Large outbreak of isoniazid-monoresistant tuberculosis in London, 1995 to 2006: case-control study and recommendations.

We conducted a case­control study to examine risk factors for isoniazid-monoresistant Mycobacterium tuberculosis in an ongoing outbreak in London. Cases were defined as individuals with an isoniazid-monoresistant strain diagnosed from 1995 to the third quarter of 2006 with an indistinguishable restriction fragment length polymorphism (RFLP) or mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeats (VNTR) pattern who were resident in or had epidemiological links with London. Controls were all other individuals reported with tuberculosis to the Health Protection Agency London regional epidemiology unit or the HPA London TB Register during 2000 to 2005. Of 293 cases, 153 (52%) were sputum smear-positive compared with 3,266 (18%) of controls. Cases were more likely to be young adults (aged between 15 and 34 years), born in the United Kingdom (OR: 2.4; 95% CI: 1.7­3.4) and of white (OR: 2.9; 95% CI: 1.8­4.8) or black Caribbean (OR: 12.5; 95% CI: 7.7­20.4) ethnicity, a prisoner at the time of diagnosis (OR: 20.2; 95% CI: 6.7­60.6), unemployed (OR: 4.1; 95% CI: 3.0­5.6), or a drug dealer or sex worker (OR: 187.1; 95% CI: 28.4­1,232.3). A total of 113 (39%) of cases used drugs and 54 (18%) were homeless. Completion of treatment gradually improved in cases from 55% among those diagnosed up to the end of 2002 compared with 65% by the end of 2006. Treatment completion increased from 79% to 83% in controls from 2000 to 2005. There are complex social challenges facing many cases in this outbreak that need to be addressed if medical interventions are to be successful.

Recent trends in tuberculosis in children in London.

BACKGROUND: Childhood tuberculosis (TB) represents a sentinel event of recent transmission and is an indication of the effectiveness of prevention and control interventions. We analysed the trends in the epidemiology of TB in children in London aged 0-14 years between 1999 and 2006. METHODS: Data were extracted from the Enhanced TB Surveillance System. RESULTS: Between 1999 and 2006, there were 1370 cases of TB in children. Incidence was higher in older children and in girls. The incidence rates in London Boroughs varied from 0.4/100,000 to 32.7/100,000. Between 1999 and 2006, Black-Africans comprised 49.2% of all TB cases in children, children from the Indian Subcontinent 21.8% and Whites 8.5%. The proportion of cases born in the UK averaged 52.4% during this period. Of non-UK-born children 79.3% were diagnosed with TB within 5 years of entry. CONCLUSIONS: Ethnicity, country of birth and age are important risk factors for development of. With an overall TB incidence in London exceeding 40/100,000, universal BCG immunization of all neonates should be considered across all London boroughs.

Predictors of failure to complete tuberculosis treatment in London, 2003-2006.

SETTING: London, 2003-2006. OBJECTIVES: To investigate tuberculosis (TB) treatment completion failure in London and associated risk factors during 2003-2006. DESIGN: Cross-sectional analysis of treatment outcome and other explanatory variables in a cohort of TB patients reported to the London TB Register from 2003 to 2006. METHODS: An innovative definition of TB treatment outcome more suitable for low-incidence industrialised countries, such as the United Kingdom, was adopted. A multivariable logistic approach was used to assess predictors of unsuccessful outcome. RESULTS: A total of 12,929 TB cases were notified from 2003 to 2006, of which 12% (n = 1536) failed to complete TB treatment. The proportion of cases failing to complete treatment showed a significant decrease from 2003 to 2006 (13% in 2003 vs. 10% in 2006). Males, the elderly, hospitalised patients, short- and long-term immigrants, Whites and the least deprived were more likely to fail to complete treatment. CONCLUSIONS: The proportion of TB treatment success in London exceeded the World Health Organization recommended threshold of 85%. Some specific categories of patients that are more likely to fail to complete treatment should be targeted by health services to enhance their engagement and adherence to the treatment regimen.

