Alcohol,tobacco and cannabis use among Nova Scotia adolescents: implications for prevention and harm reduction

OBJECTIVE: To characterize adolescent drug use in terms of a risk continuum and to explore the rationale for harm reduction as a potential approach for school-based drug prevention. DESIGN: Self-reported surveys, in 1991 and 1996, of adolescent students concerning their use of drugs, especially alcohol, tobacco and cannabis, and the harmful consequences of such use. SETTING: Nova Scotia. PARTICIPANTS: A total of 3452 (in 1991) and 3790 (in 1996) junior and high school students in randomly selected classes in the public school system. OUTCOME MEASURES: Prevalence of drug use and patterns of multiple drug use and of alcohol- and drug-related problems; independent risk factors for multiple drug use. The risk continuum for the response to alcohol problems was used as a policy framework. RESULTS: The prevalence of cigarette smoking and the use of hallucinogens and stimulants was markedly higher in 1996 than in 1991. Over one-fifth (21.9%) of the students reported multiple drug use of alcohol and tobacco and cannabis in the 12 months before the 1996 survey. The 3 main subgroups--nonusers, users of alcohol only and users of multiple drugs--had distinct patterns of use, numbers of problems and risk factors. In all, 27.1% of the students had experienced at least 1 alcohol-related problem and 6% had experienced at least 1 drug-related problem in the 12 months before the 1996 survey. CONCLUSION: There is a need for integrated school- and community-based drug prevention programs, with goals, strategies and outcome measures capturing the full spectrum of patterns of use and levels of risk among subgroups of the adolescent student population.     

Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites

Many drugs contain a chiral centre, or such a centre is introduced during metabolism of the drug in man and in animals. If a single chiral centre is present, the drug will normally exist as a mixture of two enantiomers, of which one may have quite different pharmacologic and/or toxic effects than the other. Chiral drugs that are used in psychiatry, and some other pharmacologically related drugs are identified, and the implications of the presence of one or two chiral centres in these drugs are discussed. Differences in pharmacologic properties of drug and metabolite enantiomers are identified and discussed. Also reviewed are the properties of some drugs used in psychiatry that both are chiral and display geometric isomerism.     

Reversal of eutrophication in Lake Geneva: evidence from the oligochaete communities

1. In Lake Geneva (Switzerland), total phosphorus concentrations have decreased from 90 mg m^?3 in 1979 to 55 mg m^?3 in 1990. 2. To assess the effects of this improvement, tubificid and lumbriculid communities were sampled in 1982 and in 1991 in the same areas, at a depth of 40 m. 3. Abundance of mesotrophic species (mostly Potamothrix vejdovskyi) and of eutrophic species (mostly Potamothrix hammoniensis) was lower in 1991 than in 1982; in contrast, oligotrophic species (mostly Peloscolex velutinus) were more abundant in 1991 than in 1982. 4. The changes recorded in 1991 were the same as those associated with a decrease of organic sedimentation. 5. Mean relative abundance of oligotrophic species increased from 17% in 1982 to 41% in 1991. According to these values, Lake Geneva was mesoeutrophic in 1982, but mesotrophic in 1991.     

Nonmedical drug use among adolescent students: highlights from the 1999 Ontario Student Drug Use Survey

BACKGROUND: During the 1990s, rates of nonmedical drug use among adolescents escalated. We assessed data from 5 cycles of the Ontario Student Drug Use Survey for overall trends in the proportion of students reporting illegal drug use between 1991 and 1999. METHODS: The survey is a repeated, cross-sectional, 2-stage cluster-design survey of students enrolled in grades 7, 9, 11 and 13. Outcome measures were prevalence of use of 17 drugs, including alcohol and tobacco, over the 12 months preceding the survey. RESULTS: The rates of drug use increased between 1993 and 1999. The 95% confidence intervals (CIs) for the differences in proportions between 1997 and 1999 indicated significant increases in the overall use of 6 drugs: alcohol (95% CIdiff 6.1, 1.9-10.3), cannabis (95% CIdiff 46.3, 0.2-8.4), glue (95% CIdiff 2.3, 1.3-3.3), other solvents (95% CIdiff 5.0, 3.1-6.3), barbiturates (95% CIdiff 1.9, 0.4-3.4) and hallucinogens such as mescaline and psilocybin (95% CIdiff 3.5, 0.8-6.9). Fewer grade 7 students in 1999 than in earlier cohorts reported using alcohol or cigarettes by age 9. INTERPRETATION: The public health implications of the findings are mixed. On the positive side, there is no evidence of increases in early onset of drug use. On the negative side, the overall proportion of students reporting illegal drug use has continued to rise.     

