Methadone enhances the effectiveness of 5‐aminolevulinic acid‐based photodynamic therapy for squamous cell carcinoma and glioblastoma in vitro

Although having shown promising clinical outcomes, the effectiveness of 5‐aminolevulinic acid‐based photodynamic therapy (ALA‐PDT) for squamous cell carcinoma (SCC) and glioblastoma remains to be improved. The analgesic drug methadone is able to sensitize various tumors to chemotherapy. In this in vitro study, the influence of methadone to the effectiveness of ALA‐PDT for SCC (FADU) and glioblastoma (A172) was investigated on the protoporphyrin IX (PpIX) fluorescence, survival rates, apoptosis, and cell cycle phase, each with or without the presence of methadone. The production of PpIX was increased by methadone in FADU cells while it was decreased in A172 cells. The survival rates of both cell lines treated by ALA‐PDT were significantly reduced by the combination with methadone (P < .05). Methadone also significantly increased the percentage of apoptotic cells and improved the effect of ALA‐PDT on the cell cycle phase arrest in the G0/G1 phase (P < .05). This study demonstrates the potential of methadone to influence the cytotoxic effect of ALA‐PDT for both SCC and glioblastoma cell lines.      

Effectiveness and cost effectiveness of expanding harm reduction and antiretroviral therapy in a mixed HIV epidemic: a modeling analysis for Ukraine

Background

Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine—chosen in this study as a representative country—IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study.

Methods and Findings

We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective.

Conclusions

Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics. Please see later in the article for the Editors'' Summary     

Sexual risk behaviour of Canadian participants in the first efficacy trial of a preventive HIV-1 vaccine

Background

Phase I and phase II HIV-1 vaccine trials have revealed increases in risky sexual activity among study subjects during the trials, perhaps because the subjects believe that the vaccine being tested is efficacious; subjects may thus suffer harm from their participation. We evaluated the sexual behaviour of Canadian men who have sex with men (MSM) who participated in the phase III Vax004 trial of an HIV-1 vaccine.

Methods

Using self-reports of sexual behaviours during the 6 months before trial entry as a baseline, we determined changes in reported sexual behaviour after 6, 12 and 18 months of participation in the trial.

Results

Of 291 HIV-seronegative MSM enrolled from July to October 1999, 260 (89%) completed 18 months of follow-up, 19 (7%) experienced seroconversion, and 12 (4%) did not complete follow-up. Unprotected receptive anal intercourse during the previous 6 months with partners whose HIV-1 serostatus was positive or unknown was reported by 21% of men at enrolment and by 27% at any point during 18 months of follow-up. No increase in this behaviour from baseline was reported by participants, including among men who were motivated to enrol because of expected protection from HIV-1 infection, men who believed they had received the vaccine, men who believed that the vaccine had greater than 50% efficacy, or men who believed that they had received the vaccine and that vaccine efficacy was greater than 50%.

Interpretation

MSM can be successfully enrolled in HIV-1 vaccine efficacy trials without evident increases in those sexual behaviours most associated with HIV-1 risk.Development of preventive HIV-1 vaccines requires clinical trials that effectively recruit, enrol and retain high-risk subjects, including men who have sex with men (MSM). Since candidate vaccines may prove to have little or no efficacy, these trials must also strive to minimize harms associated with participation. A major concern has been that trial participants might believe vaccination affords some protection and therefore increase their sexual risk-taking.^1,2 This concern derives in part from increases in unprotected anal intercourse observed during phase I and phase II vaccine trials. For example, self-reports of unprotected insertive anal intercourse during the previous 6 months increased among 44 gay men enrolled in San Francisco trials, from 9% at enrolment to 20% at the 12-month assessment; however, the HIV status of sexual partners was not assessed.¹ The world''s first phase III trial to evaluate a candidate preventive HIV-1 vaccine was recently completed in North America and Europe.² A consortium sponsored by the Canadian Network for Vaccines and Immunotherapeutics of Cancer and Chronic Viral Diseases (CANVAC) was formed to assess participation, retention and change in sexual risk behaviour at trial sites in this country. We report here the Canadian experience in this trial through 18 months of follow-up and assess trends in high-risk sexual behaviour reported by participants.     