Ispaghula husk in the treatment of hypercholesterolaemia: a double-blind controlled study.

BACKGROUND: Lowering cholesterol levels by natural dietary modification is an attractive first-line option for the treatment of mild-to-moderate hypercholesterolaemia. However, results have been less than impressive. The addition of soluble fibre - for example, psyllium or oat bran - to a modified diet has produced better results. In this study, the cholesterol-level-lowering effect of ispaghula husk and dietary advice was compared with placebo and dietary advice in treating patients with mild-to-moderate hypercholesterolaemia. METHODS: The double-blind, placebo-controlled, randomized comparison was conducted in 42 general practices and three hospital centres in the UK. There was an initial 8-week diet-only period and then a 1 2-week treatment period. Ispaghula treatment (7.0 or 10.5 g/day) was continued for a further 12 weeks for some patients. A total of 340 patients, aged 18 to 65, with mild-to-moderate hypercholesterolaemia [low-density lipoprotein (LDL) cholesterol levels of 4.1 mmol/l or more] entered the 12-week treatment phase. Levels of LDL cholesterol, total cholesterol, high-density lipoprotein cholesterol, triglycerides and apolipoproteins A1 and B were determined. RESULTS: LDL cholesterol and total cholesterol levels fell during the diet-only period. In members of the intention-to-treat population after the 8-week diet period, LDL cholesterol levels had fallen by 0.42 mmol/l (8.7%) for the 7.0 g ispaghula/day group after 12 weeks of treatment, whereas LDL cholesterol levels had fallen by 0.48 mmol/l (9.7%) for the 10.5 g ispaghula/day group. Ispaghula at both doses produced significantly greater reductions in LDL cholesterol levels than did placebo (7.0 g/day versus placebo, P=0.009; 10.5 g/day versus placebo, P<0.001). Ispaghula and modification of diet together reduced LDL cholesterol levels by 10.6-13.2% and total cholesterol levels by 7.7-8.9% during the 6-month period. CONCLUSIONS: Ispaghula husk as an adjunct to diet is effective and well tolerated in the management of appropriate patients with mild-to-moderate primary hypercholesterolaemia.

Crime and drug use among applicants for methadone maintenance.

The relationship between crime and drug use was examined in 313 Australian opioid addicts who applied for entry to methadone treatment. More than 90% of them had recorded one or more convictions for property or drug offences. Subjects' self-reported convictions were moderately correlated with convictions recorded by the police. Men were more likely to begin their opioid use at or after their first criminal conviction, while women were more likely to begin offending after they used opioids. The rate at which subjects accrued convictions for property offences declined as they grew older and the earlier a subject's first exposure to the criminal justice system the higher the rate at which they accrued convictions.

The characteristics of cocaine users among young adults in Sydney.

OBJECTIVE: To describe the prevalence and pattern of cocaine use among young Sydney adults interviewed during a study of the "market position" of cocaine. DESIGN: A telephone survey of young Sydney adults. PARTICIPANTS: A total of 499 young Sydney men and women aged between 14 and 35 were selected to ensure a sample of 300 persons who used alcohol and tobacco at least weekly, and who had been offered or had tried at least one illicit drug. MAIN OUTCOME MEASURES: These were the prevalence of having ever used cocaine, the frequency of cocaine use, the prevalence of daily alcohol and tobacco use, and of ever having tried marijuana, sedatives, designer drugs, amphetamines and heroin. RESULTS: Thirteen per cent of the sample (95% confidence interval [CI], 10%-16%) had ever tried cocaine, of whom only 20% (CI, 15%-25%) were current users. Cocaine users were distinguished from non-users by being more likely to be daily users of tobacco (odds ratio, 2.1; CI, 1.3-3.6) and alcohol (odds ratio, 3.0; CI, 1.7-5.6), and to have tried marijuana (odds ratio, 7.1; CI, 3.2-15.9), sedatives (odds ratio, 11.4; CI, 6.4-20.7), designer drugs (odds ratio, 17.2; CI, 9.2-32.2), amphetamines (odds ratio, 27.1; CI, 14.3-51.3), and heroin (odds ratio, 36.5; CI, 14.0-94.9). The odds of having tried cocaine increased with the number of different types of illicit drugs that the person had tried. CONCLUSIONS: The prevalence of ever having tried cocaine was low among a sample of young adults selected to ensure an over-representation of illicit drug users. Cocaine users were more likely to have experimented with a variety of different types of illicit drugs. Only a minority of those who had ever tried cocaine were current users.

