Blood naltrexone levels over time following naltrexone implant.

AIMS: Oral naltrexone is used in the management of both heroin and alcohol dependence. However, poor compliance has limited its clinical utility. The study's objective was to determine the period of therapeutic coverage (>or=2 ng/ml) provided by a 3.3 g naltrexone subcutaneous implant compared with existing data on 1.1 g and 2.2 g implants. METHODS: We assessed free blood naltrexone levels following treatment with a 3.3 g naltrexone implant in heroin dependent patients (n=50) in Perth, Western Australia. Results were compared with previously collated data for patients treated with either a 1.1 g (n=10) or 2.2 g (n=24) implant. RESULTS: Following 3.3 g naltrexone implant treatment, free blood naltrexone levels remained above 2 ng/ml for 145 days (95% CI 125-167). In comparison, 1.1 g or 2.2 g implant treatment resulted in 95 days (95% CI 69-121) and 136 days (95% CI 114-158) coverage, respectively. CONCLUSIONS: The 3.3 g implant provides longer therapeutic coverage than the 1.1 g implant but not significantly longer than the 2.2 g implant.

A comparison of mental health hospital admissions in a cohort of heroin users prior to and after rapid opiate detoxification and oral naltrexone maintenance.

Mental health (MH) hospital admissions were investigated in a cohort (N=1184) of heroin dependent persons using linked health records. All MH in-patient admissions were extracted 36 months before to 36 months after commencing rapid opioid detoxification (ROD) and oral naltrexone. Results show that the incidence rate ratio (IRR) of drug-related and other MH admissions peaked in the 3 months immediately prior to treatment. All categories subsequently declined to baseline levels by 36 months following treatment. The authors conclude that treatment for heroin dependence reduces risk of MH admissions.

Achieving long-term continuous blood naltrexone and 6-beta-naltrexol coverage following sequential naltrexone implants.

The aim of this study was to assess blood free naltrexone and 6-beta-naltrexol levels with time following treatment with sequential sustained-release naltrexone preparations. Data were collected from blood samples analysed independently for naltrexone and 6-beta-naltrexol and from clinical record review at a community heroin treatment clinic in Perth, Western Australia. Five patients received sequential 3.4 g (3.49+/-0.01 g and 3.36+/-0.05 g, respectively) naltrexone implants. The second implant was received on average within 131.2+/-15.67 days of the first implant. The mean length of follow-up was 307.2+/-18.28 days of the first implant. Blood naltrexone levels have the potential to remain above 2 and 1 ng/ml for a total of 390 and 524 days, respectively, and blood 6-beta-naltrexol was maintained above 10 ng/ml for a total of 222 days following insertion of these implants. No patient relapsed to dependent heroin use during the implant coverage period while blood naltrexone concentrations were above 2 ng/ml. Results indicate that blood naltrexone and 6-beta-naltrexol levels can be maintained above therapeutic levels for prolonged periods following use of sequential 3.4 g naltrexone implants. These extended periods of coverage will offer significant benefits for managing the heroin-dependent patient.

Blood naltrexone and 6-beta-naltrexol levels following naltrexone implant: comparing two naltrexone implants.

The aim of this study was to profile and compare blood naltrexone and 6-beta-naltrexol levels with time following treatment with two sustained-release naltrexone preparations produced by GoMedical Industries, Australia at a community heroin treatment clinic in Perth, Western Australia. A sample of 10 patients who each received a 1.7 g naltrexone implant were compared to 24 patients who each received a 3.4 g naltrexone implant as treatment for heroin dependence. Blood naltrexone levels following treatment with the 1.7 g naltrexone implant remained above 2 and 1 ng/ml for approximately 90 and 136 days, respectively. Use of the 3.4 g naltrexone implant extended the period of coverage to approximately 297 (1 ng/ml) or 188 (2 ng/ml) days. Blood 6-beta-naltrexol levels remained above 10 ng/ml for approximately 18 and 83 days, respectively, following use of the 1.7 g and 3.4 g naltrexone implants. The current study data indicate that blood naltrexone and 6-beta-naltrexol levels following treatment with either the 1.7 g or 3.4 g naltrexone implant are greater than those reported in other published data on other sustained-release naltrexone preparations. Furthermore, duration of blood naltrexone and 6-beta-naltrexol levels achieved following use of the 3.4 g implant were superior to those achieved with the 1.7 g naltrexone implant, with naltrexone blood levels maintained above 2 ng/ml for a period of approximately 6.3 months compared to 3 months, respectively. The implications of this in managing the heroin-dependent patient, especially those who find it difficult to shift away from dependent use patterns, are discussed.

A psychometric experiment in causal inference to estimate evidential weights used by epidemiologists.