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction

Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen‐response element single nucleotide polymorphism (ERE‐SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R‐ or S‐) of 2‐ethylidene‐1,5‐dimethyl‐3,3‐dipheny‐pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug‐seeking behaviour, implicating oestradiol‐CYP‐EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up‐regulates methadone‐associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration‐induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6‐ERE‐SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add‐on therapy clinical trial introducing SERM in MMT regimen is suggested.     

Progression of HIV infection in misusers of injected drugs who stop injecting or follow a programme of maintenance treatment with methadone.

OBJECTIVE--To see whether misusers of injected drugs who stop injecting or switch to a programme of maintenance treatment with methadone have a reduced risk of progression of HIV infection when compared with a group of persistent misusers. DESIGN--Observational cohort study in HIV seropositive subjects with a current or past history of misusing injected drugs. SETTING--HIV outpatient clinic at the University Hospital of Zurich, Switzerland. PATIENTS--297 Current and former parenteral drug misusers (median age 27) with asymptomatic HIV infection. During the observation period 80 subjects adhered to a programme of maintenance treatment with methadone, 124 continued with parenteral drug misuse, and 93 former misusers remained free of illicit drugs. No antiretroviral treatment was given during the study. MAIN OUTCOME MEASURES--Probability of progression of HIV infection from asymptomatic to symptomatic (Centers for Disease Control stage IV) as calculated by life table analysis and compared in the three groups of patients by means of a log rank test, and predictors of disease progression as analysed with a Cox proportional hazards regression model. RESULTS--The 297 patients were followed up for a median of 16 months. The median duration of injecting drug misuse before enrollment was 7.1 years. There were no significant differences among the three groups with respect to CD4+ counts at the beginning of the study (median 0.44 x 10(9)/l). Life table analysis showed a significantly lower probability of progression of HIV disease in both the methadone treated group and former drug misusers than in persistent injecting drug misusers. Multivariate regression analysis showed a relative risk of progression of the disease of 1.78 (95% confidence interval 1.20 to 2.67; p less than 0.01) in persistent injecting drug misusers, 0.48 (0.29 to 0.77; p less than 0.01) in the methadone treated group, and 0.66 (0.41 to 1.06; p = 0.085) in former drug misusers. CONCLUSIONS--Stopping the misuse of injected drugs slows the progression of HIV disease in infected subjects. Drug treatment programmes are effective in secondary prevention of HIV associated morbidity.     

Efficacy of tacrine and lecithin in mild to moderate Alzheimer's disease: double blind trial.

OBJECTIVE--To assess the efficacy of tacrine and lecithin in treating Alzheimer''s disease over nine months. DESIGN--Double blind randomised controlled trial. SETTING--Outpatients clinic of university department of geriatric medicine. SUBJECTS--53 subjects (26 women, 27 men) with probable Alzheimer''s disease. 41 completed the dose finding phase and were randomised to treatment. 32 (14 tacrine, 18 placebo) completed nine months'' treatment. INTERVENTIONS--Lecithin and tacrine or lecithin and placebo for 36 weeks. MAIN OUTCOME MEASURES--Scores on neuropsychological tests sensitive to deficits in the cholinergic system; mini-mental state score; behaviour change; mood; functional state; and stress in carers. RESULTS--The tacrine and placebo groups were similar except that the tacrine group had a longer duration of disease (mean 5.4 v 2.5 years in placebo group; P = 0.003). Only 17 of the 32 patients could tolerate the maximum dose of tacrine (100 mg). No significant difference was found between the groups for any of the tests after nine months'' treatment except for the digit backwards test, which is insensitive to cholinergic deficit. Analysis of subjects taking the maximum dose of tacrine and of subjects with mild dementia also found no differences. CONCLUSIONS--Tacrine produces no clinically relevant improvement over 36 weeks at the doses tolerated by these patients.     

