The history of a transdermal product: From innovation to generic.

The development, registration and successful launch of a novel, innovative transdermal pharmaceutical product requires an idea, structured planning and a highly skilled, specialist team. It is not often that the opportunity arises to document this activity. This paper demonstrates the multidisciplinary effort required to take such a product (Axiron®, a transdermal testosterone product) from innovation to market and also describes its ultimate fate after the generic drug industry took an interest in its commercial success. Although many understand various aspects of this drug development process this understanding is often, by necessity, limited to the specialities of each of the individuals involved. It is hoped that this paper will provide an interesting overview of the entire process from beginning (innovation) to end (genericization).

Standardised survey method for identifying catchment risks to water quality.

This paper describes the development and application of a systematic methodology to identify and quantify risks in drinking water and recreational catchments. The methodology assesses microbial and chemical contaminants from both diffuse and point sources within a catchment using Escherichia coli, protozoan pathogens and chemicals (including fuel and pesticides) as index contaminants. Hazard source information is gathered by a defined sanitary survey process involving use of a software tool which groups hazards into six types: sewage infrastructure, on-site sewage systems, industrial, stormwater, agriculture and recreational sites. The survey estimates the likelihood of the site affecting catchment water quality, and the potential consequences, enabling the calculation of risk for individual sites. These risks are integrated to calculate a cumulative risk for each sub-catchment and the whole catchment. The cumulative risks process accounts for the proportion of potential input sources surveyed and for transfer of contaminants from upstream to downstream sub-catchments. The output risk matrices show the relative risk sources for each of the index contaminants, highlighting those with the greatest impact on water quality at a sub-catchment and catchment level. Verification of the sanitary survey assessments and prioritisation is achieved by comparison with water quality data and microbial source tracking.

Long-term clinical and functional outcome following treatment for Paget-Schroetter syndrome.

BACKGROUND: Effort-related thrombosis of the axillosubclavian vein (Paget-Schroetter syndrome, PSS) is uncommon. It tends to affect young, active individuals and yet consensus on management is lacking. The aim here was to analyse late outcomes in a series of patients treated for PSS using a standard protocol. METHODS: The medical records of patients treated for PSS over 16 years were analysed. Patients were divided into four groups according to their management. Clinical and functional outcomes were analysed regarding residual venous defects after treatment, and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores, respectively. RESULTS: Some 117 patients (52 men and 65 women, mean age 32 years) were included. Catheter-directed thrombolysis was successful in 42 of 56 treated patients. Thoracic outlet decompression surgery was performed in 95 patients. DASH scores improved significantly in patients treated surgically (P < 0.001 to P = 0·009); early surgery had a better outcome than delayed surgery (P = 0·040). Patients who were managed conservatively showed no improvement (P = 0·116). Where venoplasty was necessary, it was successful in 18 of 25 patients. A short duration of lysis (less than 24 h) increased the risk of rethrombosis (P = 0·020). The method of postoperative anticoagulation had no influence on the rate of rethrombosis. CONCLUSION: Patients treated surgically for PSS had better functional outcomes than those managed conservatively. Prompt thrombolysis and surgery was superior to delayed management with respect to rethrombosis and functional outcome.

Modelling skin penetration using the Laplace transform technique.

The Laplace transform is a convenient mathematical tool for solving ordinary and partial differential equations. The application of this technique to problems arising in drug penetration through the skin is reviewed in this paper.

Predicting skin penetration of actives from complex cosmetic formulations: an evaluation of inter formulation and inter active effects during formulation optimization for transdermal delivery.

