Sudaxshina Murdan

Drug permeation and barrier damage in Leishmania-infected mouse skin

OBJECTIVESnPathological disorder can disrupt the barrier integrity of the skin, thereby altering the drug delivery from topical formulations to the target site. Cutaneous leishmaniasis (CL) is an infection of the dermal layers of the skin and manifests as a variety of skin lesions from defined nodular forms to plaques and chronic ulcers. The aim of this work was to characterize the physiology and barrier integrity of the Leishmania-infected BALB/c mouse skin and how they impacted delivery of drugs into the skin.nnnMETHODSnA histological evaluation of the structural differences between uninfected and infected skin was performed using haematoxylin/eosin, elastic Van Gieson and Iba-1 stains. As a CL nodule developed and progressed, the skin pH, hydration and trans-epidermal water loss (TEWL) were recorded. Finally, Franz diffusion cells were used to evaluate the influence of the infection on drug delivery through the skin.nnnRESULTSnWe found: (i) structural changes in both the epidermal and dermal layers due to the ingress of inflammatory cells, as shown by immunohistochemistry; (ii) a significant increase in TEWL; and (iii) significantly higher permeation of the model permeants caffeine and ibuprofen and the antileishmanial drugs buparvaquone and paromomycin, for Leishmania-infected skin compared with uninfected skin. The infection had no measurable influence on skin pH and hydration.nnnCONCLUSIONSnWe report profound changes in the skin barrier physiology, function and permeability to drugs of Leishmania-infected skin.

Implementation of antimicrobial stewardship interventions recommended by national toolkits in primary and secondary healthcare sectors in England: TARGET and Start Smart Then Focus

OBJECTIVESnTo assess and compare the implementation of antimicrobial stewardship (AMS) interventions recommended within the national AMS toolkits, TARGET and Start Smart Then Focus, in English primary and secondary healthcare settings in 2014, to determine the prevalence of cross-sector engagement to drive AMS interventions and to propose next steps to improve implementation of AMS.nnnMETHODSnElectronic surveys were circulated to all 211 clinical commissioning groups (CCGs; primary sector) and to 146 (out of the 159) acute trusts (secondary sector) in England. Response rates were 39% and 63% for the primary and secondary sectors, respectively.nnnRESULTSnThe majority of CCGs and acute trusts reported reviewing national AMS toolkits formally or informally (60% and 87%, respectively). However, only 13% of CCGs and 46% of acute trusts had developed an action plan for the implementation of these toolkits. Only 5% of CCGs had antimicrobial pharmacists in post; however, the role of specialist antimicrobial pharmacists continued to remain embedded within acute trusts, with 83% of responding trusts having an antimicrobial pharmacist at a senior grade.nnnCONCLUSIONSnThe majority of healthcare organizations review national AMS toolkits; however, implementation of the toolkits, through the development of action plans to deliver AMS interventions, requires improvement. For the first time, we report the extent of cross-sector and multidisciplinary collaboration to deliver AMS interventions in both primary and secondary care sectors in England. Results highlight that further qualitative and quantitative work is required to explore mutual benefits and promote best practice. Antimicrobial pharmacists remain leaders for implementing AMS interventions across both primary and secondary healthcare sectors.

Efficacy of Paromomycin-Chloroquine Combination Therapy in Experimental Cutaneous Leishmaniasis

ABSTRACT The 4-aminoquinoline chloroquine (CQ) is clinically used in combination with doxycycline to cure chronic Q fever, as it enhances the activity of the antibiotic against the causative bacterium Coxiella burnetii residing within macrophage phagolysosomes. As there is a similar cellular host-pathogen biology for Leishmania parasites, this study aimed to determine whether such an approach could also be the basis for a new, improved treatment for cutaneous leishmaniasis (CL). We have evaluated the in vitro and in vivo activities of combinations of CQ with the standard drugs paromomycin (PM), miltefosine, and amphotericin B against Leishmania major and Leishmania mexicana. In 72-h intracellular antileishmanial assays, outcomes were variable for different drugs. Significantly, the addition of 10 μM CQ to PM reduced 50% effective concentrations (EC50s) by over 5-fold against L. major and against normally insensitive L. mexicana parasites. In murine models of L. major and L. mexicana CL, daily coadministration of 50 mg/kg of body weight PM and 25 mg/kg CQ for 10 days resulted in a significant reduction in lesion size but not in parasite load compared to those for mice given the same doses of PM alone. Overall, our data indicate that PM-CQ combination therapy is unlikely to be a potential candidate for further preclinical development.