The cost-effectiveness of Vancouver's supervised injection facility

Background

The cost-effectiveness of Canada''s only supervised injection facility has not been rigorously evaluated. We estimated the impact of the facility on survival, rates of HIV and hepatitis C virus infection, referral to methadone maintenance treatment and associated costs.

Methods

We simulated the population of Vancouver, British Columbia, including injection drug users and persons infected with HIV and hepatitis C virus. The model used a time horizon of 10 years and the perspective of the health care system. We compared the situation of the supervised injection facility with one that had no facility but that had other interventions, such as needle-exchange programs. The effects considered were decreased needle sharing, increased use of safe injection practices and increased referral to methadone maintenance treatment. Outcomes included life-years gained, costs, and incremental cost-effectiveness ratios discounted at 5% per year.

Results

Focusing on the base assumption of decreased needle sharing as the only effect of the supervised injection facility, we found that the facility was associated with an incremental net savings of almost $14 million and 920 life-years gained over 10 years. When we also considered the health effect of increased use of safe injection practices, the incremental net savings increased to more than $20 million and the number of life-years gained to 1070. Further increases were estimated when we considered all 3 health benefits: the incremental net savings was more than $18 million and the number of life-years gained 1175. Results were sensitive to assumptions related to injection frequency, the risk of HIV transmission through needle sharing, the frequency of safe injection practices among users of the facility, the costs of HIV-related care and of operating the facility, and the proportion of users who inject in the facility.

Interpretation

Vancouver''s supervised injection site is associated with improved health and cost savings, even with conservative estimates of efficacy.Supervised injection sites offer a safe and hygienic environment for people to inject their previously obtained illicit drugs under supervision.^1,2 Observational studies from the facility in Vancouver, British Columbia, have demonstrated positive effects: a decrease in needle sharing and reuse of syringes, fewer people injecting drugs in public, an increase in referrals to social services and addiction counselling, a decrease in the number of publicly discarded syringes, no apparent increase in police reports of drug dealing or crime, and no observed increase in new initiates into drug use.^3–5 Although an expert advisory committee recently concluded that the Vancouver facility has beneficial effects, prominent law enforcement groups have argued that the resources allocated to the facility would be more effectively spent elsewhere.^6,7We used computer simulation to estimate the projected impact of Vancouver''s supervised injection site on survival, rates of HIV and hepatitis C virus infection, referral to methadone maintenance treatment and associated costs. Our goal was to assess the cost-effectiveness of the facility and thus provide important insights into this policy debate.     

Chronotherapeutic dose schedule of phenytoin and carbamazepine in epileptic patients

The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic-clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100-400 mg/day OD or BD, tablet carbamazepine 200-800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two-thirds or three-fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.     

Methadone maintenance in general practice: patients,workload, and outcomes.

OBJECTIVE--To assess recruitment to and work-load associated with methadone maintenance clinics in general practice; to investigate the characteristics of patients and outcomes associated with treatment. DESIGN--Study of case notes. SETTING--Methadone maintenance clinics run jointly by general practitioners and drug counsellors in two practices in Glasgow. PARTICIPANTS--46 injecting drug users receiving methadone maintenance during an 18 month period, 31 of whom were recruited to clinic based methadone maintenance treatment and 15 of whom were already receiving methadone maintenance treatment from the general practitioners. Mean (SD) age of patients entering treatment was 29.6 (5.5) years; 29 were male. They had been injecting opiates for a mean 9.9 (5.1) years, and most had a concurrent history of benzodiazepine misuse. Average reported daily intake of heroin was approximately 0.75 g. Participants in treatment had high levels of preexisting morbidity, and most stated that they committed crime daily. RESULTS--2232 patient weeks of treatment were studied. Mean duration of treatment during the study period was 50.7 (21.1) weeks and retention in treatment at 26 weeks was 83%. No evidence of illicit opiate use was obtained at an average of 78% of patients'' consultations where methadone had been prescribed in the previous week; for opiate injection the corresponding figure was 86%. CONCLUSIONS--Providing methadone maintenance in general practice is feasible. Although costs are considerable, the reduction in drug use, especially of intravenous opiates, is encouraging. Attending clinics also allows this population, in which morbidity is considerable, to receive other health care.     

