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Introduction The present study generated preliminary data on the acceptability and pharmacokinetics of nicotine administered by a simple metered-dose inhaler (MDI). Methods We conducted a nonrandomized, open-label cross-over trial of 10 current smokers. On Day 1, a single cigarette was smoked ad libitum. On Day 2, participants took 10 puffs (20 inhalations) of 50 microg nicotine/puff through the inhaler, and on Day 3, they took 10 puffs (20 inhalations) of 100 microg nicotine/puff, each over 5 min. Nicotine pharmacokinetics, changes in heart rate and blood pressure, and the acceptability of the inhalers were measured and recorded. Results Nicotine administered by an MDI produced a median maximum plasma concentration that was about 50% of that obtained by smoking a cigarette (12.5 vs. 25.9 ng/ml) and took twice the time to reach that concentration, 6 versus 3 min. Self-rated satisfaction and reduced urge to smoke were similar for the MDIs and a cigarette. Discussion The results suggest that nicotine can be delivered effectively by the pulmonary route using a standard MDI. The inhaler appears to provide a satisfaction level and reduction in the urge to smoke relatively similar to that provided by smoking a cigarette. These conclusions require verification in a larger controlled study.

Background: Several studies have described improved outcomes for HIV-infected patients admitted to the intensive care unit (ICU) since the introduction of highly active antiretroviral therapy (HAART). A study was undertaken to examine the outcome from the ICU for HIV-infected patients and to identify prognostic factors. Methods: A retrospective study of HIV-infected adults admitted to a university affiliated hospital ICU between January 1999 and December 2005 was performed. Information was collected on patient demographics, receipt of HAART (no patient began HAART on the ICU), reason for ICU admission and hospital course. Outcomes were survival to ICU discharge and to hospital discharge. Results: 102 patients had 113 admissions to the ICU; HIV infection was newly diagnosed in 31 patients. Survival (first episode ICU discharge and hospital discharge) was 77% and 68%, respectively, compared with 74% and 65% for general medical patients. ICU and hospital survival was 78% and 67% in those receiving HAART, and 75% and 66% in those who were not. In univariate analysis, factors associated with survival were: haemoglobin (OR = 1.25, 95% CI 1.03 to 1.51, for an increase of 1 g/dl), CD4 count (OR = 1.59, 95% CI 0.98 to 2.58, for a 10-fold increase in cells/µl), APACHE II score (OR = 0.51, 95% CI 0.29 to 0.90, for a 10 unit increase) and mechanical ventilation (OR = 0.29, 95% CI 0.10 to 0.83). Conclusions: The outcome for HIV-infected patients admitted to the ICU was good and was comparable to that in general medical patients. More than a quarter of patients had newly diagnosed HIV infection. Patients receiving HAART did not have a better outcome.

Objective: To determine whether measurement of cotinine in saliva is a sensitive measure of exposure to secondhand smoke (SHS) among customers in bars. Design: Before/after comparison of saliva cotinine and subjective assessments of SHS. Setting: Three bars in Wellington, New Zealand, June 2003. Participants: Eleven non-smoking medical students spent three hours in each location. They provided saliva samples before and after the visit, counted numbers of lit cigarettes in each bar, and assessed the smokiness of the venue. Samples were tested for cotinine using liquid chromatography coupled with mass spectrometry. Results: Cotinine levels post-visit were consistently higher than baseline. The mean difference was 1.03 ng/mL with a 95% confidence interval of 0.76–1.30 ng/mL. Adjustments to post-visit levels for metabolism and clearance of cotinine made very little difference to these results. Males tended to have higher baseline levels than females, and to show smaller increases. The bar with the greatest increase in cotinine was judged to be the smokiest on the basis of averaged cigarette counts and scores for presence of smoke and odour. Conclusion: The cotinine in saliva, when tested with the analytic methods described here, provides a means of assessing relatively short-term exposures to SHS.

