Assertive outreach treatment versus care as usual for the treatment of high-need, high-cost alcohol related frequent attenders: study protocol for a randomised controlled trial.

BACKGROUND: Alcohol-related hospital admissions have doubled in the last ten years to > 1.2 m per year in England. High-need, high-cost (HNHC) alcohol-related frequent attenders (ARFA) are a relatively small subgroup of patients, having multiple admissions or attendances from alcohol during a short time period. This trial aims to test the effectiveness of an assertive outreach treatment (AOT) approach in improving clinical outcomes for ARFA, and reducing resource use in the acute setting. METHODS: One hundred and sixty ARFA patients will be recruited and following baseline assessment, randomly assigned to AOT plus care as usual (CAU) or CAU alone in equal numbers. Baseline assessment includes alcohol consumption and related problems, physical and mental health comorbidity and health and social care service use in the previous 6 months using standard validated tools, plus a measure of resource use. Follow-up assessments at 6 and 12 months after randomization includes the same tools as baseline plus standard measure of patient satisfaction. Outcomes for CAU + AOT and CAU at 6 and 12 months will be compared, controlling for pre-specified baseline measures. Primary outcome will be percentage of days abstinent at 12 months. Secondary outcomes include emergency department (ED) attendance, number and length of hospital admissions, alcohol consumption, alcohol-related problems, other health service use, mental and physical comorbidity 6 and 12 months post intervention. Health economic analysis will estimate the economic impact of AOT from health, social care and societal perspectives and explore cost-effectiveness in terms of quality adjusted life years and alcohol consumption at 12-month follow-up. DISCUSSION: AOT models piloted with alcohol dependent patients have demonstrated significant reductions in alcohol consumption and use of unplanned National Health Service (NHS) care, with increased engagement with alcohol treatment services, compared with patients receiving CAU. While AOT interventions are costlier per case than current standard care in the UK, the rationale for targeting HNHC ARFAs is because of their disproportionate contribution to overall alcohol burden on the NHS. No previous studies have evaluated the clinical and cost-effectiveness of AOT for HNHC ARFAs: this randomized controlled trial (RCT) targeting ARFAs across five South London NHS Trusts is the first. TRIAL REGISTRATION: International standard randomized controlled trial number (ISRCTN) registry: ISRCTN67000214, retrospectively registered 26/11/2016.

Improving screening and brief intervention activities in primary health care: Secondary analysis of professional accuracy based on the AUDIT-C.

INTRODUCTION AND OBJECTIVE: The ODHIN trial found that training and support and financial reimbursement increased the proportion of patients that were screened and given advice for their heavy drinking in primary health care. However, the impact of these strategies on professional accuracy in delivering screening and brief advice is underresearched and is the focus of this paper. METHOD: From 120 primary health care units (24 in each jurisdiction: Catalonia, England, the Netherlands, Poland, and Sweden), 746 providers participated in the baseline and the 12-week implementation periods. Accuracy was measured in 2 ways: correctness in completing and scoring the screening instrument, AUDIT-C; the proportion of screen-negative patients given advice, and the proportion of screen-positive patients not given advice. Odds ratios of accuracy were calculated for type of profession and for intervention group: training and support, financial reimbursement, and internet-based counselling. RESULTS: Thirty-two of 36 711 questionnaires were incorrectly completed, and 65 of 29 641 screen-negative patients were falsely classified. At baseline, 27% of screen-negative patients were given advice, and 22.5% screen-positive patients were not given advice. These proportions halved during the 12-week implementation period, unaffected by training. Financial reimbursement reduced the proportion of screen-positive patients not given advice (OR = 0.56; 95% CI, 0.31-0.99; P < .05). CONCLUSION: Although the use of AUDIT-C as a screening tool was accurate, a considerable proportion of risky drinkers did not receive advice, which was reduced with financial incentives.

Codeine use, dependence and help-seeking behaviour in the UK and Ireland: an online cross-sectional survey.

