A Swedish case-control network for studies of drug-induced morbidity--acute pancreatitis

OBJECTIVE: To evaluate risk factors - notably drugs - for developing acute pancreatitis. METHODS: A population-based, case-control study, encompassing 1.4 million inhabitants aged 20-85 years from four regions in Sweden between 1 January 1995 and 31 May 1998. A total of 462 cases were hospitalised in surgical departments with their first episode of acute pancreatitis without previously known biliary stone disease. From a population register, 1781 controls were randomly selected. Information was obtained from medical records and through telephone interviews. RESULTS: Fifty-seven percent of the cases were males. An expert group found evidence for biliary stones in 50% of the cases, alcohol intake in 23%, but in 29% neither of these factors were present. In all, "other" factors, e.g. drugs, could have contributed to the development of acute pancreatitis in 52% of the cases. In a multivariate analysis, the adjusted odds ratios (ORs) for H(2) antagonists were 2.4 (95% CI 1.2-4.8) for proton pump inhibitors (PPIs), 2.1 (1.2-3.4) for non-steroidal anti-inflammatory drugs (NSAIDs), 2.3 (1.3-4.0) for those derived from acetic acid and 1.9 (1.1-3.2) for antibacterials for systemic use. Significant ORs were found for a history of gastrointestinal tract disorders [1.5 (1.1-1.9)] and inflammatory bowel disease (IBD) [3.4 (1.5-7.9)]. Smoking was significantly associated with acute pancreatitis [1.7 (1.2-2.1)] and, for those smoking more than 20 cigarettes per day, the OR was 4.0 (2.2-7.5). Alcohol in moderate amounts did not increase the risk, but for those drinking more than 420 g alcohol per week the OR was 4.1 (2.2-7.5). CONCLUSION: In addition to cholelithiasis, smoking and heavy alcohol use, drugs may be an important risk factor for acute pancreatitis.     

Levormeloxifene: safety, pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator

AIMS: The safety, pharmacodynamics and pharmacokinetics of levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. METHODS: The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. RESULTS: Levormeloxifene was tolerated well after single doses in the range of 2.5--320 mg and multiple once daily dosing in the range of 20--160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg levormeloxifene. Five weeks of treatment with 20--160 mg levormeloxifene and 8 weeks of treatment with 40 or 80 mg levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLaps) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19--25% and 28--35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2--3 h), a slow elimination (mean t1/2: 4.8--8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3--5). CONCLUSIONS: Short-term administration of levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.     

Supersensitivity of human metabotropic glutamate 1a receptor signaling in L929sA cells

The effect of antagonist pretreatment on the signaling properties of the human metabotropic glutamate 1a (hmGlu1a) receptor was examined in stably transfected L929sA cells. Pre-exposure of hmGlu1a receptor-expressing cells to the mGlu1 receptor antagonists (S)-4-carboxy-3-hydroxyphenylglycine and 7-(hydroxyimino)cyclo-propa[b]chromen-1a-carboxylate ethyl ester dramatically enhanced subsequent glutamate-induced phosphoinositide hydrolysis and intracellular [Ca(2+)] rise. We found clear indications that the antagonist-mediated enhancement of glutamate-evoked mGlu1a receptor signaling is caused by the development of mGlu1a receptor supersensitivity: the potency of glutamate was increased by 3-fold after 24 h antagonist pretreatment and the potency of the antagonists was significantly decreased in antagonist-pretreated cells. The kinetic profile of the antagonist-mediated enhancement showed that the maximal increase in intracellular [Ca(2+)] was already reached after 30-min pretreatment, suggesting that de novo receptor synthesis is not involved in the process of mGlu1a receptor supersensitization. Glutamate-mediated phosphoinositide hydrolysis increased up to 24 h after antagonist treatment. Although it seemed likely that the hmGlu1a receptor could desensitize after activation by endogenously present glutamate, removal of glutamate from the extracellular medium with GPT resulted in a much smaller enhancement of glutamate responsiveness. Moreover, the magnitude of antagonist-mediated receptor supersensitivity was much larger than the magnitude of agonist-induced receptor desensitization. These results suggest that antagonist-evoked mGlu1 receptor supersensitivity is not merely the result of a blockade of agonist-induced desensitization. Finally, we found that antagonist pretreatment doubled the amount of receptors at the cell surface. Our findings are the first lines of evidence that prolonged antagonist treatment can supersensitize the hmGlu1a receptor. In view of the potential therapeutic application of mGlu1 receptor antagonists, it will be important to know whether these phenomena occur in vivo.     

