Minor pathological changes are induced by naltrexone-poly(DL-lactide) implants in pregnant rats.

Oral naltrexone is used to treat alcohol and heroin dependence but is associated with poor patient compliance. Sustained-release preparations have been developed to overcome noncompliance. Many sustained-release preparations are composed of polymers combined with naltrexone. Limited data indicate that polymers induce variable levels of tissue reactivity and that naltrexone may increase this effect. A slow-release subcutaneous naltrexone-poly (DL-lactide) implant is currently being trialed to treat heroin dependence in Western Australia. A minority of women fall pregnant and, although tissue reactivity in nonpregnant humans is relatively minor, detailed chronological data during pregnancy are lacking. Histological changes in pregnant rats were assessed; a single active tablet containing poly[trans-3,6-dimethyl-1,4-dioxyane-2,5-dione] (DL-lactide) loaded with 25 mg of naltrexone was implanted subcutaneously, and tissue response was compared with inactive polymer implantation. Rats were timed mated at 13-26 days postimplant. Tissue assessment up to 75 days by a pathologist showed that naltrexone induced chronic inflammatory response in a dose-dependent manner, although still at a low level. Furthermore, for inactive implants, minimal foreign body reaction and fibrosis, together with low-level inflammation, suggested good long-term biocompatibility. We conclude that the Australian naltrexone-poly(DL-lactide) implant is tolerated in pregnant rats, reinforcing its potential role for managing alcohol and heroin dependence in pregnant humans.

The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data.

Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current "gold standard", and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a micro-opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial micro-opioid receptor agonist and a kappa-opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term.

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.

Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans.

In order to assess the histological tissue changes over time around the site of implant, tissue biopsies were taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects who had received the Australian subcutaneous naltrexone-poly(DL-lactide) implant for heroin dependence. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue samples by pathologists showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Sufficient evidence was not available to conclude that the poly(DL-lactide) implant matrix was totally biodegradable within the study period. While implant material was not identified in most of the latter biopsies, its presence was noted in one biopsy at 26 months post-implant. Nevertheless the study results did demonstrate the implant's biocompatibility by the lack of inflammation, foreign body reaction, and fibrosis detected by 25+ months. It seems highly probable that surgical technique rather than the implant itself was associated with the additional finding of fat necrosis. Moderate fat necrosis was observed as a common feature of biopsies carried out during the first 6 months following implant. It subsided to mild levels over the next 18 months, and was notably absent by 25+ months. The results of the study indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated and may have a role for use in the management of medical conditions such as heroin dependence.

Adolescent emergency department presentations with alcohol- or other drug-related problems in Perth, Western Australia.

AIMS: To identify the morbidity, type of substance used and the pattern of presentation by adolescents with problems related to alcohol or other drug (AOD) use. DESIGN: A 4-week retrospective review of hospital records. SETTING: Four metropolitan hospitals in Perth, Australia. PARTICIPANTS: There were 1064 presentations by people aged 12-19 years of which 160 (15%) were related to AOD use. The median age of the AOD cases was 17 (interquartile range 16-19) of whom 97 (61%) were male and 19 (12%) were Indigenous Australians. FINDINGS: Alcohol was the most frequent precursor to presentation (66, 41%) followed by heroin (24, 15%) and prescription/over-the-counter drugs (24, 15%). Injury was the most common diagnosis at presentation (50, 31%), followed by overdose/drug use (47, 29%). A diagnosis of injury was significantly more likely following the use of alcohol than other categories of substances (chi(2) = 42.07, df = 3, p < 0.001). Deliberate self-harm (DSH) occurred in more female than male cases (chi2 = 7.4, df = 1, p < 0.01). Presentations were more frequent over the weekend (102, 64%) than on weekdays, and the length of stay was significantly shorter for weekend cases (Mann-Whitney U 2132, p < 0.05). CONCLUSIONS: Given the small window of opportunity to provide AOD treatment to youth following hospital presentation, a number of suggestions are made. From a harm-minimization perspective the focus of interventions should be on alcohol use by male youth and DSH associated with prescription/over-the-counter drug use by female adolescents. In addition, Indigenous youth are over-represented in hospital presentations, but there is currently a lack of evaluated interventions designed for them.

Application of sulfobutylether-beta-cyclodextrin with specific degrees of substitution for the enantioseparation of pharmaceutical mixtures by capillary electrophoresis.