BACKGROUND: Codeine misuse and dependence poses a clinical and public health challenge. However, little is known about dependence and treatment needs in the UK and Ireland. AIM: To characterize codeine use, dependence and help-seeking behaviour. DESIGN: An online cross-sectional survey advertised on Facebook, Twitter, health and drug websites and e-mail circulars. METHODS: The survey collected data on demographics and codeine use amongst adults from the UK and Ireland. The Severity of Dependence Scale measured the level of codeine dependence. RESULTS: The sample of 316 respondents had a mean age of 35.3 years (SD = 12.3) and 67% were women. Of the 316 respondents, 54 scored ≥5 on the Severity of Dependence Scale indicating codeine dependence (17.1%). Our study found that codeine dependence is a problem with both prescribed and 'over-the-counter' codeine. Codeine dependence was associated with daily use of codeine, faking or exaggerating symptoms to get a prescription for codeine and 'pharmacy shopping' ( P < 0.01). A higher number of respondents had sought advice on the Internet (12%) rather than from their general medical practitioner (GP) (5.4%). Less than 1% of respondents had sought advice from a pharmacist. CONCLUSIONS: Codeine dependent users were more likely to seek help on the Internet to control their use of codeine than from a GP, which may indicate a potential for greater specialized addiction treatment demand through increased identification and referrals in primary care.

Novel psychoactive substances: An investigation of temporal trends in social media and electronic health records.

BACKGROUND: Public health monitoring is commonly undertaken in social media but has never been combined with data analysis from electronic health records. This study aimed to investigate the relationship between the emergence of novel psychoactive substances (NPS) in social media and their appearance in a large mental health database. METHODS: Insufficient numbers of mentions of other NPS in case records meant that the study focused on mephedrone. Data were extracted on the number of mephedrone (i) references in the clinical record at the South London and Maudsley NHS Trust, London, UK, (ii) mentions in Twitter, (iii) related searches in Google and (iv) visits in Wikipedia. The characteristics of current mephedrone users in the clinical record were also established. RESULTS: Increased activity related to mephedrone searches in Google and visits in Wikipedia preceded a peak in mephedrone-related references in the clinical record followed by a spike in the other 3 data sources in early 2010, when mephedrone was assigned a 'class B' status. Features of current mephedrone users widely matched those from community studies. CONCLUSIONS: Combined analysis of information from social media and data from mental health records may assist public health and clinical surveillance for certain substance-related events of interest. There exists potential for early warning systems for health-care practitioners.

Release of a wound-healing agent from PLGA microspheres in a thermosensitive gel.

The purpose of this research was to develop a topical microsphere delivery system in a thermosensitive 20% poloxamer 407 gel (Pluronic F127) to control release of KSL-W, a cationic antimicrobial decapeptide, for a period of 4-7 days for potential application in combat related injuries. KSL-W loaded microsphere formulations were prepared by a solvent extraction-evaporation method (water-oil-water), with poly (D,L-lactic-co-glycolic acid) (PLGA) (50 : 50, low-weight, and hydrophilic end) as the polymeric system. After optimization of the process, three formulations (A, B, and C) were prepared with different organic to water ratio of the primary emulsion while maintaining other components and manufacturing parameters constant. Formulations were characterized for surface morphology, porous nature, drug loading, in vitro drug release, and antimicrobial activity. Microspheres containing 20% peptide with porous surfaces and internal structure were prepared in satisfactory yields and in sizes varying from 25 to 50 µm. Gels of 20% Pluronic F127, which were liquid at or below 24.6°C and formed transparent films at body temperature, were used as carriers for the microspheres. Rheological studies showed a gelation temperature of 24.6°C for the 20% Pluronic F127 gel alone. Gelation temperature and viscosity of formulations A, B, and C as a function of temperature were very close to those of the carrier. A Franz diffusion cell system was used to study the release of peptide from the microspheres suspended in both, phosphate-buffered saline (PBS) and a 20% Pluronic F127 gel. In vitro release of greater than 50% peptide was found in all formulations in both PBS and the gel, and in one formulation there was a release of 75% in both PBS and the gel. Fractions collected from the release process were also tested for bactericidal activity against Staphylococcus epidermidis using the broth microdilution method and found to provide effective antimicrobial activity to warrant consideration and testing in animal wound models for treating combat-related injuries.