The importance of stereoselective determination of drugs in the clinical laboratory

About 56% of the drugs currently in use are chiral compounds, and 88% of these chiral synthetic drugs are used therapeutically as racemates. Only a few of these drugs qualify for a stereospecific determination in a clinical laboratory for therapeutic drug monitoring of patients. If the qualitative and quantitative pharmacokinetic and pharmacodynamic effects are similar, the enantiomers do not need to be separated. However, if the metabolism of the different stereoisomers is handled by different enzymes which are either polymorphic or can be induced or inhibited, and if their pharmacodynamic effects have differences either in strength or in quality, enantiospecific analysis is urgently needed. Unfortunately, there are many racemic drugs where the stereospecificity of the metabolism and/or the pharmacodynamic effects of the enantiomers is not known today. For these drugs, there is a great need for studies concentrating on these differences to improve treatment of the patients.     

OBSERVATIONS OF FLORIDA MANATEES(TRICHECHUS MANATUS LATIROSTRIS) AROUND SELECTED POWER PLANTS IN WINTER

Sixty-four aerial surveys were flown during cold, winter weather between December 1982 and February 1772 to provide an index of trends in abundance of the Florida manatee ( Trichechus manatus latirostris )around five Florida Power & Light Company (FPL) plants. The surveys documented high winter use of warm-water discharges at four of the plants (Canaveral, Riviera. Port Everglades, and Fort Myers). The total number of manatees sighted at the five primary plants surveyed during a single survey ranged from 6 to 765 manatees (= 330 ± 45 manatees per survey): thus, up to 41% of the total Florida manatee minimum population of 1.850 animals may be found on cold days at FPL plants. The number of calves sighted at the plants during winter has decreased; similarly, for three consecutive years (winter 1989–1970 through winter 1991–1992), the percentage of the manatees that are calves sighted at the plants has decreased. Although data from the surveys of FPL plants do not necessarily reflect what may be happening with manatees located elsewhere in Florida, a possible reduction in calf numbers, coupled with increasing numbers of dead calves being documented by scientists involved in manatee carcass salvage work, is cause for concern in this slow-reproducing, endangered species.     

Excavations in drug chirality: 1. Cyclothiazide

There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of "several stereoisomers." Inspection of the chemical structure of the drug, 6-chloro-3,4-dihydro-3-(5-norbornen-2-yl)-2H-1,2,4-benzothiadiazin e-7- sulfonamide 1,1-dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.     

Simultaneous chiral separation of tramadol and methadone in tablets,human urine,and plasma by capillary electrophoresis using maltodextrin as the chiral selector

The stereoselective analysis and separation of racemic drugs play an important role in pharmaceutical industry to eliminate the unwanted isomer and find the right therapeutic control for the patient. Present study suggests a maltodextrin‐modified capillary electrophoresis method for a single‐run chiral separation of two closely similar opiate pain relief drugs: tramadol (TRA) and methadone (MET). The best separation method possible for the both enantiomers was achieved on an uncoated fused‐silica capillary at 25°C using 100 mM phosphate buffer (pH 8.0) containing 20% (w v^?1) maltodextrin with dextrose equivalent of 4–7 and an applied voltage of 16 kV. Under optimal conditions, the baseline resolution of TRA and MET enantiomers was obtained in less than 12 minutes. The relative standard deviations (n = 3) of 20 μg mL^?1 TRA and MET were 2.28% and 3.77%, respectively. The detection limits were found to be 2 μg mL^?1 for TRA and 1.5 μg mL^?1 for MET. This method was successfully applied to the measurement of drugs concentration in their tablets, urine, and plasma samples.     

Phospholipids chiral at phosphorus. Absolute configuration of chiral thiophospholipids and stereospecificity of phospholipase D