Rates of Fetal Polydrug Exposures in Methadone-Maintained Pregnancies from a High-Risk Population

Methadone maintenance treatment (MMT) is the standard of care during pregnancy for opioid-dependency, showing efficacy in improving prenatal care and reducing risk of relapse. By design, however, MMT is only intended to prevent withdrawal thus facilitating cognitive behavioural interventions. In order to maximize the benefits of MMT, it is essential that methadone is both properly prescribed and that additional addiction treatment is concurrently administered. This study aims to determine the effectiveness of MMT engagement in high-risk pregnant women in reducing polydrug use by objective laboratory examination of neonatal meconium.

Patients and Methods

Over a 29-month period, the Motherisk Laboratory at the Hospital for Sick Children in Toronto analyzed meconium samples as per request by social services and hospitals for drugs of abuse.

Results

Of the 904 meconium samples received, 273 were tested for methadone with 164 positive and 109 negative for methadone. Almost half of the methadone positive samples (46.34%) were also positive for at least one other opioid compound, which did not differ statistically from the methadone-negative control samples (46.79%; Chi square test, p=0.94). No differences were found between the methadone positive and negative groups in rates of concurrent amphetamines, cocaine, cannabis, and alcohol use indicating a similar risk of polydrug use between pregnant women taking or not taking methadone in this population.

Discussion

The high rates of additional opioid and other drug use in the MMT group, suggest that MMT is failing this population of patients. It is possible that methadone doses during pregnancy are not appropriately adjusted for changes in pharmacokinetic parameters (e.g. blood volume, renal function) during the second and third trimesters. This may result in sub-therapeutic dosing creating withdrawal symptoms leading to additional substance use. Alternatively, these results may be demonstrating a substantial lack in delivery of addiction support services in this vulnerable population.     

Chronotherapeutic Dose Schedule of Phenytoin and Carbamazepine in Epileptic Patients

The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic‐clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100–400 mg/day OD or BD, tablet carbamazepine 200–800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two‐thirds or three‐fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.     

Problem drug use in a central London general practice.

OBJECTIVE--To describe the profile of problem drug users presenting in general practice and to determine whether they can be cared for in general practice. DESIGN--Study of consultations by problem drug users. SETTING--Central London general practice. SUBJECTS--150 problem drug users presenting over two years. MAIN OUTCOME MEASURES--Stopping drug use, alterations in lifestyle, obtaining paid work, and stopping drug related crime. RESULTS--Of the 150 patients, 111 were men and 39 women, and 106 were unemployed. 121 patients used heroin, 112 of whom injected. 145 patients accepted a methadone reduction programme and 81 completed it. A further 25 were stabilised on reducing doses of methadone, until places became available for them as inpatients at drug dependency units or rehabilitation projects. CONCLUSION--Withdrawal programmes for patients who misuse drugs can be successfully managed in general practice.     

Hepatitis C Virus Infection Influences the S-Methadone Metabolite Plasma Concentration

Background and Objectives

Heroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan.

Methods

A total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening.

Results

Of the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P = 0.02) and ALT (Wilcoxon Rank-Sum test, P = 0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, P = 0.043) and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P = 0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose ( = 14.65 and 14.13; P = 0.029 and 0.03) and the S-EDDP/methadone dose ratio ( = −0.41 and −0.40; P = 0.00084 and 0.002) in both univariate and multivariate regression analyses.

Conclusions

We conclude that HCV may influence the methadone dose and plasma S-EDDP/methadone dose ratio in MMT patients in this preliminary study.     