Twenty products, containing a radiolabelled form of each active in typical cosmetic formulations, were made and applied to female human epidermal membranes mounted in Franz diffusion cells for 48 h under 'in use' conditions. The products consisted of combinations of five formulations (a hydro-alcoholic gel, an oil in water emulsion, a water in oil emulsion, a microemulsion and an oil) with four model drug actives (testosterone, hydrocortisone, 5-fluorouracil and ketoconazole). Steady-state flux appeared to be reached by 8 h and maintained for all products, other than for the microemulsions, consistent with the actives being present in the residual formulation on the skin at saturation. The recovery for each active at the end of the 48-h study (from a series of stratum corneum tape strips, the remaining skin, cumulative amount penetrating into the receptor solution, product washed from the skin and on the donor chamber cap) ranged from 86.5% to 100.6%. The rank order of the fluxes for the actives from the hydro-alcoholic gel is consistent with the known active molecular size and polarity determinants for maximum epidermal flux. Actives with similar steady-state (maximum) fluxes from a range of formulations had retention in the stratum corneum and similar transport rate constants through the stratum corneum. The microemulsion formulation significantly enhanced both the stratum corneum steady-state flux and transport rate constant for 5-fluorouracil, hydrocortisone and testosterone. The penetration flux of each active could be related to its size and polarity and appeared maximal when the actives in the different cosmetic formulations applied to the skin under 'in use' conditions were likely to remain in the residual product on the skin as a saturated solution after solvent evaporation. Enhanced penetration fluxes can be achieved by formulation selection and an appropriate choice/mix of emollients/adjuvants. The principles described here provide a framework for understanding the delivery of cosmetic ingredients from various formulations.

Influence of penetration enhancer on drug permeation from volatile formulations.

Previously we have reported the influence of supersaturation on the permeation of fentanyl across model membranes and skin. The findings indicated that the vehicle and, specifically its residence time in skin, influence the ability of the formulation to enhance membrane drug permeation. The aim of the present study was to probe the role of vehicle components on (trans)dermal drug delivery in more detail. To this end, three commonly used chemical penetration enhancers were selected for investigation namely, propylene glycol (PG), octyl salicylate (OSAL) and isopropyl myristate (IPM). A further objective was to clarify the mechanism of action of OSAL. Model spray formulations were prepared consisting of 10% (v/v) of individual enhancers in ethanol. Saturated and supersaturated systems were evaluated for their ability to promote fentanyl transport across human skin in vitro. Mass balance studies and determination of the extent of uptake of enhancers by skin were also conducted. The results indicated that increasing the degree of drug saturation (DS) does not promote drug permeation for formulations in PG but increasing drug DS did promote drug permeation for IPM and some OSAL systems. This probably reflects faster depletion of PG compared with IPM and OSAL. Non-linear modelling of the permeation data indicated that PG and IPM act to promote drug solubility in the membrane whereas OSAL appears to act as a skin penetration enhancer by increasing drug diffusivity in the skin.

Assessment of the lateral diffusion and penetration of topically applied drugs in humans using a novel concentric tape stripping design.

PURPOSE: To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique. METHOD: Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin. RESULTS: CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3 mins ranged between 83.0 and 92.9 % and decreased to between 64.5 and 66.9 % at 3 h. IBU recovery further decreased to 47.7 ± 5.6 % at 6 h, correlating with greater in vitro penetration relative to CAF and HC. CONCLUSION: Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.

Formulation issues associated with transdermal fentanyl delivery.

Supersaturation has previously been studied as a mechanism to enhance membrane transport of fentanyl from propylene glycol:water formulations (PG:H(2)O) across silicone. In this study these supersaturated fentanyl formulations were evaluated in human skin. A number of polymers were also screened for their ability to stabilise the supersaturated formulations and permeation was evaluated for both infinite and finite doses. For infinite dose studies, permeation in skin increased linearly with increasing degree of drug saturation (DS) for formulations containing 0.5, 1, 2 DS of fentanyl and a 3 DS formulation stabilised with 1% (w/v) hydroxypropylcellulose (HPC). An excellent correlation was obtained for flux values in silicone compared with flux values in skin, for infinite dose studies for formulations containing 0.5, 1, 2 DS of fentanyl and the 3 DS formulation stabilised HPC. The concentration of the fentanyl in the stratum corneum also increased in proportion to the DS. However the same trend was not observed for finite dose studies. This is because the depletion of the solvent carrier promotes drug crystallisation with consequent implications for membrane transport. Tape-stripping experiments indicated that supersaturation of the drug is maintained in the outer layers of the stratum corneum. The ideal vehicle must, therefore, maintain the drug in solution on and in the skin in a sustained manner for effective transdermal delivery.