Separate diastereomers of 1,2-dipalmitoyl-sn-glycero-3- thiophosphoethanolamine ( DPPsE ) were prepared in 97% diastereomeric purity and characterized by 31P, 13C, and 1H nuclear magnetic resonance (NMR). The isomers hydrolyzed by phospholipases A2 and C specifically were designated as isomer B (31P NMR delta 59.13 in CDCl3 + Et3N ) and isomer A (59.29 ppm), respectively, analogous to the isomers B and A of 1,2-dipalmitoyl-sn-glycero-3- thiophosphocholine ( DPPsC ) [ Bruzik , K., Jiang , R.-T., & Tsai, M.-D. (1983) Biochemistry 22, 2478-2486]. Phospholipase D from cabbage was shown to be specific to isomer A of DPPsC in transphosphatidylation . The product DPPsE was shown to be isomer A. The absolute configuration of chiral DPPsE at phosphorus was elucidated by bromine-mediated desulfurization in H2 18O to give chiral 1,2-dipalmitoyl-sn-glycero-3-[18O]phosphoethanolamine ( [18O]DPPE) followed by 31 P NMR analysis [ Bruzik , K., & Tsai, M.-D. (1984) J. Am. Chem. Soc. 106, 747-754]. The absolute configuration of chiral DPPsC was elucidated by desulfurization in H2 18O mediated by bromine or cyanogen bromide to give chiral 1,2-dipalmitoyl-sn-glycero-3-[18O]phosphocholine ( [18O]DPPC), which was then converted to [18O]DPPE by phospholipase D with retention of configuration [ Bruzik , K., & Tsai, M.-D. (1984) Biochemistry (preceding paper in this issue)]. The results indicate that isomer A of both DPPsE and DPPsC is SP whereas isomer B is RP.     

Role of capillary electrophoresis methods in the drug development process

In the past several years, capillary electrophoresis (CE) has generated considerable interest from pharmaceutical companies for control of both the chiral and achiral purity of bulk drugs and drug products. This paper evaluates the use of CE as: (1) a technique complementary to HPLC for the determination of peak homogeneity of a drug, (2) for determination of chiral purity, and (3) for determination of achiral purity. It would be greatly advantageous if CE could be used to determine both the chiral and achiral purity in a single assay. This investigation compares the results obtained for the separation of the enantiomers of duloxetine using several neutral cyclodextrins to those obtained using anionic cyclodextrins (sulfobutyl ether derivatives) as chiral selectors added to the separation buffer. In addition, it reports chiral separations obtained by using neutral cyclodextrins in a sulfonic acid-coated capillary column, which give a negatively charged capillary surface and electro-osmotic flow even in low pH buffers. The possible mechanism of separation is discussed. © 1996 Wiley-Liss, Inc.     

Surveys of diseases of winter barley in England and Wales, 1981–1991

Samples from 200–400 randomly selected winter barley crops were taken annually at growth stage 71–73 from 1981 to 1991, with the exception of 1984 and 1985. The number of samples from each region was proportional to the area of barley growth in each region. The percentage of the area of the top two leaves affected by diseases and the severity of stem base diseases were recorded. Mildew (Erysiphe graminis) was the most widespread of the foliar diseases and in three years (1982, 1986 and 1991) was also the most severe. Rhynchosporium (Rhynchosporium secalis), net blotch (Pyrenophora teres) and brown rust (Puc-cinia hordei) were also prevalent in some years. Of the stem base diseases, fusarium was often the most widespread. Eyespot (Pseudocercosporella her-potrichoides) severity varied widely from year to year ranging from 1.2% of stems affected by moderate or severe symptoms in 1982 to 24.1% in 1988. There were regional differences in the severity of mildew, rhynchosporium, brown rust, halo spot (Selenophoma donacis) and eyespot. Cultivar resistance affected disease severity and previous cropping affected eyespot and less frequently mildew, rhynchosporium and net blotch. Eyespot, and to a lesser extent, sharp eyespot, were less severe in late- than in early-sown crops. The percentage of crops treated with a fungicidal spray increased from 72% in 1981 to 95% in 1991. The use of benzimidazole fungicides for the control of eyespot declined in response to the development of resistance, and more recently the use of prochlo-raz also declined. Broad spectrum DMI fungicides were widely used, and the use of morpholines to improve mildew control increased significantly. The proportion of crops grown from seed treated with a non-mercurial fungicidal seed dressing reached a peak of 47% in 1986 but subsequently declined to 22% in 1990 and 1991.     

Investigation of maltodextrin‐based synergistic system with amino acid chiral ionic liquid as additive for enantioseparation in capillary electrophoresis

The combined use of chiral ionic liquids (ILs) and chiral selectors in capillary electrophoresis (CE) to establish a synergistic system has proven to be an effective approach for enantioseparation. In this article, tetramethylammonium‐L‐arginine, a kind of amino acid chiral IL, was applied to investigate its potential synergistic effect with maltodextrin in CE enantioseparation. The established maltodextrin‐based synergistic system showed markedly improved enantioseparations compared with the single maltodextrin system. Parameters such as the chiral IL concentration, maltodextrin concentration, buffer pH, applied voltage, and capillary temperature were optimized. Satisfactory enantioseparation of the five studied drugs, including nefopam, duloxetine, ketoconazole, cetirizine, and citalopram was achieved in 50 mM Tris‐H₃PO₄ buffer solution (pH 3.0) containing 7.0% (m/v) maltodextrin and 60 mM tetramethylammonium‐L‐arginine. In addition, the chiral configuration of tetramethylammonium‐L‐arginine was also investigated to demonstrate the existence of a synergistic effect between chiral ILs and maltodextrin.     