A psychometric experiment in causal inference was performed on 159 Australian and New Zealand epidemiologists. Subjects each decided whether to attribute causality to 12 summaries of evidence concerning a disease and a chemical exposure. The 1,748 unique summaries embodied predetermined distributions of 19 characteristics generated by computerized evidence simulation. Effects of characteristics of evidence on causal attribution were estimated from logistic regression, and interactions were identified from a regression tree analysis. Factors with the strongest influence on the odds of causal attribution were statistical significance (odds ratio = 4.5 if 0.001 < or = P < 0.05 and 7.2 if P < 0.001, vs P > or = 0.05); refutation of alternative explanations (odds ratio = 8.1 for no known confounder vs none adjusted); strength of association (odds ratio = 2.0 if 1.5 < relative risk < or = 2.0 and 3.6 if relative risk > 2.0, vs relative risk < or = 1.5); and adjunct information concerning biological, factual, and theoretical coherence. The refutation of confounding reduced the cutpoint in the regression tree for decision-making based on strength of association. The effect of the number of supportive studies reached saturation after it exceeded 12 studies. There was evidence of flawed logic in the responses concerning specificity of effects of exposure and a tendency to discount evidence if the P-value was a "near miss" (0.050 < P < 0.065). Evidential weights based on regression coefficients for causal criteria can be applied to actual scientific evidence.

Peptide hormones influence in vitro interrenal secretion of cortisol in the trout, Oncorhynchus mykiss.

Adrenocorticotrophic hormone (ACTH), angiotensin II (AII), and the urophysial peptides, urotensins I and II (UI and UII), stimulate cortisol secretion by interrenal preparations of seawater (SW) and freshwater (FW) adapted trout. Steroid secretion was not disturbed in sham-treated control groups. The increased cortisol secretion following perifusion of tissue with 10(-7) M ACTH in combination with 10(-7) M AII, 10(-7) M UI, or 10(-7) M UII was greater than after separate administration of ACTH, AII, UI, or UII. These responses were no greater than the summation of the separate effects of ACTH, AII, or UII in SW and FW derived tissue or of ACTH and UI in FW derived tissue. However, the increased cortisol secretion (600-700%) after UI and ACTH in combination in SW adapted fish was significantly higher than the summated responses (100-200%) to UI and ACTH when administered separately. These results suggest that in SW fish interrenal UI enhances the steroidogenic action of ACTH, a potentially important response in SW teleost fish.

Atrial natriuretic factor stimulates in-vivo and in-vitro secretion of cortisol in teleosts.

Atrial natriuretic factor (ANF) has been shown to increase circulating cortisol levels in cannulated, free-swimming seawater (SW)-adapted flounders. Increases were apparent within 30 min of i.v. injection of human ANF (hANF;10 micrograms/kg bw) and the increase in plasma cortisol was maintained throughout the 5h experimental period. No such increase was observed in vehicle-injected controls. This apparent steroidogenic effect of ANF was supported by an ANF-induced increase in in-vitro secretion of cortisol by interrenal tissue from SW-adapted trout. By contrast hANF had no significant effect on tissue derived from freshwater adapted trout. An ANF-induced increase in plasma cortisol by a direct effect on interrenal steroidogenesis in SW teleosts would be an appropriate response for survival in hypertonic media.

Urotensin I and its N-terminal flanking peptide from the flounder, Platichthys flesus.

The caudal spinal cord region of teleost fish terminates in a neurosecretory organ, the urophysis. Two peptides have been purified to homogeneity from an extract of the urophysis of a teleost fish, the flounder. The primary structure of one peptide, Ser-Glu-Asp-Pro-Pro-Met-Ser-Ile-Asp-Leu10-Thr-Phe-His-Met-Leu-Arg- Asn-Met-Ile- His20-Met-Ala-Lys-Met-Glu-Gly-Glu-Arg-Glu-Gln30-Ala-Gln-Ile- Asn-Arg-Asn-Leu-Leu - Asp-Glu40-Val, indicates identity with urotensin I. By analogy with other urotensins, the COOH-terminal residue is probably alpha-amidated. A second peptide was present in the extract in a concentration that was approximately equimolar with that of urotensin I. The amino acid composition of this peptide indicated a total of approximately 65 residues. The amino acid sequence of a fragment produced by digestion with trypsin was established as: Ala-Ala-Ala-Ala-Gly5-Asp-Ser-Ala-Ala-Ser10-Asp-Leu-Leu-Gly-Asp1 5-Asn-Ile-Leu- Arg. This sequence shows partial homology to carp prepro-urotensin I(41-59)-peptide as deduced from the nucleotide sequence of a cloned cDNA. It is concluded that the second peptide probably represents the N-terminal flanking peptide of pro-urotensin I which, it has previously been suggested, may function as a urotensin-binding peptide (urophysin) analogous to the neurophysins.

Steroidogenic role of the caudal neurosecretory system in the flounder, Platichthys flesus.

Transfer of flounders from seawater (SW) to fresh water (FW) resulted in a small reduction in circulating cortisol levels and urophysial protein storage. Transfer of flounders from FW to SW resulted in a larger increase in plasma cortisol and specific urophysial protein storage. Over the first 4 days after transfer from FW to SW there was a positive correlation between the observed changes in urophysial urotensin I (UI) content and plasma cortisol. This apparent steroidogenic effect of UI was supported by the increases in plasma cortisol observed following iv injection of crude flounder urophysial gland extract and synthetic Catostomus commersoni UI. The study supports a contribution of the caudal neurosecretory system to the control of interrenal steroidogenesis as part of the integrated osmoregulatory physiology of euryhaline species like the flounder.