Venous thoracic outlet compression and the Paget-Schroetter syndrome: a review and recommendations for management.

Paget Schroetter syndrome, or effort thrombosis of the axillosubclavian venous system, is distinct from other forms of upper limb deep vein thrombosis. It occurs in younger patients and often is secondary to competitive sport, music, or strenuous occupation. If untreated, there is a higher incidence of disabling venous hypertension than was previously appreciated. Anticoagulation alone or in combination with thrombolysis leads to a high rate of rethrombosis. We have established a multidisciplinary protocol over 15 years, based on careful patient selection and a combination of lysis, decompressive surgery, and postoperative percutaneous venoplasty. During the past 10 years, a total of 232 decompression procedures have been performed. This article reviews the literature and presents the Exeter Protocol along with practical recommendations for management.

Enhanced permeation of fentanyl from supersaturated solutions in a model membrane.

The aim of the present study was to investigate the permeation of fentanyl from supersaturated formulations when applied to silicone membrane. Silicone was chosen in order to separate the effects of supersaturation from other possible influences of volatile formulation components on biological membranes. Supersaturated formulations containing either propylene glycol/water (PG/H(2)O) or propylene glycol/ethanol (PG/Et) were prepared containing varying degrees of saturation (DS) of fentanyl. Permeation of finite and infinite doses of the PG/H(2)O formulations, and finite doses of the PG/Et formulations was investigated using Franz-type diffusion cells. For the PG/H(2)O formulations a good correlation between the flux and the DS of the formulation up to 5 DS for infinite dose studies (r(2)=0.99), and up to 7 DS for finite dose studies (r(2)=0.98), was evident. Similarly, for the PG/Et formulations there is a good correlation between the mean flux and the theoretical DS of the formulation (r(2)=0.95). Except for the 2 DS formulations, no significant differences were seen in the mean flux between PG/H(2)O and PG/Et finite dose studies. The larger fluxes observed for infinite doses of the PG/H(2)O formulations versus finite doses reflect changes in the effective area of diffusion over the time of the experiment for the latter set of experiments. The permeation enhancement observed for PG/Et formulations confirms that enhanced drug thermodynamic activity was induced by ethanol evaporation.

Oxybutynin permeation in skin: the influence of drug and solvent activity.

The influence of degree of saturation (DS) of oxybutynin on permeation from octyl salicylate (OSAL) or propylene glycol (PG) vehicles was investigated, in vitro, in human skin. The permeation of OSAL and PG was also evaluated and the quantity of drug and solvent in the skin at the end of the diffusion study was measured. For OSAL the permeation of oxybutynin increased linearly with DS of drug for both 25 and 50% OSAL formulations. However, no differences were seen in oxybutynin permeation for formulations with the same DS but with different OSAL amounts, although the drug permeation was always slightly higher for 50% OSAL formulations. There was a decrease in the amount of OSAL extracted from skin with drug concentration (up to 5 DS). There was also a good correlation between the DS calculated from the amount of oxybutynin and OSAL extracted from the skin, and the actual DS of the formulation. In contrast oxybutynin DS did not affect PG permeation and there were no significant differences in oxybutynin permeation for the formulations with different DS. The lack of permeation enhancement for PG formulations appears to be related to PG depletion from the skin. The findings emphasise the importance of maintaining the drug in solution in order to achieve effective permeation from dermal and transdermal formulations.

Glue ablation of a late-presentation urinary fistula after partial nephrectomy.