Excretion of methadone in semen from methadone addicts; Comparison with blood levels

The concentration of methadone was measured in the semen of seven methadone maintenance subjects and compared with the concentration of the drug in blood. The daily dose of methadone in these subjects ranged between 20 and 80 mg and was administered by mouth in the local methadone clinic in the usual manner. Samples of blood and semen were obtained from each subject one to four hours after dosage. The concentration of methadone in the blood ranged between 59 and 126 ng/ml in six of the volunteers. The concentration of methadone in semen ranged between 73 and 420 ng/ml in the seven subjects. The ratio of the concentration of the drug in semen to the concentration in blood ranged from 0.82 to 4.72. Methadone is excreted in small amounts in human semen and is transmitted from male to female during sexual intercourse.     

Stable HIV-1 integrase diversity during initial HIV-1 RNA Decay suggests complete blockade of plasma HIV-1 replication by effective raltegravir-containing salvage therapy

Background

There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, thus undermining efficacy of treatment. The goal of this study was to characterize viral resistance emergence and address viral population evolution during the first phase of viral decay after treatment containing initiation.

Findings

454 sequencing was used to characterize viral genetic diversity and polymorphism composition of the HIV-1 integrase gene during the first two weeks following initiation of raltegravir-containing HAART in four ART-experienced subjects. No low-prevalence Raltegravir (RAL) drug resistance mutations (DRM) were found at baseline. All patients undergoing treatment received a fully active ART according to GSS values (GSS?≥?3.5). No emergence of DRM after treatment initiation was detected. Longitudinal analysis showed no evidence of any other polymorphic mutation emergence or variation in viral diversity indexes.

Conclusions

This suggests that fully active salvage antiretroviral therapy including raltegravir achieves a complete blockade of HIV-1 replication in plasma. It is unlikely that raltegravir-resistant HIV-1 may be selected in plasma during the early HIV-1 RNA decay after treatment initiation if the administered therapy is active enough.

     

Method for determination of methadone in exhaled breath collected from subjects undergoing methadone maintenance treatment

At present drugs of abuse testing using exhaled breath as specimen is only possible for alcohol. However, we recently discovered that using modern liquid chromatography–mass spectrometry technique amphetamine and methamphetamine is detectable in exhaled breath following intake in drug addicts. We therefore undertook to develop a method for determination of methadone in exhaled breath from patients undergoing methadone maintenance treatment. Exhaled breath was collected from 13 patients after intake of the daily methadone dose. The compounds were trapped by filtering the air through a C18 modified silica surface. After elution of any trapped methadone the extract was analysed by a combined liquid chromatography–tandem mass spectrometry method. Recovery of trapped methadone from the filter surface was 96%, no significant matrix effect was observed, and the quantification using methadone-d3 as an internal standard was accurate (<10% bias) and precise (coefficient of variation 1.6–2.0%). Methadone was indisputably identified by means of the mass spectrometry technique in exhaled breath samples from all 13 patients. Identification was based on monitoring two product ions in selected reaction monitoring mode with correct relative ratio (±20%) and correct retention time. Excretion rates ranged from 0.39 to 78 ng/min. No methadone was detected in 10 control subjects. This finding confirms that breath testing is a new possibility for drugs of abuse testing. Collection of exhaled breath specimen is likely to be more convenient and safe as compared to other matrices presently in use.     

Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase: observations on analysis of the normal range.

Single serum progesterone determinations were made in 79 apparently normal women with a regular menstrual cycle. A normal range (40 subjects) was derived from the concentrations in the follicular phase and used to define an "anovular" range for luteal phase values (nine out of 39 subjects). The remaining luteal phase values were used to construct an "ovular" range for the luteal phase and, within this range, to define a group of values (less than the 20th centile) which could be described as a "defective luteal phase." The cut off limits between ovular and anovular and between normal and defective luteal phases were respectively two and four times the follicular phase median. It is proposed that the numerical findings of this study may be used as a rule of thumb for defining normality and abnormality from a single serum progesterone determination.     