Isoeffective dose: a concept for biological weighting of absorbed dose in proton and heavier-ion therapies.

When reporting radiation therapy procedures, International Commission on Radiation Units and Measurements (ICRU) recommends specifying absorbed dose at/in all clinically relevant points and/or volumes. In addition, treatment conditions should be reported as completely as possible in order to allow full understanding and interpretation of the treatment prescription. However, the clinical outcome does not only depend on absorbed dose but also on a number of other factors such as dose per fraction, overall treatment time and radiation quality radiation biology effectiveness (RBE). Therefore, weighting factors have to be applied when different types of treatments are to be compared or to be combined. This had led to the concept of 'isoeffective absorbed dose', introduced by ICRU and International Atomic Energy Agency (IAEA). The isoeffective dose D(IsoE) is the dose of a treatment carried out under reference conditions producing the same clinical effects on the target volume as those of the actual treatment. It is the product of the total absorbed dose (in gray) used and a weighting factor W(IsoE) (dimensionless): D(IsoE)=D×W(IsoE). In fractionated photon-beam therapy, the dose per fraction and the overall treatment time (in days) are the two main parameters that the radiation oncologist has the freedom to adjust. The weighting factor for an alteration of the dose per fraction is commonly evaluated using the linear-quadratic (α/ß) model. For therapy with protons and heavier ions, radiation quality has to be taken into account. A 'generic proton RBE' of 1.1 for clinical applications is recommended in a joint ICRU-IAEA Report [ICRU (International Commission on Radiation Units and Measurements) and IAEA (International Atomic Energy Agency). Prescribing, recording and reporting proton-beam therapy. ICRU Report 78, jointly with the IAEA, JICRU, 7(2) Oxford University Press (2007)]. For heavier ions (e.g. carbon ions), the situation is more complex as the RBE values vary markedly with particle type, energy and depth in tissue.

Patient specific treatment planning for systemically administered radiopharmaceuticals using PET/CT and Monte Carlo simulation.

The efficacy of systemically administered radiopharmaceuticals depends on the physiological path of the targeting molecule and the physical characteristics of the attached radionuclide. NM404 is a candidate for patient specific dosimetry because it can be used concurrently for both diagnosis and therapy. Radiolabeling NM404 with [(124)I] affords the possibility of performing noninvasive PET imaging while [(131)I] allows for radiotherapy. Patient specific dosimetry for radiation treatment planning for NM404 uses serial PET/CT data and Monte Carlo. [(124)I]NM404 PET helps to determine the organ at risk by which the maximum injected activity of [(131)I]NM404 will depend. The subsequent work uses a software interface (SCMS) to convert patient PET/CT data of a liver metastasis into a Monte Carlo environment for radiation transport analysis. Thereby, the dosimetry within the liver and tumor during both diagnostic and therapeutic procedures was determined. The results showed that per MBq injected of [(124)I] and [(131)I], the tumor receives an average of 1.2 and 1.5mGy, respectively, while the liver receives 0.031 and 0.022mGy, respectively.

Maximum proton kinetic energy and patient-generated neutron fluence considerations in proton beam arc delivery radiation therapy.