Drug use, injecting practices and sexual behaviour of opioid users in Sydney, Australia.

This paper examines drug use, injection practices, and sexual behaviour in a sample of 100 opioid users, both in and out of current opiate treatment. Approximately three-quarters of subjects reported that they had used more than one illicit substance in the month prior to being interviewed. Needle sharing was common, with 29% of subjects having used a needle in the past month after it had been used by someone else, and 25% having passed on a needle after they had used it. The level of condom use was low, with 66.7% of subjects never having used a condom with their regular partner in the month prior to interview, and 20.7% of subjects who had engaged in sex with a casual partner during this period not having used a condom. Variables which were predictive of HIV risk-taking behaviour in relation to needle use were poly-drug use, not being in current treatment, and level of heroin use. Only age was predictive of risky sexual behaviour, with younger subjects being associated with more risk-taking behaviour. It was concluded that while opiate treatment was associated with lower levels of risky injecting practices, there was no association between treatment and safer sexual practices. Given the importance of sexual transmission of HIV more attention needs to be given to the sexual risk-taking behaviour of intravenous drug users.

The drug market position of cocaine among young adults in Sydney.

A study was undertaken to explore the 'market position' of cocaine among young adults in Sydney, Australia. The intention was to estimate how likely Australia is to experience an epidemic of cocaine use if the availability of the drug was to increase. A sample of 499 young adults in which illicit drug users were overrepresented were surveyed. The results suggested that there was not a large untapped market for cocaine. In terms of risk and attraction, cocaine was perceived to be more like the traditional 'hard drugs' of heroin, stimulants and hallucinogens than the traditional 'soft drugs' of alcohol and marijuana. Only 5% of the sample were prepared to try cocaine if offered it by a close friend.

The effects of polymorphism, particle size and compression pressure on the dissolution rate of phenylbutazone tablets.

The dissolution rate of phenylbutazone from tablets after disintegration has been used to determine whether the drug particles underwent crushing or bonding during compression. Two polymorphic forms of the drug were used and the predominant effect for high drug concentration (60%), during compression was dependent upon the original particle size of the drug and its polymorphic form. With a low drug concentration (10%) in the tablet, the diluent protected the drug particles from bonding together. The particle size change of the drug during compression was affected by the nature of the diluent present. Lactose had an abrasive action on Form A phenylbutazone compared with Avicel but had little effect on the more ductile Form B. When the contact time of compression was decreased from 29 to 0.26 s, the 6 microns particles of drug showed less bonding at the shorter time (faster rate of compression) but the effect observed with the larger particles was independent the compression rate.

Thermal behaviour and dissolution properties of phenylbutazone polymorphs.

Five different polymorphic forms of phenylbutazone were prepared and characterized by differential scanning calorimetry (D.S.C.). Rapid heating rates produced single endothermic peaks due to melting but slower heating rates resulted in interconversion of three of the polymorphs to the more stable form. Interconversion on grinding the polymorphs was also observed. From equilibrium solubility and intrinsic dissolution rates it was concluded that the dissolution process could be described by the Berthoud model. The effect of some tablet excipients on the dissolution process is briefly reported.