Urinary fistula is an acknowledged complication of partial nephrectomy. We describe a case of a urinary fistula that failed to respond to conventional treatment and the subsequent use of percutaneous Hystoacryl glue to achieve its resolution.

One hundred questions of importance to the conservation of global biological diversity.

We identified 100 scientific questions that, if answered, would have the greatest impact on conservation practice and policy. Representatives from 21 international organizations, regional sections and working groups of the Society for Conservation Biology, and 12 academics, from all continents except Antarctica, compiled 2291 questions of relevance to conservation of biological diversity worldwide. The questions were gathered from 761 individuals through workshops, email requests, and discussions. Voting by email to short-list questions, followed by a 2-day workshop, was used to derive the final list of 100 questions. Most of the final questions were derived through a process of modification and combination as the workshop progressed. The questions are divided into 12 sections: ecosystem functions and services, climate change, technological change, protected areas, ecosystem management and restoration, terrestrial ecosystems, marine ecosystems, freshwater ecosystems, species management, organizational systems and processes, societal context and change, and impacts of conservation interventions. We anticipate that these questions will help identify new directions for researchers and assist funders in directing funds.

The effect of drug concentration on solvent activity in silicone membranes.

The effects of supersaturated formulations on drug permeation through artificial and biological membranes have been reported by a number of research groups. However, little information is known about solvent permeation from these supersaturated formulations, and in particular the effect of high drug concentrations and degree of saturation (DS) on solvent activity. The aim of this study was to determine the effect of the DS of a model drug, oxybutynin, on solvent and drug permeation. Supersaturated residues of oxybutynin in propylene glycol (PG) or (octyl salicylate) OSAL were prepared by the solvent evaporation method. In both formulations a high percentage (25%, v/v) of solvent was used in order to avoid solvent depletion. Permeation of PG and OSAL through silicone was monitored by GC and HPLC, respectively. All OSAL formulations permeated to a higher extent than PG formulations. A decrease in OSAL permeation with 5 DS formulations was observed in comparison with 1 DS or 2 DS formulations, indicating a decrease in solvent activity with drug concentration. In addition, the drug transport from the 5 DS formulation of OSAL was higher than the 1 and 2 DS formulations but lower than predicted. Based on both solvent and drug permeation, this suggests that the low drug permeation observed with 5 DS resulted from a decrease in solvent thermodynamic activity rather than a decrease in solute activity as a result of drug crystallisation. Using PG formulations, the PG permeation remained unaffected with the DS of the formulation, up to 5 DS.

Audit of the use of IVC filters in the UK: experience from three centres over 12 years.

AIM: To audit the use of inferior vena cava (IVC) filter insertions at three UK centres over 12 years to assess whether trends in filter use in the UK mirrored those seen elsewhere. MATERIALS AND METHODS: Radiology department databases were interrogated for IVC filter insertions and removals between 1994 and 2006. Reports for these interventions, along with prior and subsequent imaging reports, were analysed. Follow-up data were obtained when available. RESULTS: Five hundred and sixteen filters were placed with a significant year-on-year trend towards increasing use. Fifty-seven percent of filters placed were for absolute indications and 37% for relative indications. The filters were used for prophylaxis in 6% of patients in the absence of proven pulmonary embolism (PE) or deep vein thrombosis (DVT). A retrievable filter was used in 74% of cases with retrieval attempted in 40% of these and no evidence of an increasing rate of retrieval over time. A significant complication related to insertion or retrieval was encountered in 0.4 and 1% of procedures, respectively. Mean 24 h and 30 day mortalities were 1 and 8%, respectively. There was an absence of organized follow-up at all three centres. CONCLUSION: IVC filter use in the UK is increasing. The use of retrievable filters has not resulted in increased filter retrieval. Filter insertion and retrieval is associated with a low risk of significant complication, but lack of systematic follow-up limits conclusions regarding safety and efficacy.

A novel "cheese wire" technique for stent positioning following difficult iliac artery subintimal dissection and aortic re-entry.