Several compact proton accelerator systems for use in proton therapy have recently been proposed. Of paramount importance to the development of such an accelerator system is the maximum kinetic energy of protons, immediately prior to entry into the patient, that must be reached by the treatment system. The commonly used value for the maximum kinetic energy required for a medical proton accelerator is 250 MeV, but it has not been demonstrated that this energy is indeed necessary to treat all or most patients eligible for proton therapy. This article quantifies the maximum kinetic energy of protons, immediately prior to entry into the patient, necessary to treat a given percentage of patients with rotational proton therapy, and examines the impact of this energy threshold on the cost and feasibility of a compact, gantry-mounted proton accelerator treatment system. One hundred randomized treatment plans from patients treated with IMRT were analyzed. The maximum radiological pathlength from the surface of the patient to the distal edge of the treatment volume was obtained for 180 degrees continuous arc proton therapy and for 180 degrees split arc proton therapy (two 90 degrees arcs) using CT# profiles from the Pinnacle (Philips Medical Systems, Madison, WI) treatment planning system. In each case, the maximum kinetic energy of protons, immediately prior to entry into the patient, that would be necessary to treat the patient was calculated using proton range tables for various media. In addition, Monte Carlo simulations were performed to quantify neutron production in a water phantom representing a patient as a function of the maximum proton kinetic energy achievable by a proton treatment system. Protons with a kinetic energy of 240 MeV, immediately prior to entry into the patient, were needed to treat 100% of patients in this study. However, it was shown that 90% of patients could be treated at 198 MeV, and 95% of patients could be treated at 207 MeV. Decreasing the proton kinetic energy from 250 to 200 MeV decreases the total neutron energy fluence produced by stopping a monoenergetic pencil beam in a water phantom by a factor of 2.3. It is possible to significantly lower the requirements on the maximum kinetic energy of a compact proton accelerator if the ability to treat a small percentage of patients with rotational therapy is sacrificed. This decrease in maximum kinetic energy, along with the corresponding decrease in neutron production, could lower the cost and ease the engineering constraints on a compact proton accelerator treatment facility.

Contribution to Neutron Fluence and Neutron Absorbed Dose from Double Scattering Proton Therapy System Components.

Proton therapy offers low integral dose and good tumor comformality in many deep-seated tumors. However, secondary particles generated during proton therapy, such as neutrons, are a concern, especially for passive scattering systems. In this type of system, the proton beam interacts with several components of the treatment nozzle that lie along the delivery path and can produce secondary neutrons. Neutron production along the beam's central axis in a double scattering passive system was examined using Monte Carlo simulations. Neutron fluence and energy distribution were determined downstream of the nozzle's major components at different radial distances from the central axis. In addition, the neutron absorbed dose per primary proton around the nozzle was investigated. Neutron fluence was highest immediately downstream of the range modulator wheel (RMW) but decreased as distance from the RMW increased. The nozzle's final collimator and snout also contributed to the production of high-energy neutrons. In fact, for the smallest treatment volume simulated, the neutron absorbed dose per proton at isocenter increased by a factor of 20 due to the snout presence when compared with a nozzle without a snout. The presented results can be used to design more effective local shielding components inside the treatment nozzle as well as to better understand the treatment room shielding requirements.

Review of deaths related to analgesic- and cough suppressant-opioids; England and Wales 1996-2002.

OBJECTIVE: The data on England and Wales voluntarily supplied by Coroners to the National Programme on Substance Abuse Deaths for the August 1996-December 2002 time frame were analyzed. METHODS: All cases in which at least one analgesic- and cough suppressant-opioid other than heroin/morphine, methadone or buprenorphine was identified were extracted from the database. We hypothesized that: a) populations of addicts and non-addicts presented differences in patterns of drugs involved; and b) within the population of addicts and non-addicts, intentional and non-intentional deaths presented different patterns of substance consumption. RESULTS: A total of 2024 deaths related to selected opioids, either alone or in combination, were included in the analysis. Typically, non-addicts were older than 45 and died as a result of intentional poisoning whilst majority of addicts were young, males and victims of accidental deaths. In about 93% of cases the selected opioids were reported in combination with another substance. Most frequently identified narcotics were propoxyphene, codeine and dihydrocodeine. Co-proxamol, Co-codamol and Co-dydramol were typically prescribed for non-addicts, whilst dihydrocodeine was mostly given to addicts. In non-addicts, alcohol was mostly represented in accidental deaths and antidepressants were typically represented in intentional deaths. Conversely, illicit drugs and hypnotics/sedatives were typically reported in addicts' accidental deaths. CONCLUSIONS: The present report constitutes the largest available collection of analgesic- and cough suppressant-opioid mortality data in the UK. Users should be educated about risks associated with polydrug misuse.