The objective of this study was to determine the clinical effects of party pills containing benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) when taken alone and in combination with alcohol. The study was a randomised, double-blind, placebo-controlled trial conducted in a hospital-based clinic in Wellington, New Zealand. Thirty-five volunteers who had previously used party pills containing BZP were included in this trial. Participants received one of the following four treatments: 300 mg/74 mg BZP/TFMPP and placebo, 300 mg/74 mg BZP/TFMPP and 57.6 g (6 units) alcohol, placebo and 57.6 g (6 units) alcohol and double placebo. The primary outcome variable was a measure of driving performance, the standard deviation of lateral position (SDLP) measured at 6.5 h. Secondary measures included adverse events, cardiovascular effects, psychological function and delayed effects on sleep. The study was stopped early, after 35 of the planned 64 subjects had undertaken testing, because of severe adverse events that occurred in four of 10 BZP/TFMPP-only subjects, three of seven combined BZP/TFMPP and alcohol subjects, none of the 6 placebo subjects, and none of the 12 alcohol-only subjects. The overall rate of severe adverse events (defined as causing considerable interference with usual activity and/or rated by subject as severe) in those receiving BZP/TFMPP was seven of 17 (41.2%, 95% CI 18.4—67.1). The severe events included agitation, anxiety, hallucinations, vomiting, insomnia and migraine. BZP/TFMPP significantly improved the driving performance, decreasing SDLP at −4.2 cm (95% CI −6.8 to −1.6, P = 0.002). The effect of alcohol was to increase SDLP: 2.3 cm (95% CI −0.3 to 4.9, P = 0.08). BZP/TFMPP also resulted in increased heart rate and blood pressure and in difficulty in getting to sleep. BZP/TFMPP alone or with alcohol carries a significant risk of severe adverse events when taken in similar doses to those recommended by manufacturers.

Aim: To measure exposure to second-hand smoke (SHS) in New Zealand bars before and after comprehensive smoke-free legislation enacted on 10 December 2004. Methods: Cotinine is the main specific metabolite of nicotine and a well-established biomarker for SHS exposure. We measured cotinine levels in saliva of non-smoking volunteers before and after a 3 h visit to 30 randomly selected bars in 3 cities across the country. Two measures of cotinine before the smoke-free law change during winter and spring 2004, and two follow-up measurements in the same volunteers and venues during winter and spring 2005, were included. Results: Before the smoke-free law change, in all bars and in all volunteers, exposure to SHS was evident with an average increase in saliva cotinine of 0.66 ng/ml (SE 0.03 ng/ml). Increases in cotinine correlated strongly with the volunteers’ subjective observation of ventilation, air quality and counts of lit cigarettes. However, even venues that were judged to be “seemingly smoke free” with “good ventilation” produced discernable levels of SHS exposure. After the law change, there remained some exposure to SHS, but at much lower levels (mean saliva cotinine increase of 0.08 ng/ml, SE 0.01 ng/ml). Smoking indoors in bars was almost totally eliminated: in 2005 only one lit cigarette was observed in 30 visits. Conclusions: Comprehensive smoke-free legislation in New Zealand seems to have reduced exposure of bar patrons to SHS by about 90%. Residual exposures to SHS in bars do not result from illicit smoking indoors.

The effect of total particulate matter (TPM) from cigarette smoke on the expression and binding properties of nicotinic acetylcholine receptors (nAChRs) was investigated using a human neuroblastoma cell line (SH-SY5Y). TPM but not nicotine on its own inhibited cell growth at nicotine concentrations above 5 microM. To examine effects on nAChR expression, intact cells were incubated with 3H-epibatidine, and a Bmax of 13 fmoles/10(5) cells (7.8 x 10(4) binding sites/cell) was measured in unexposed cells as well as in cells treated with 2 microM nicotine alone or with TPM containing 2 microM nicotine. Using Scatchard analysis, we measured a Kd of 0.3 nM for 3H-epibatidine binding to nAChRs. This Kd was increased to 1.3 nM by addition of nicotine or TPM extract, both at 2 microM nicotine. Bmax, however, was unaffected, suggesting competitive binding of nicotine to its receptor. Short-term and prolonged 3-day exposures of SH-SY5Y cells to either TPM or nicotine at nicotine concentrations ranging from 0.2 microM to 20 microM increased specific binding, suggesting upregulation of nAChR expression. Most significant, binding was consistently greater in cells pretreated with TPM than in cells pretreated with nicotine. We conclude that TPM contains compounds that are toxic to cells at high concentrations (cell growth inhibition) but that do not compete with nicotine for binding to nAChRs (Scatchard analysis). These non-nicotinic compounds are capable of increasing the expression of one or more of the nAChR subunits. Furthermore, our cell culture assay provides a useful in vitro model for assessing the relative addictiveness of different tobacco products, including that of non-nicotine components.