Counteraction of the rapid tolerance to 8-hydroxy-2-(di-n-propylamino)tetralin-induced hypothermia in rats by activation of the GABAA receptor-chloride channel complex

The effects of compounds that open the GABAA receptor-chloride channel complex on the rapidly developed tolerance to the 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide(8-OH-DPAT)-induced hypothermia in rats were examined. The test compound was injected 15 min. before 1 mg/kg subcutaneous 8-OH-DPAT or saline and 24 hr later a challenge dose of 0.1 mg/kg subcutaneous 8-OH-DPAT was given. The rectal temperature was measured before the challenge dose and 30, 60, 90 and 120 min. thereafter. The hypothermic effect was calculated as the area under the curve. It was found that all the GABAergic compounds examined significantly counteracted the 8-OH-DPAT-induced tolerance to the hypothermic response: muscimol at 3 mg/kg subcutaneous, diazepam at 1 - 3 mg/kg subcutaneous, pentobarbitone sodium at 20 mg/kg subcutaneous, and chlormethiazole at 40 mg/kg subcutaneous. Combined treatment of the rats with the GABAA receptor antagonist, bicucculine, or the GABAA receptor-chloride channel blocker, picrotoxin and diazepam, pentoparbitone sodium or chlormethiazole significantly antagonised this counteraction of the 8-OH-DPAT-induced tolerance. Depletion of 5-HT by pretreatment of the rats with the tryptophan hydroxylase inhibitor p-chlorophenylalanine did not counteract the 8-OH-DPAT-induced tolerance to the hypothermic response. Pretreatment of the rats with dexamethazone did not change the development of the tolerance to 8-OH-DPAT-induced hypothermic effect which seems to exclude the involvement of the hypothalamo-pituitary-adrenocortical axis in the tolerance development. It is concluded that the results support the hypothesis that GABA neurones beyond the 5-HT neurones are involved in the mechanism causing tolerance to the 5-HT1A receptor-mediated hypothermia in rats.     

The chemical UV-filter 3-benzylidene camphor causes an oestrogenic effect in an in vivo fish assay

Chemical UV-filters are used in sun protection products and various kinds of cosmetics. The lipophilic chemical UV-filter 3-benzylidene camphor was investigated for its capability to cause vitellogenin induction, possibly via oestrogen receptor binding, in a well-established in vivo fish assay (juvenile rainbow trout, Oncorhynchus mykiss, vitellogenin ELISA). A clear relationship was demonstrated between the dose of injected 3-benzylidene camphor and the concentration of plasma vitellogenin with a 105-times induction from 68 mg 3-benzylidene camphor /kg/injection and above compared to the control vitellogenin level. The relationship between the injected dose of 3-benzylidene camphor and the percent of responding fish (vitellogenin) was evaluated by logistic regression analysis and effective dose-values (ED-values) were determined. ED10, ED50 and ED90 of 3-benzylidene camphor after 6 days (2 injections) were 6.4, 16 and 26 mg/kg/ injection, respectively. These ED-values place 3-benzylidene camphor among the more potent xenooestrogens discovered to date and necessitates investigations on the distribution, concentration, persistence and bioaccumulation of 3-benzylidene camphor and other UV-filters in nature.     

Tobacco and oral health--the role of the world health organization

In addition to several other chronic diseases, tobacco use is a primary cause of many oral diseases and adverse oral conditions. For example, tobacco is a risk factor for oral cancer, periodontal disease, and congenital defects in children whose mothers smoke during pregnancy. The epidemic of tobacco use is one of the greatest threats to global health; sadly the future appears worse because of the globalization of marketing. The World Health Organization (WHO) has strengthened the work for effective control of tobacco use. At the World Health Assembly in May 2003 the Member States agreed on a groundbreaking public health treaty to control tobacco supply and consumption. The treaty covers tobacco taxation, smoking prevention and treatment, illicit trade, advertising, sponsorship and promotion, and product regulation. Oral health professionals and dental associations worldwide should consider this platform for their future work for tobacco prevention since in several countries they play an important role in communication with patients and communities. The WHO Oral Health Programme gives priority to tobacco control in many ways through the development of national and community programmes which incorporates oral health and tobacco issues, tobacco prevention through schools, tobacco risk assessment in countries, and design of modern surveillance systems on risk factors and oral health. Systematic evaluation of coordinated efforts should be carried out at country and inter-country levels.     

Alpha-synuclein and presynaptic function: implications for Parkinson's disease

This article focuses on alpha-synuclein's role in normal and pathological axonal and presynaptic functions and its relationship to Parkinson's disease. It is not possible to mention all the contributions to aspects of this area. Readers interested in alpha-synuclein's relation to aggregation, Lewy lesions, and pathological modifications are referred to the many reviews (see Goldberg and Lansbury 2000; Galvin 2001a; Goedert 2001).     

EEG measurements by means of radiotelemetry after intracerebroventricular (ICV) cannulation in rodents

The utility of implanted radiotelemetry transmitters for the measurement of electroencephalogram (EEG), locomotor activity, body temperature and cardiovascular parameters has been well documented. This paper focuses on the methodology, of combining radiotelemetry with intracerebroventricular (ICV) cannulation. The two excitatory neuropeptides, orexin-A and orexin-B, can only be given by ICV injection, therefore we examined their effects on the normal sleep-wake cycle of rodents in the present study. The effects of orexins on sleep architecture have been extensively studied in tethered models demonstrating increased levels of wakefulness. In this study, both orexin neuropeptides, especially orexin-A, increase wakefulness within the first sleep period followed by an increase in slow wave (SW) sleep and paradoxical sleep (PS), towards the end of a 5-h recording period which may be a rebound phenomena. The present study has demonstrated that ICV cannulation can be used effectively in studying the effects of pharmacological agents on the sleep-wake cycle of rodents by measuring EEG and EMG by radiotelemetry.