In this research the separation of the enantiomers of the basic drug bidisomide (SC-40230) from five closely related known process impurities was investigated using several neutral and anionic sulfobutylether beta-cyclodextrins (SBE-beta-CDs) as isomer selectors. Several novel sulfobutylether derivative mixtures and purified charge types having a specific degree of substitution were used to study the effect of selector charge on the efficiency and selectivity of both chiral and achiral separations. The effects of run buffer pH, selector type, and selector concentration on the chiral separation of bidisomide and the achiral separation of the related process impurities was also investigated. The related process impurity, SC-47500, displayed significant peak tailing with SBE-beta-CD mixtures which contained mono- to deca-substituted cyclodextrins. This problem was explored using isolated SBE-beta-CD charge types having degrees of substitution from one to seven. Peak tailing increased as the charge on the selector increased, suggesting that the distortion was due to electrodispersion and the large countercurrent mobility of the negatively charged complexes. Pure charge types having a lower degree of substitution provided adequate chiral and achiral selectivity, while eliminating the severe peak distortion caused by electrodispersion. The complete analysis of the bidisomide enantiomers and the related impurities was achieved with a pH 2.5 running buffer containing 5-10 mM of the isolated sulfobutylether charge types SBE[2]ds(1)sr-beta-CD or SBE[3]ds(1)sr-beta-CD. These conditions gave baseline resolution of bidisomide enantiomers and all five impurities, thus allowing both chiral and achiral purity to be determined in a single run.

Isolation and characterization by NMR spectroscopy of three monosubstituted 4-sulfobutyl ether derivatives of cyclomaltoheptaose (beta-cyclodextrin).

The substitution profile of 4-sulfobutyl ether derivatives of cyclomaltoheptaose (beta-cyclodextrin) (SBE-beta-CD) prepared in our laboratories has been previously described. However, in those studies, no attempt was made to characterize the positional or regional isomers of this material. SBE-beta-CD derivatives with degrees of substitution of two or higher represent a large number of possible isomers dependent on this positional and regional substitution. The monosubstituted SBE derivative, however, cannot have regional isomers and, therefore, has only three possible substitution products related to the 2-, 3-, and 6-hydroxyl groups of a glucose unit. In this study the isomers were fractionated by preparative anion-exchange chromatography with the progress of the elution being followed by a capillary electrophoretic (CE) method that resolved these isomers. The eluent containing the isomers was processed, and the pure materials were characterized by nuclear magnetic resonance spectroscopy (1H NMR, DEPT, HETCOR, HOHAHA). Through this analysis the assignment of the positional isomers was made.

Evaluation of the utility of capillary electrophoresis for the analysis of sulfobutyl ether beta-cyclodextrin mixtures.

A capillary electrophoresis (CE) method for the analysis of a sulfobutyl ether beta-cyclodextrin (SBE-beta-CD) mixture is described. The SBE-beta-CD has been prepared as a parenterally safe solubilizing agent and has historically been characterized by elemental analysis and nuclear magnetic resonance spectroscopy. While these methods provide gross values for the degree of substitution, the CE method described resolves the mixture of positional and regional isomers based on the degree of SBE substitution. The method uses benzoic acid in the running buffer and detects the CD by a decrease in background absorbance of the benzoic acid due to complexation. The necessity of a defined column was sequence between injections was evaluated. The reproducibility of migration times and peak areas/heights for 10 components of the mixture was determined. The modular CE system gave a relative standard deviation of 2.5% (n = 3) for six of the 10 peaks. Further refinements (pH buffer effects) were explored to improve the reproducibility with remaining components. The method was used to evaluate the reproducibility of the synthesis (21 different lots) and the effect of reaction variables (time, temperature and base) on the composition pattern of the modified CD.

Characterization of sulphoalkyl ether derivatives of beta-cyclodextrin by capillary electrophoresis with indirect UV detection.

A capillary electrophoresis method which characterizes the degrees of substitution of heterogeneous sulphoalkyl ether beta-cyclodextrin derivatives is described. The separation is based on the different electrophoretic mobilities observed from changes in the overall charge of the molecule as a result of substitution. Individual peaks of the electropherogram then provide a measure of each degree of substitution of the present beta-cyclodextrin. Detection of these beta-cyclodextrin derivatives is performed by indirect UV detection.