Trends in morphine prescriptions, illicit morphine use and associated harms among regular injecting drug users in Australia

This paper examines population trends in morphine prescriptions in Australia, and contrasts them with findings from annual surveys with regular injecting drug users (IDU). Data on morphine prescriptions from 1995 to 2003 were obtained from the Drug Monitoring System (DRUMS) run by the Australian Government Department of Health and Ageing. Data collected from regular IDU as part of the Australian Illicit Drug Reporting System (IDRS) were analysed (2001-2004). The rate of morphine prescription per person aged 15-54 years increased by 89% across Australia between 1995 and 2003 (from 46.3 to 85.9 mg per person). Almost half (46%) of IDU surveyed in 2004 reported illicit morphine use, with the highest rates in jurisdictions where heroin was less available. Recent morphine injectors were significantly more likely to be male, unemployed, out of treatment and homeless in comparison to IDU who had not injected morphine. They were also more likely to have injected other pharmaceutical drugs and to report injection related problems. Among those who had injected morphine recently, the most commonly reported injecting harms were morphine dependence (38%), difficulty finding veins into which to inject (36%) and scarring or bruising (27%). Morphine use and injection is a common practice among regular IDU in Australia. In some cases, morphine may be a substitute for illicit heroin; in others, it may be being used to treat heroin dependence where other pharmacotherapies, such as methadone and buprenorphine, are perceived as being unavailable or undesirable by IDU. Morphine injection appears to be associated with polydrug use, and with it, a range of problems related to drug injection. Further research is required to monitor and reduce morphine diversion and related harms by such polydrug injectors.

Physical enhancement of transdermal drug application: is delivery technology keeping up with pharmaceutical development?

Advances in molecular biology have given us a wide range of protein and peptide-based drugs that are unsuitable for oral delivery because of their high degree of first-pass metabolism. Though parenteral delivery is the obvious answer, for the successful development of commercial chronic and self-administration usage formulations it is not the ideal choice. Transdermal delivery is emerging as the biggest application target for these agents, however, the skin is extremely efficient at keeping out such large molecular weight compounds and therapeutic levels are never going to be realistically achieved by passive absorption. Physical enhancement mechanisms including: iontophoresis, electroporation, ultrasound, photomechanical waves, microneedles and jet-propelled particles are emerging as solutions to this topical delivery dilemma. Adding proteins and peptides to the list of other large molecular weight drugs with insufficient passive transdermal fluxes to be therapeutically useful, we have a collection of pharmacological agents waiting for efficient delivery methods to be introduced. This article reviews the current state of physical transdermal delivery technology, assesses the pros and cons of each technique and summarises the evidence-base of their drug delivery capabilities.

Prescription drug samples: Does this marketing strategy counteract policies for quality use of medicines?

Prescription drug samples, as used by the pharmaceutical industry to market their products, are of current interest because of their influence on prescribing, and their potential impact on consumer safety. Very little research has been conducted into the use and misuse of prescription drug samples, and the influence of samples on health policies designed to improve the rational use of medicines. This is a topical issue in the prescription drug debate, with increasing costs and increasing concerns about optimizing use of medicines. This manuscript critically evaluates the research that has been conducted to date about prescription drug samples, discusses the issues raised in the context of traditional marketing theory, and suggests possible alternatives for the future.

A convergent solution-phase synthesis of the macrocycle Ac-Phe-[Orn-Pro-D-Cha-Trp-Arg], a potent new antiinflammatory drug