Racemization and hydrolysis of tropic acid alkaloids in the presence of cyclodextrins

Because of the constantly increasing demand for optically pure drugs it is of great importance to elucidate factors affecting stereochemistry, in order to provide a stable formulation with a high chiral quality of the desired isomer. Therefore, the effects of cyclodextrins (CyDs) and their alkylated and hydroxyalkylated derivatives on racemization and hydrolysis of (?)-(S)-hyoscyamine and (?)-(S)-scopolamine were examined kinetically and spectroscopically (NMR). Direct methods, based on a chiral and achiral chromatographic phase system, were used to determine their degradation products and enantiomer composition during stability tests. All different CyDs, except α-CyD, retarded racemization and hydrolysis. The inclusion of the drug substances in CyDs inhibits the attack of hydroxyl ions and/or water molecules and thus retards the racemization and hydrolysis. The racemization of the tropic acid alkaloids is dependent on the pH and temperature. NMR studies were used to evidence the formation of a soluble 1:1 complex in aqueous solution. © 1993 Wiley-Liss, Inc.     

Determination of (R)- and (S)-Disophyramide in human plasma using a chiral α1-acid glycoprotein column

The direct resolution and quantitation of (R)- and (S)-disopyramide, isolated from human plasma, was accomplished using a chiral α₁-acid glycoprotein column. A LiChrosorb RP-2 column (50 × 3.0 mm I.D.) was used as a precolumn. Phosphate buffer, pH 6.20, containing 2-propanol and N,N-dimethyloctylamine was used as mobile phase, expressed as the relative standard deviation, was 1.8% and 3.3% for (R)- and (S)-disopyramide, respectively, at a drug level of 0.5 μg/ml. In two subjects who received a single capsule of racemic disopyramide (150 mg), the plasma levels of the (R) isomer were about half those of the (S) isomer. The half-lives of (R)- and (S)-disopyramide were similar.     

Higher northern latitude normalized difference vegetation index and growing season trends from 1982 to 1999

Normalized difference vegetation index data from the polar-orbiting National Oceanic and Atmospheric Administration meteorological satellites from 1982 to 1999 show significant variations in photosynthetic activity and growing season length at latitudes above 35°N. Two distinct periods of increasing plant growth are apparent: 1982–1991 and 1992–1999, separated by a reduction from 1991 to 1992 associated with global cooling resulting from the volcanic eruption of Mt. Pinatubo in June 1991. The average May to September normalized difference vegetation index from 45°N to 75°N increased by 9% from 1982 to 1991, decreased by 5% from 1991 to 1992, and increased by 8% from 1992 to 1999. Variations in the normalized difference vegetation index were associated with variations in the start of the growing season of –5.6, +3.9, and –1.7 days respectively, for the three time periods. Our results support surface temperature increases within the same period at higher northern latitudes where temperature limits plant growth. Received: 25 October 2000 / Revised: 20 August 2001 / Accepted: 22 August 2001     

Method for determination of optical purity of 2‐arylpropanoic acids using urea derivatives based on a 1,1′‐binaphthalene skeleton as chiral NMR solvating agents: Advantages and limitations thereof

Five optically active urea derivatives ( 1 ‐ 5 ) were used as NMR solvating agents for analysis of the optical purity of different 2‐arylpropanoic acids commonly used as nonsteroidal anti‐inflammatory drugs. These novel chiral solvating agents were more efficient at discriminating the respective enantiomers of targets than the chiral solvating agents known so far, without the need to add a base for achieving the signal splitting. The advantages and limits of the use of these novel chiral solvating agents were studied.     