[Salvia divinorum--representation of a new drug in the Internet]. / Salvia divinorum--Präsenz einer neuen Droge im Internet.

AIM OF THE STUDY: The German pages of the Internet were searched for the presence of the hallucinogenic herbal drug Salvia divinorum, which is not dealt with in current addiction medicine or psychiatric text books. The investigation is part of the EU sponsored project "Psychonaut" as preparatory work for the development of an Internet-based early warning system. METHODS: The first 100 websites of the search using "Salvia divinorum" were compared with the search results for "cannabis" and "LSD". The following aspects of the sites were especially analyzed: the originator, marketing of drugs, and the attitude towards drug use. RESULTS: Salvia was offered for sale on approximately a third of the sites (29%); cannabis and LSD were not marketed on any sites. Official websites such as those from governmental organizations or universities were seldom found when searching for "Salvia divinorum", and then only under the last hits. The percentage of institutional sites (e. g. public organizations) were 12% with Salvia, 21% with cannabis, and 38% with LSD. A drug-friendly attitude was found at 64 % of the sites with regard to Salvia, 58% for cannabis, and 24% for LSD. CONCLUSION: The drug help system must be aware of that the Internet is a source of drug-related information, and of drug trade. As this investigation shows, sites often have a drug-friendly attitude. The low availability of official information on Salvia divinorum (also outside the Internet) relative to the presence of drug-friendly or drug trading sites is an indication that new trends of drug consumption can be tracked in the Internet before they will be found in official literature.

The RBE issues in ion-beam therapy: conclusions of a joint IAEA/ICRU working group regarding quantities and units.

This paper summarises the conclusions of a working group established jointly by the International Atomic Energy Agency (IAEA) and the International Commission on Radiation Units and Measurements (ICRU) to address some of the relative biological effectiveness (RBE) issues encountered in ion-beam therapy. Special emphasis is put on the selection and definition of the involved quantities and units. The isoeffective dose, as introduced here for radiation therapy applications, is the dose that delivered under reference conditions would produce the same clinical effects as the actual treatment in a given system, all other conditions being identical. It is expressed in Gy. The reference treatment conditions are: photon irradiation, 2 Gy per fraction, 5 daily fractions a week. The isoeffective dose D(IsoE) is the product of the physical quantity absorbed dose D and a weighting factor W(IsoE). W(IsoE) is an inclusive weighting factor that takes into account all factors that could influence the clinical effects like dose per fraction, overall time, radiation quality (RQ), biological system and effects. The numerical value of W(IsoE) is selected by the radiation-oncology team for a given patient (or treatment protocol). It is part of the treatment prescription. Evaluation of the influence of RQ on W(IsoE) raises complex problems because of the clinically significant RBE variations with biological effect (late vs. early) and position in depth in the tissues which is a problem specific to ion-beam therapy. Comparison of the isoeffective dose with the equivalent dose frequently used in proton- and ion-beam therapy is discussed.

In vitro cytotoxicity of mitoxantrone-incorporated albumin microspheres on acute promyelocytic leukaemia cells.

