rural Bangladesh. PARTICIPANTS: A total of 3874 ever-married rural women age 10-49 years. Measurements: Age, education, working, religion, clinic visit, association with media, place and types of attendants at delivery. RESULTS: About 94% deliveries took place at homes and 67% were assisted by the untrained traditional birth attendants called Dai. The qualified doctors and nurses (professionals) assisted only 9% of the deliveries while about 13% are by the trained traditional birth attendants. Age group has a significant effect on safe-delivery practices. Education of the respondents as well as their partner's has direct effect on delivery practices. The uneducated women were less likely to have their delivery assisted by the medically trained persons (MTPs) while women with 10 or more years of schooling had 29 times higher probability than the uneducated women. Currently working and religion had also statistically significant. Mass media influences directly delivery practices in rural areas. The women who listen to radio and watch television had more than 2 times higher probability of having delivery assisted by MTPs than that of non-user counterparts. There is more than 4 times higher chance of delivery assisted by the MTPs than that of women with no reading of news papers or magazines. CONCLUSIONS: Delivery practices in rural Bangladesh are unsafe, took place at homes, conducted by untrained traditional birth attendants and associated positively with demographic, socio-economic, cultural and programmatic factors.     

Metabolic syndrome, hyperinsulinemia, and cancer

The term metabolic syndrome describes the association between obesity, insulin resistance, and the risk of several prominent chronic diseases, including cancer. The causal link between many of these components remains unexplained, however. What is clear are the events that precede the development of the syndrome itself. In animal models, a fat-supplemented diet causes 1) lipid deposition in adipose depots, 2) insulin resistance of liver and skeletal muscle, and 3) hyperinsulinemia. One hypothesis relating fat deposition and insulin resistance involves enhanced lipolysis in the visceral depot, which leads to an increase in free fatty acid (FFA) flux. Increased mass of stored lipid and insulin resistance of visceral adipocytes favors lipolysis. Additionally, hypersensitivity of visceral adipose cells to sympathetic nervous system stimulation leads to increased lipolysis in the obese state. However, little evidence is available for enhanced plasma FFA concentrations in the fasting state. We measured FFA concentrations over a 24-h day in obese animals and found that plasma FFAs are elevated in the middle of the night, peaking at 0300. Therefore, it is possible that nocturnal lipolysis increases exposure of liver and muscle to FFAs at night, thus causing insulin resistance, which may play a role in hyperinsulinemic compensation to insulin resistance. Nocturnal lipolysis secondary to sympathetic stimulation may not only cause insulin resistance but also be responsible for hyperinsulinemia by stimulating secretion and reducing clearance of insulin by the liver. The resulting syndrome-elevated nocturnal FFAs and elevated insulin-may synergize and increase the risk of some cancers. This possible scenario needs further study.     

Arsenic methylation, GSTT1, GSTM1, GSTP1 polymorphisms, and skin lesions

OBJECTIVE: We investigated whether primary and secondary arsenic methylation ratios were associated with skin lesions and whether GSTT1, GSTP1, and GSTM1 polymorphisms modify these relationships. METHODS: A case-control study of 600 cases and 600 controls that were frequency matched on age and sex was conducted in Pabna, Bangladesh, in 2001-2002. Individual well water, urine, and blood samples were collected. Water arsenic concentration was determined using inductively coupled plasma mass spectrometry (ICP-MS). Urinary arsenic speciation was determined using high performance liquid chromatography hydride with generator atomic absorption spectrometry and ICP-MS. Genotyping was conducted using multiplex polymerase chain reaction and TaqMan. RESULTS: A 10-fold increase in primary methylation ratio [monomethylarsonic acid (MMA)/(arsenite + arsenate] was associated with a 1.50-fold increased risk of skin lesions (multivariate odds ratio = 1.50; 95% confidence interval, 1.00-2.26). We observed significant interaction on the multiplicative scale between GSTT1 wildtype and secondary methylation ratio [dimethylarsinic acid/MMA; likelihood ratio test (LRT), p = 0.01]. No significant interactions were observed for GSTM1 or GSTP1 or for primary methylation ratios. CONCLUSION: Our findings suggest that increasing primary methylation ratios are associated with an increase in risk of arsenic-related skin lesions. The interaction between GSTT1 wildtype and secondary methylation ratio modifies risk of skin lesions among arsenic-exposed individuals.