Estrogen receptor stereochemistry: ligand binding and hormonal responsiveness

Estrogen stimulation of the uterus produces a spectrum of biochemical responses that are customarily linked together. This report is an overview of a series of studies by our laboratory investigating the role of different ligand structures in eliciting hormonal responses. Diethylstilbestrol (DES) and certain structural analogs, indenestrol A (IA), indenestrol B (IB), and pseudo-DES, were used as probes to segregate various genomic responses previously considered interrelated, most notably the events of specific protein synthesis and DNA synthesis. These compounds have weak uterotrophic activity; however, they interact with high affinity specifically with mouse uterine estrogen receptors (ERs). All of them produce stoichiometrically similar amounts of ER complex in the nucleus. Indenestrol A and IB possess a single chiral carbon atom and exist as a mixture of enantiomers (ENTs). Competitive binding assays of pure ENTs and cytosolic ERs demonstrated a stereochemical chiral preference for the IA isomer but not IB. This preference was also evident from nuclear ER occupancy experiments. Biologic activity of the IA ENTs also demonstrated differences as seen by receptor binding. Ornithine decarboxylase (ODC) activity was stimulated 600% by DES and partially by IA (rac). All of the ODC activity produced by IA (rac) was due to the IA(C3)-S ENT. Uterine DNA synthesis was measured after treatment with the IA compounds. Indenestrol A (rac) increased DNA synthesis to 40% of the level seen with DES. The weak ENTs showed no activity and the active ENTs were weaker than the IA racemic. These compounds should be useful probes for studying the individual responses involved in estrogen-induced uterine growth.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fluorescence determination of enantiomeric composition of pharmaceuticals via use of ionic liquid that serves as both solvent and chiral selector

A new method has been developed for the sensitive and accurate determination of enantiomeric compositions of a variety of drugs, including propranolol, naproxen, and warfarin. The method is based on the use of the fluorescence technique to measure diastereomeric interactions between both enantiomeric forms of a drug with an optically active room temperature ionic liquid (RTIL) followed by partial least squares analysis of the data. The chiral RTIL used in this study, S-[(3-chloro-2-hydroxypropyl) trimethylammonium] [bis((trifluoromethyl)sulfonyl)amide] (S-[CHTA](+) [Tf(2)N](-)), is a novel chiral RTIL that has been synthesized successfully recently in our laboratory in optically pure form using a simple one-step reaction with commercially available reagents. The high solubility power and strong enantiomeric recognition ability make it possible to use this chiral RTIL to solubilize a drug and to induce diastereomeric interactions for the determination of enantiomeric purity, that is, to use it as both solvent and chiral selector. Enantiomeric compositions of a variety of pharmaceutical products with different shapes, sizes, and functional groups can be determined sensitively (microgram concentration) and accurately (enantiomeric excess as low as 0.30% and enantiomeric impurity as low as 0.08%) by use of this method.     

Inpatient deaths from acute myocardial infarction, 1982-92: analysis of data in the Nottingham heart attack register.

OBJECTIVE: To assess longitudinal trends in admissions, management, and inpatient mortality from acute myocardial infarction over 10 years. DESIGN: Retrospective analysis based on the Nottingham heart attack register. SETTING: Two district general hospitals serving a defined urban and rural population. SUBJECTS: All patients admitted with a confirmed acute myocardial infarction during 1982-4 and 1989-92 (excluding 1991, when data were not collected). MAIN OUTCOME MEASURES: Numbers of patients, background characteristics, time from onset of symptoms to admission, ward of admission, treatment, and inpatient mortality. RESULTS: Admissions with acute myocardial infarction increased from 719 cases in 1982 to 960 in 1992. The mean age increased from 62.1 years to 66.6 years (P < 0.001), the duration of stay fell from 8.7 days to 7.2 days (P < 0.001), and the proportion of patients aged 75 years and over admitted to a coronary care unit increased significantly from 29.1% to 61.2%. A higher proportion of patients were admitted to hospital within 6 hours of onset of their symptoms in 1989-92 than in 1982-4, but 15% were still admitted after the time window for thrombolysis. Use of beta blockers increased threefold between 1982 and 1992, aspirin was used in over 70% of patients after 1989, and thrombolytic use increased 1.3-fold between 1989 and 1992. Age and sex adjusted odds ratios for inpatient mortality remained unchanged over the study period. CONCLUSIONS: Despite an increasing uptake of the "proved" treatments, inpatient mortality from myocardial infarction did not change between 1982 and 1992.     

Patterns of medical drug use - a community focus.

The pattern and extent of medical use of drugs was examined by survey in a rural Ontario community (Smithville) and a suburban (Burlington) family practice. Changes in established patterns of drug use that occur after the introduction of a nurse practitioner were also examined in the suburban practice. In both surveys 60% of respondents were using at least one medication and 30% were taking at least one medication prescribed or suggested by a doctor. There were consistently high rates of use of nonprescribed drugs at all ages, especially among females. Vitamins and tonics were the most commonly used drugs, and were taken by 25 to 28% of the respondents, 40% of whom used them on the advice of a physician. From 8.8 to 10.5% of respondents used sedatives or tranquillizers, and reduction in the prescribed use of these drugs was found among patients managed by the nurse practitioners. Self-medication is apparently unrelated to the frequency of medical consultation.