In the present study, the preparation and characterization of bovine serum albumin (BSA) microspheres and the evaluation of the in vitro cytotoxicity of these microspheres on acute promyelocytic leukaemia (HL-60) cells were described. Mitoxantrone (MTZ)-incorporated microspheres were evaluated for particle size, drug loading, release characteristics and surface morphology. The biological effect of MTZ released from BSA microspheres was determined on an in vitro cultured HL-60 cell line, showing that, after encapsulation, MTZ still retains cytotoxic activity. For this purpose, methyl-thiazol-tetrazolium (MTT) assay was used to evaluate the in vitro cytotoxicity of MTZ-loaded microspheres. Particle size of BSA microspheres was determined between 17.61-20.38 microm and they were smooth and spherical in shape. Encapsulation efficiency of the drug-loaded microspheres was between 22.26-60.50%. For MTZ-containing microspheres, the cell death ratios were greater than 80% for all formulations. This study demonstrate that BSA microspheres were well suited for the controlled release of MTZ and were promising for anti-cancer chemotherapy.

Intranasal delivery of PEGylated salmon calcitonins: hypocalcemic effects in rats.

To evaluate the hypocalcemic effect of polyethylene gtycol-conjugated salmon calcitonins (PEG-sCT) in rats, mono-PEGylated sCTs (mono-PEG-sCTs) and unmodified sCT were administered via the intranasal route and serum calcium levels were measured by colorimetric assay using o-cresolphthalein. Mono-PEG-sCTs were prepared with different sizes of succinimidyl succinate monomethoxy PEG molecules (PEG2K), PEG5K, PEG12K) and characterized by HPLC and MALDI-TOF mass spectrometry. Nasal instillation of mono-PEG2K-sCT at a dose of 2 IU/kg resulted in sustained reduction in serum calcium levels over 8 hr, with a maximum reduction (% maxd) of 13% after 6 hr of application. Whereas unmodified sCT showed a transient decrease in serum calcium levels with the maximum reduction (5%) observed after 30 min of administration. The overall reductions in serum calcium levels expressed as the net change in AUC relative to control in 8 hr were 11.9 +/- 0.2, 4.6 +/- 0.7, and 2.6 +/- 0.7% for mono-PEG2K-, mono-PEG5K-, and mono-PEG12K-sCT, respectively, compared to 3.2 +/- 0.6% for unmodified sCT. The relative bioavailability of nasally administered 2 IU/kg of mono-PEG2K-sCT was approximately 4-fold higher than nasally administrated unmodified sCT, and the absolute bioavailability was approximately 91% of intravenously injected sCT in 8 hr. It can be concluded that the intranasal absorption of mono-PEG-sCTs was inversely related to the molecular weights of the PEG attached. Of the PEGylated sCTs examined, mono-PEG2K-sCT showed the most pronounced hypocalcemic effect. Therefore the intranasal application would probably be an alternative route of administration for mono-PEG-sCTs in achieving sustained calcium-lowering effects.

Measurement of the tissue to A-150 tissue equivalent plastic kerma ratio at two p(66)Be neutron therapy facilities.

The ICRU tissue to A-150 tissue equivalent plastic kerma ratio is needed for neutron therapy dosimetry. The current ICRU protocol for neutron dosimetry recommends using a common conversion factor of 0.95 at all high-energy neutron therapy facilities. In an effort to determine facility specific ICRU tissue to A-150 plastic kerma ratios, an experimental approach was pursued. Four low pressure proportional counters that differed in wall materials (i.e. A-150, carbon, zirconium and zirconium-oxide) were used as dosimeters and integral kerma ratios were determined directly in the clinical beam. Measurements were performed at two p(66)Be facilities: iThemba LABS near Cape Town and Fermilab near Chicago. At the iThemba facility the clinical neutron beam is routinely filtered by a flattening and hardening filter combination. The influence of beam filtration on the kerma ratio was evaluated. Using two recent gas-to-wall dose conversion factor (r(m,g) value) evaluations a mean ICRU tissue to A-150 plastic kerma ratio of 0.93 +/- 0.05 was determined for the clinical beam at iThemba LABS. The respective value for the Fermilab beam is 0.95 +/- 0.05. The experimentally determined ICRU tissue to A-150 plastic kerma ratios for the two clinical beams are in agreement with theoretical evaluations. Beam filtration reduces the kerma ratio by 3 +/- 2%.