Occupational exposure to blood-borne pathogens remains an important and largely preventable issue in hospital practice. This article argues that formal training can increase use of best practice phlebotomy. A survey of at-risk healthcare workers at a central London hospital was conducted to identify factors associated with use of an evacuated blood collection system (BD Vacutainer®) and gloves while taking blood. Eighty per cent of doctors and 37% of non-doctors performing percutaneous venepuncture did not use the Vacutainer system exclusively. Doctors qualified less than three years were particularly likely to prefer needle and syringe. Venepuncture technique training significantly increased the probability of always using the Vacutainer system from 7% to 46%. The only factor independently associated with glove use was operator experience. There is considerable room for improvement in phlebotomy technique, particularly among junior doctors. The Modernising Medical Careers initiative provides a unique opportunity to implement this.

Nicotine is the major addictive compound in tobacco and is responsible for tobacco dependence. It is primarily metabolized to cotinine (COT) and trans-3'-hydroxycotinine (3HC) by the liver enzyme cytochrome P-450 2A6 (CYP2A6). The 3HC/COT ratio measured in the saliva of smokers is highly correlated with the intrinsic hepatic clearance of nicotine and, therefore, may be a useful non-invasive marker of CYP2A6 activity and metabolic rate of nicotine. This study assessed within-subject variation in salivary 3HC/COT ratios in six regular daily smokers. Our data provide evidence that 1. variation in the 3HC/COT ratio is not dependent on the time of sampling during the day (i.e., morning vs. night ) (P > 0.1) and 2. the average within-subject biological variation in the 3HC/COT ratio is approximately 26%. These findings should be useful for designing large-scale population surveys to assess the variation in the metabolic rate of nicotine (via CYP2A6) in smokers.

Drug screening methods were developed to detect alprazolam, clobazam, clonazepam, diazepam, midazolam, oxazepam, temazepam, triazolam, zopiclone, and selected metabolites in human hair and nail samples employing liquid–liquid extraction and tandem liquid chromatography–mass spectrometry (LC–MS–MS). Hair and nail samples were obtained from patients who had recently discontinued or were currently prescribed one or more of the targeted drugs. Prazepam was used as the internal standard for all compounds. Some components in the hair matrix gave the same transitions as some of the analytes but did not compromise the analyses because their retention times differed from those for the target compounds. The analytical run time was 8–10 min. Results of the hair analysis of a DFSA victim are also presented.

Testing for drugs in oral fluid is a convenient procedure for determining recent drug use. A number of issues are still to be resolved and this paper investigates the effects of storage systems on drug stability and recovery using three different collection devices supplied by Cozart, Immunalysis and Microgenics (third party). Drugs were analysed using a range of immunoassay systems followed by MS confirmation and quantitation. The reproducibility of the weight of specimen collected was excellent (CV