Relatively few cyclic peptides have reached the pharmaceutical marketplace during the past decade, most produced through fermentation rather than made synthetically. Generally, this class of compounds is synthesized for research purposes on milligram scales by solid-phase methods, but if the potential of macrocyclic peptidomimetics is to be realized, low-cost larger scale solution-phase syntheses need to be devised and optimized to provide sufficient quantities for preclinical, clinical, and commercial uses. Here, we describe a cheap, medium-scale, solution-phase synthesis of the first reported highly potent, selective, and orally active antagonist of the human C5a receptor. This compound, Ac-Phe[Orn-Pro-D-Cha-Trp-Arg], known as 3D53, is a macrocyclic peptidomimetic of the human plasma protein C5a and displays excellent antiinflammatory activity in numerous animal models of human disease. In a convergent approach, two tripeptide fragments Ac-Phe-Orn-(Boc)-Pro-OH and H-D-Cha-Trp(For)-Arg-OEt were first prepared by high-yielding solution-phase couplings using a mixed anhydride method before coupling them to give a linear hexapeptide which, after deprotection, was obtained in 38% overall yield from the commercially available amino acids. Cyclization in solution using BOP reagent gave the antagonist in 33% yield (13% overall) after HPLC purification. Significant features of the synthesis were that the Arg side chain was left unprotected throughout, the component Boe-D-Cha-OH was obtained very efficiently via hydrogenation Of D-Phe with PtO2 in TFA/water, the tripeptides were coupled at the Pro-Cha junction to minimize racemization via the oxazolone pathway, and the entire synthesis was carried out without purification of any intermediates. The target cyclic product was purified (>97%) by reversed-phase HPLC. This convergent synthesis with minimal use of protecting groups allowed batches of 50100 g to be prepared efficiently in high yield using standard laboratory equipment. This type of procedure should be useful for making even larger quantities of this and other macrocyclic peptidomimetic drugs.

Pilot study to determine the ability of health-care professionals to undertake drug dose calculations

Background: It is essential for health-care professionals to calculate drug doses accurately. Previous studies have demonstrated that many hospital doctors were unable to accurately convert dilutions (e.g. 1:1000) or percentages (e.g. percentage w/v) of drug concentrations into mass concentrations (e.g. mg/mL). Aims: The aims of the present study were to evaluate the ability of health-care professionals to perform drug dose calculations accurately and to determine their preferred concentration convention when calculating drug doses. Methods: A selection of nurses, medical students, house surgeons, registrars and pharmacists undertook a written survey to assess their ability to perform five drug dose calculations. Participants were also asked which concentration convention they preferred when calculating drug doses. The surveys were marked then analysed for health-care professionals as a whole and then by subgroup analysis to assess the performance of each health-care-professional group. Results: Overall, less than 14% of the surveyed health-care professionals could answer all five questions correctly. Subgroup analysis revealed that health-care pro-fessionals' ability to calculate drug doses were ranked in the following order: registrars approximate to pharmacists > house surgeons > medical students >> nurses. Ninety per cent of health-care professionals preferred to calculate drug doses using the mass concentration convention. Conclusions: Overall, drug dose calculations were performed poorly. Mass concentration was clearly indicated as the preferred convention for calculating drug doses.

Which drug combination for hormone-refractory prostate cancer

Patients with metastatic hormone-refractory prostate cancer have a progressive disease with a median survival of similar to 11 months, and currently no treatment offers a survival advantage. The standard drug treatment is a corticosteroid and chemotherapy with mitoxantrone. In a comparison of docetaxel every 3 weeks and prednisone, versus mitoxantrone and prednisone, with a follow-up of similar to 21 months, there were less deaths in the docetaxel group than in the mitoxantrone group (166 of 335 patients and 201 of 337 patients, respectively). Docetaxel also prolonged the duration of survival compared with mitoxantrone (18.9 and 16.5 months, respectively). When given with prednisone, docetaxel was also shown to reduce pain and serum prostate specific antigen levels and improve quality of life compared with mitoxantrone/prednisone. In another trial in hormone-resistant prostate cancer patients, which compared docetaxel and estramustine with mitoxantrone and prednisone during a median follow-up of 32 months, there were fewer deaths with docetaxel/estramustine than with mitoxantrone/prednisone, which were 217 of 338 and 235 of 336 patients, respectively. Median survival was also longer in the docetaxel and estramustine group than in the mitoxantrone/prednisone group (17.5 and 15.6 months, respectively). In conclusion, two combinations (docetaxel/prednisone and docetaxel/estramustine) have been shown to be superior to mitoxantrone/prednisone in hormone-refractory prostate cancer and both should be considered for use. With the present information, there is little to distinguish between these combinations.