Mapping health in the Great Lakes areas of concern: a user-friendly tool for policy and decision makers.

The role of the physical environment as a determinant of health is a major concern reported by the general public as well as by many policymakers. However, it remains one of the health determinants for which few available measures or indicators are readily available. This lack of data is compounded by the fact that evidence for direct cause-and-effect relationships in the literature is often equivocal, leading to feelings of uncertainty among the lay public and often leading to indecision among policymakers. In this article we examine one aspect of the physical environment--water pollution in the Great Lakes Areas of Concern (AOCs)--and its potential impacts on a wide range of (plausible) human health outcomes. Essentially, the International Joint Commission, the international agency that oversees Great Lakes water quality and related issues, worked with Health Canada to produce a report for each of the 17 AOCs on the Canadian side of the Great Lakes, outlining a long list of health outcomes and the potential relationships these might have with environmental exposures known or suspected to exist in the Great Lakes basin. These reports are based solely on secondary health data and a thorough review of the environmental epidemiologic literature. The use of these reports by local health policymakers as well as by public health officials in the AOCs was limited, however, by the presentation of vast amounts of data in a series of tables with various outcome measures. The reports were therefore not used widely by the audience for whom they were intended. In this paper we report the results of an undertaking designed to reduce the data and present them in a more policy-friendly manner, using a geographic information system. We do not attempt to answer directly questions related to cause and effect vis-à-vis the relationships between environment and health in the Great Lakes; rather, this work is a hypothesis-generating exercise that will help sharpen the focus of research into this increasingly important area of public health concern.

Return to fertility after extended chemical castration with a GnRH antagonist.

BACKGROUND: Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats. METHODS: Two groups of male rats received either 120-day orntide microspheres (8.8 mg orntide/kg/120 days) or vehicle alone (control group). Serum orntide and testosterone levels in both groups were monitored at certain intervals for 9 months from the initiation of treatment. After recovery of normal serum testosterone levels in the treated animals, each rat was housed with two proven breeder, but drug-naive, females. RESULTS: All mates of treated rats achieved pregnancy as rapidly as the mates of control rats although two of the control rats did not sire a litter with either female and one sired only one litter. The mean size of the litters of treated (12.3 offspring per litter) and control (10.6 offspring per litter) were similar. All offspring were grossly normal morphologically and behaviorally during the time to weaning. CONCLUSIONS: These results suggest that lack of fertility due to testosterone suppression is reversible after cessation of treatment with this GnRH antagonist.

Preparation, characterization and in vivo evaluation of 120-day poly(D,L-lactide) leuprolide microspheres.

A 120-day poly(D,L-lactide) (PLA) microsphere delivery system for a luteinizing hormone-releasing hormone (LHRH) analogue, leuprolide, was prepared and evaluated. Leuprolide microspheres were prepared with PLA (m.w. 11000 Da) by a dispersion/solvent extraction-evaporation method and characterized for drug load by HPLC, particle size by laser diffractometry and surface morphology by scanning electron microscopy. In vitro peptide release and polymer degradation were studied using a modified dialysis method. Serum peptide and testosterone levels were analyzed after subcutaneous administration using a rat model. Spherical microspheres with a mean diameter of 52 microm containing 13.4% peptide released 10% of the peptide within 24 h, followed by a linear release for 150 days. Serum leuprolide levels increased immediately after administration of the microspheres to 45.6 ng/ml, but then fell to 4.3 ng/ml at 15 days and approximately 2.0 ng/ml at 30 days where they remained for 120 days. The testosterone levels increased initially to 15 ng/ml and then decreased to below 0.5 ng/ml by day 4 where they remained for 120 days. In conclusion, a 120-day microsphere formulation of leuprolide was developed with excellent controlled peptide release characteristics and in vivo efficacy.