Subintimal wire dissection is a well-established method for traversing difficult vascular occlusions. This technique relies on re-entry of the true lumen distal to the occlusion, which may be difficult in diseased vessels with significant calcification. This case report describes a novel "cheese wire" technique to allow stent positioning without the use of proprietary re-entry devices.

The occurrence of antibiotics in an urban watershed: from wastewater to drinking water.

The presence of 28 antibiotics in three hospital effluents, five wastewater treatment plants (WWTPs), six rivers and a drinking water storage catchment were investigated within watersheds of South-East Queensland, Australia. All antibiotics were detected at least once, with the exception of the polypeptide bacitracin which was not detected at all. Antibiotics were found in hospital effluent ranging from 0.01-14.5 microg L(-1), dominated by the beta-lactam, quinolone and sulphonamide groups. Antibiotics were found in WWTP influent up to 64 microg L(-1), dominated by the beta-lactam, quinolone and sulphonamide groups. Investigated WWTPs were highly effective in removing antibiotics from the water phase, with an average removal rate of greater than 80% for all targeted antibiotics. However, antibiotics were still detected in WWTP effluents in the low ng L(-1) range up to a maximum of 3.4 microg L(-1), with the macrolide, quinolone and sulphonamide antibiotics most prevalent. Similarly, antibiotics were detected quite frequently in the low ng L(-1) range, up to 2 microg L(-1) in the surface waters of six investigated rivers including freshwater, estuarine and marine samples. The total investigated antibiotic concentration (TIAC) within the Nerang River was significantly lower (p<0.05) than all other rivers sampled. The absence of WWTP discharge to this river is a likely explanation for the significantly lower TIAC and suggests that WWTP discharges are a dominant source of antibiotics to investigated surface waters. A significant difference (p<0.001) was identified between TIACs at surface water sites with WWTP discharge compared to sites with no WWTP discharge, providing further evidence that WWTPs are an important source of antibiotics to streams. Despite the presence of antibiotics in surface waters used for drinking water extraction, no targeted antibiotics were detected in any drinking water samples.

Embolization of renal angiomyolipoma: immediate complications and long-term outcomes.

AIMS: To report the outcomes of elective and emergency embolization of renal angiomyolipoma and describe an angiographic sign that will help localize the symptomatic aneurysm in emergency cases. MATERIALS AND METHODS: A retrospective review of all patients undergoing embolization of renal angiomyolipoma at a two centres between 1998-2007. Indications for treatment and angiographic images were reviewed. Incidence of acute rupture during embolization was noted. RESULTS: Seventeen patients underwent 23 episodes of embolization using polyvinyl alcohol (PVA) particles, bead block, and coils. Thirteen were elective procedures for large or symptomatic angiomyolipoma and 10 were acute procedures for patients presenting with retroperitoneal haemorrhage. Patients presenting acutely with haemorrhage tended to have extensive multifocal renal involvement. Active bleeding on diagnostic angiography was seen in a single patient who presented with retroperitoneal haemorrhage 48h after elective embolization with PVA alone. Seven out of 10 (70%) of the acute cases displayed splaying of adjacent vessels due to peri-aneurysmal haematoma, known locally as the "light bulb sign". This allowed treatment to be focused on the symptomatic aneurysm. The light bulb sign was not present in any patient undergoing elective embolization. Aneurysm rupture with active extravasation occurred following embolization of the distal tumour circulation with PVA in four of 10 (40%) of the patients in the acute group and three of 13 (23%) patients in the elective group. Five patients required a subsequent embolization, three at a different site. Two patients in the elective group required repeat embolization of the target site, one for delayed haemorrhage and the other whose tumour did not shrink following the initial incomplete treatment. CONCLUSIONS: Embolization of renal angiomyolipoma produces durable results. The presence of the light bulb sign is a strong indicator of the site of haemorrhage within the kidney. We advocate using a combination of particulate material and coils, as embolization with PVA alone may predispose to acute haemorrhage occurring during or after embolization.