Mycobacterium tuberculosis is a significant threat to global health. Mycobacterium bovis BCG vaccine provides only partial protection, and the skin test reagent used to aid diagnosis of both active and latent tuberculosis, purified protein derivative (PPD), lacks specificity and sensitivity. The use of genetically detoxified Bordetella pertussis adenylate cyclase toxin (CyaA) as a delivery system for two immunodominant proteins of M. tuberculosis that are of greater specificity than PPD, early-secreted antigenic target 6-kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10), was therefore investigated. CyaA toxoids incorporating these antigens were able to restimulate T cells from more than 91% tuberculosis patients and healthy sensitized donors. Delivery of antigen by CyaA decreased by 10-fold the amount of ESAT-6 and CFP-10 required to restimulate T cells, and in low responders, the overall frequency of gamma interferon-producing cells detected by enzyme-linked immunospot assay was increased ( P < 0.01 for both antigens). Delivery of ESAT-6 and CFP-10 by CyaA enabled the detection of both CD4 + and CD8 + T cells: these responses could be blocked by inhibition of major histocompatibility complex class II or class I, respectively. Covalent linkage of antigen to the CyaA vector was required for enhancement to occur, as a mixture of mock CyaA toxoid plus recombinant ESAT-6 did not lead to enhancement. In a simplified whole-blood model to detect tuberculosis infection, the frequency of positive responses to CFP-10 was increased by CyaA delivery, a potentially important attribute that could facilitate the identification of latent infection.

Forensic toxicology laboratories are often required to implicate or exclude poisoning as a factor in a death or unexplained illness. An analytical tool which enables toxicologists to screen a wide variety of common poisons would be extremely useful. In this paper, we describe the use of a bacterial biosensor for detecting the presence of commonly encountered potentially toxic chemicals in urine. The biosensor responds to any chemical that causes metabolic stress to the bacterial cell and the response is in direct proportion to the concentration of the stressor. This allows a measure of the concentration of a toxicant in urine, without knowing exactly what the toxic compound(s) may be. This affords a distinct advantage over conventional analytical techniques, which require an extensive screening program before it is even known that a toxic compound is present. This preliminary investigation has shown that this biosensor can indicate the presence, in urine, of herbicides such as glyphosate, 2,4-dichlorophenoxyacetic acid, and 2,4,5-trichlorophenoxyacetic acid; the biocide pentachlorophenol; or inorganic poisons such as arsenic, mercury, and cyanide. The biosensor was also shown to be sensitive to a concentration range of these toxicants likely to be found in samples submitted for toxicological analysis.

This study compares the utility of gastric washings (GWs) and bronchoscopy in the diagnosis of smear-negative pulmonary tuberculosis (TB). The aim of the study was to identify which investigation or combination of investigations provided the greatest yield of positive Mycobacterium tuberculosis cultures of samples from patients with smear-negative pulmonary TB. We retrospectively analyzed the medical records of 180 patients with smear-negative pulmonary TB. The positive culture yield for bronchoalveolar lavage fluid (62 [34%] of 180 patients) was significantly greater than that for specimens from 3 GWs (32 [21%] of 149 patients) (P=.02). Combining GW and bronchoscopy increased the positive culture yield: bronchoscopy combined with 2 GWs resulted in a positive culture rate of 38%. Bronchoscopy is superior to GW in the diagnosis of smear-negative pulmonary TB; however, the combination of bronchoscopy and 2 GWs should be regarded as optimal for the diagnosis of smear-negative pulmonary TB.

A method Is presented for the gas-liquid chromatographic determination of procyclidine in blood at therapeutic and toxic concentrations. Procyclld|ne levels in blood samples taken from patients on regular procyclidine therapy (10-30 mg per day), and in a postmortem blood sample were 0.1-0.7/aglml and 7.8/Jg/ml, respectively.

A method involving gas-fiquid chromatography with nitrogenphosphorus detection is presented for the determination of toxic and therapeutic pheniramine levels in blood and toxic levels in tissue. Therapeutic levels of pheniramine in six subjects two hours after taking 75 mg pheniramine maleate were found to vary from 0.01 to 0.19Fg/mL of blood. Blood and tissue levels from two postmortem cases are reported.

Three different extraction procedures were used to determine drug levels in liver samples subjected to alcalase digestions. A micro-scale 1-chlorobutane extraction produced the most consistent results for a wide range of drug types.