BMS-354825: a novel drug with potential for the treatment of imatinib-resistant chronic myeloid leukaemia

The BCR-ABL tyrosine kinase inhibitor imatinib has greatly improved the outcome for patients with chronic myeloid leukaemia (CML). Unfortunately, mutations causing resistance to imatinib are leading to relapses in some patients. In addition to inhibiting the wild-type BCR-ABL, BMS-354825 inhibited 14 of 15 BCR-ABL mutants. BMS-354825 treatment of immunodeficient mice prevented the progression of the disease in mice treated with the most clinical common imatinib-resistant mutant Met351Thr. The safety and efficacy of BMS-354825 is presently being evaluated in a phase I/II clinical trial in CML patients with imatinib resistance. The frequency of clinical use of SMS-3548125 in CML patients will depend on its efficacy/safety profile in clinical trial.

Effect of drug concentration on adsorption of levofloxacin by polyacrylonitrile haemofilters

We studied an in vitro model of continuous venovenous haemofiltration to determine levofloxacin adsorption by polyacrylonitrile (PAN) filters. Four doses of levofloxacin (5, 25, 50 and 100 mg) were used, resulting in circulating concentrations of levofloxacin at 120 min of 3.56 +/- 0.14, 15.84 +/- 2.08, 31.42 +/- 1.95 and 58.23 +/- 1.10 mg/L, respectively. Adsorption at 2 h was 0.65 +/- 0.17, 5.99 +/- 2.49, 12.30 +/- 2.34 and 30.13 +/- 1.32 mg, respectively (P < 0.001). From 2 h to 4 h, increasing the blood pump rate and the ultrafiltration rate had no effect on adsorption. When the concentration was decreased from 3.55 +/- 0.13 mg/L at 4 h to 2.16 +/- 0.11 mg/L at 5 h by addition of lactated Ringer's solution, adsorption decreased from 0.67 +/- 0.16 mg to 0.21 +/- 0.25 mg (P < 0.05). These data show that adsorption of levofloxacin by PAN haemofilters is concentration dependent and reversible in vitro and suggest that adsorption by haemofilters is unlikely to affect levofloxacin pharmacokinetics significantly in vivo. (c) 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

The effect of complexation on characteristics and drug release from PLGA microspheres loaded by cyclosporine-cyclodextrin complex

The purpose of this study was to evaluate the effect of cyclosporine (CyA)-cyclodextrin (CD) complex incorporated within PLGA inicrospheres on microsphere characteristics, with particular emphasis on drug release kinetics. For this purpose, microspheres encapsulated with CyA and those loaded by CyA-CD complex were prepared by solvent evaporation and multiple emulsification solvent evaporation methods, respectively. Morphology, size, encapsulation efficiency and drug release pattern from microspheres were evaluated. Also, physicochemical properties of drug inside microspheres were characterized by differential scanning calorimetry (DSC) and infrared spectroscopy (IR) studies. Scanning electron microscopy (SEM) studies showed that microspheres encapsulated with CyA had islands on the microsphere surface but the islands were not seen on the surface of microspheres loaded by complex. Size range varied from 1 to 25 mu m for CyA encapsulated microspheres and 1 to 50 mu m for complex loaded microspheres. The release of CyA was biphasic with an initial more rapid release phase followed by a slower phase but drug release was twice as fast for complex loaded microspheres. IR studies did not indicate any chemical interaction between the components of microspheres and DSC thermograms revealed that CyA was present either in its amorphous state in microspheres or the presence of CyA as an inclusion complex within microspheres loaded by complex. In conclusion, using CyA as an inclusion complex with CD within microspheres can affect microsphere characteristics and drug release and it is possible to modify microsphere properties like drug release by incorporating CDs as complexing agents.

Transdermal drug delivery: Basic principles for the veterinarian

The use of topical pharmaceutical formulations is increasingly popular in veterinary medicine. A potential concern is that not all formulations are registered for the intended species, yet current knowledge strongly suggests that simple extrapolation of transdermal drug pharmacokinetics and pharmacodynamics between species, including humans, cannot be done. In this review, an overview is provided of the underlying basic principles determining the movement of topically applied molecules into and through the skin. Various factors that may affect transdermal drug penetration between species, between individuals of a particular species and regional differences in an individual are also discussed. A good understanding of the basic principles of transdermal drug delivery is critical to avoid adverse effects or lack of efficacy when applying topical formulations in veterinary medicine. (c) 2005 Elsevier Ltd. All rights reserved.