The physiological and psychological relaxing effects of viewing rose flowers in office workers

Background

In recent years, the physiological relaxing effect brought by nature is becoming clear; however, many workers find it difficult to be exposed to nature in their working environment. Exposure to fresh flowers represents an opportunity to incorporate nature into their working lives. In this study, we examined the effects of exposure to roses on physiological and psychological variables (heart rate variability, pulse rate, and subjective responses) in office workers.

Results

The experimental site was Mizuho Information & Research Institute, Inc., in the Tokyo metropolitan area. Thirty-one male office workers were included in the present study. The subjects were exposed to thirty unscented pink roses (Rosa, Dekora) arranged in a cylindrical glass vase for 4 min. In the control condition, the subjects were not exposed to flowers. After the experiments, the subjects completed a questionnaire. The order of exposure was counterbalanced among subjects. Among subjects exposed to roses, the high-frequency component of heart rate variability was significantly higher than in controls. Similarly, ''comfortable,’ ''relaxed’ and ''natural’ feelings were more common in subjects exposed to roses.

Conclusions

Data from this study support the presence of physiological and psychological relaxing effects of being exposed to flowers on office workers.     

Creating a new drug service in Edinburgh.

After one year Edinburgh''s Community Drug Problem Service has shown that if psychiatric services offer consultation and regular support for drug users many general practitioners will share the care of such patients and prescribe for them, under contract conditions, whether the key worker is a community psychiatric nurse or a drug worker from a voluntary agency. This seems to apply whether the prescribing is part of a "harm reduction" strategy over a long period or whether it is a short period of methadone substitution treatment. Given the 50% prevalence of HIV infection among drug users in the Edinburgh area and the fact that only half of them have been tested for seropositivity, the health and care of this demanding group of young people with a chaotic lifestyle are better shared among primary care, community based drug workers, and specialist community drugs team than treated exclusively by a centralised hospital drug dependency unit. As the progression to AIDS is predictable in a larger proportion of drug users who are positive for HIV, there is an even greater need for coordinated care between specialists and community agencies in the near future.     

Mortality among Methadone Maintenance Clients in China: A Six-Year Cohort Study

Objective

To assess the overall mortality of methadone maintenance treatment (MMT) clients in China and its associated factors.

Methods

A total of 1,511 MMT clients, all of whom enrolled in China''s first eight MMT clinics between March and December 2004, were included in this cohort study and followed for approximately six years, until June 2010. Mortality and its predictors were examined using Cox proportional hazards regression models.

Results

A total of 154 deaths were observed within 5,391 person-years (PY) of follow-up for an all-cause mortality rate of 28.6 per 1,000 PY. The leading causes of death were drug overdose (33.8%), HIV/AIDS-unrelated disease (21.4%), and HIV/AIDS (16.9%). The all-cause mortality rate of clients engaged in MMT for one year or less was roughly three times that of clients who stayed in MMT for four years or more (14.0 vs. 4.6, p<0.0001), HIV-positive subjects was nearly four times mortality rate than that of HIV-negative individuals (28.1 vs.6.8, p<0.0001). ART-naive HIV-positive subjects had approximately two times higher mortality rate than those receiving ART (31.2 vs. 17.3, <0.0001). After adjusting for confounding variables, we found that being male (HR = 1.63, CI: 1.03–2.57, p = 0.0355) and being HIV-positive (HR = 5.16, CI: 3.70–7.10, p<0.0001) were both associated with higher risk of death whereas increased durations of methadone treatment were associated with a lower risk of death (HR = 0.26, CI: 0.18–0.38, p<0.0001 for two to three years, HR = 0.08, CI: 0.05–0.14, p<0.0001 for four or more years).

Conclusion

Overall mortality was high among MMT clients in China. Specific interventions aimed at decreasing mortality among MMT clients are needed. Our study supports the need for keeping client at MMT longer and for expanding ART coverage and suggests the potential benefits of integrated MMT and ART services for drug users in China.