Investigations on the in vitro dose-related metabolism of indomethacin in four laboratory species.

The influence of dose on the in vitro metabolism of indomethacin has been investigated in four laboratory species (rat, rabbit, guinea pig, hamster). It was found that in the rat and guinea pig the ratio of deacylated to demethylated metabolites was dependent on the substrate concentration of indomethacin, whereas in the rabbit the ratio remained constant in the dosage range investigated (1-10 mumoles). No demethylated product was found in the hamster but a high level of activity of the deacylase enzyme was observed. These findings may help to explain species-dependent toxicity.

Comparison of the in vitro dissolution behaviour of various indomethacin formulations with their in vivo bioavailability.

The effects of the core toi colloid wall ratio and particle size of the core on the in vitro release of indomethacin microcapsules prepared by the gelatin-acacia complex coacervation process have been examined. All formulations showed a zero order release pattern after an initial burst phase. The release rate increased with increasing core to coat ratios and decreasing particle size of core material. In vivo plasma level studies showed no difference in bioavailability between different microcapsule formulations or a conventional indomethacin capsule. In vitro release studies on a commercially available sustained release formulation of indomethacin (Indocid R) were slower than any of the microcapsule formulations and exhibited a square root t dependence indicating a diffusion controlled process from a matrix formulation. In vivo studies show this formulation to have a longer smoother plasma concentration than the microcapsule formulation, and to avoid high initial peak values of drug. Thus from the in vitro studies a sustained release effect was not unexpected but the in vitro differences between the microcapsule products were not paralleled by the in vivo behaviour. These results illustrate some of the problems in extrapolation of in vitro dissolution data to the in vivo situation.

Influence of crystal form on tensile strength of compacts of pharmaceutical materials.

The tensile strengths of compacts of different crystal forms of aspirin, sulfathiazole, and barbital were determined with a modified tablet hardness tester. For each material, the tensile strength could be correlated with the amount of plastic flow and/or crushing undergone by each crystal form during compression.

The crystallization behaviour of sulphathiazole.

Previous investigations into the dissolution kinetics of sulphathiazole Form 1 have shown the process to be first order with respect to driving force. However, below 37 degrees first order kinetics did not apply, due to the surface reaction becoming the rate controlling factor. The present study examines the kinetics of crystallization over the temperature range 25 to 50 degrees. Crystallization is a process greatly dependent upon the high-entropy surface integration step which, unlike the dissolution process, is much more sensitive to crystal growth inhibitors. In the absence of inhibitors crystallization above 34 degrees follows first order kinetics but below 34 degrees the process changes to third order. Similar temperature effects on the dissolution of sulphathiazole have been previously reported.

The influence of crystal form on the radial stress transmission characteristics of pharmaceutical materials.

Various crystal forms of sulphathiazole, barbitone and aspirin were compressed in a single-punch tablet machine instrumented to monitor axially applied and radially transmitted forces, and upper punch movement. The changes in radial stress during the compression cycle depended upon the polymorphic form of the compressed material. The results were rationalized in terms of the degree of plastic flow/crushing that occurred with each material, and the degree to which the final compact underwent elastic compression. It is postulated that the reduction in the transition temperature of polymorphic forms of sulphathiazole and barbitone and the polymorphic transition of sulphathiazole Form II was due to the production of dislocations in the crystal and the crystals at crystal boundaries formed in the compressed materials.

Changes in the particle size distribution during tableting of sulphathiazole powder.

Five size fractions of sulphathiazole powder (volume surface mean diameter 155, 133, 86, 50 and 41 mum) were compressed into 12 mm diameter tablets on an instrumented single punch tablet machine. The size analysis of the tablet material after compression showed an attrition of the coarser fraction and an agglomeration of the finer fraction. It is postulated that there is a critical particle size where the effects of crushing and bonding cancel each other. The changes in particle size are discussed in relation to some of the compressive characteristics of the powder.