UV-curable gel formulations: Potential drug carriers for the topical treatment of nail diseases

Nail diseases are common, cause significant distress and treatments are far from successful. Our aim was to investigate the potential of UV-curable gels - currently used as cosmetics - as topical drug carriers for their treatment. These formulations have a long residence on the nail, which is expected to increase patient compliance and the success of topical therapy. The gels are composed of the diurethane dimethacrylate, ethyl methacrylate, 2-hydroxy-2-methylpropiophenone, an antifungal drug (amorolfine HCl or terbinafine HCl) and an organic liquid (ethanol or NMP) as drug solvent. Following its application to a substrate and exposure to a UVA lamp for 2 min, the gel polymerises and forms a smooth, glossy and amorphous film, with negligible levels of residual monomers. No drug-polymer interactions were found and drug loading did not affect the films properties, such as thickness, crystallinity and transition temperatures. In contrast, the organic solvent did influence the films properties; NMP-containing films had lower glass transition temperatures, adhesion and water resistance than ethanol-based ones. Water-resistance being a desired property, ethanol-based formulations were investigated further for stability, drug release and ungual permeation. The films were stable under accelerated stability testing conditions. Compared to terbinafine, amorolfine was released to a greater extent, had a higher ungual flux, but a lower concentration in the nailplate. However, both drugs were present at considerably high levels in the nail when their MICs are taken into account. We thus conclude that UV-curable gels are promising candidates as topical nail medicines.

In vivo measurement of the surface energy of human fingernail plates

The surface energy of the human nail plate is expected to influence the adhesion of microorganisms (and subsequent colonization and infections) as well as that of medicines (and subsequent drug permeation) and of cosmetics. The aim of the study was therefore to measure the surface energy of nail plates in vivo. The surface energy of healthy human fingernails (untreated, hydrated and abraded) and of hoof membranes (often used as a model for the nail plate) was estimated from contact angle measurements of liquids (water, formamide, diiodomethane and glycerol) on the nail plate and subsequent computation using the Lifshitz–van der Waals/acid–base (LW‐AB) approach. The surface energy of untreated fingernail plates was found to be 34u2003mJu2003m−2. Most of this total energy was from the apolar Lifshitz–van der Waals component. When the polar component of the surface energy was analysed, the electron donor component was considerably larger than the electron acceptor one. Hydrating the nail plate had no significant influence on the surface energy. In contrast, abrasion caused a small, but statistically significant increase in the apolar surface energy component. The surface energy of bovine hoof membrane was similar to that of the fingernail plate. We conclude that the human fingernail plate is a low‐energy surface and that bovine hoof membranes may be used as a substitute for the nail plate in certain experiments.

Application of Hansen Solubility Parameters to predict drug-nail interactions, which can assist the design of nail medicines.

We hypothesised that Hansen Solubility Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) determine the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/solubility in organic liquids, (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of experimentally-determined affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match experimental reports of these drugs affinities to keratin. We therefore propose that drug and nail Hansen Solubility Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.

Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal

Abstract The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex‐dependent manner. As ranitidine is a substrate for the efflux transporter P‐glycoprotein (P‐gp), we hypothesized that the sex‐related influence could be due to interactions between PEG 400 and P‐gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P‐gp substrate (ampicillin) and of a non‐P‐gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P‐gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (p < 0.05) the bioavailability of ampicillin (the P‐gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non‐P‐gp substrate, metformin in male or female rats. Inhibition of P‐gp by oral pre‐treatment with cyclosporine A increased the bioavailability of the P‐gp substrates (ampicillin and ranitidine) in males and females (p < 0.05), and to a greater extent in males, but had no influence on the bioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex‐specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P‐gp. Graphical abstract Figure. No Caption available.

Nail disorders in older people, and aspects of their pharmaceutical treatment.

The aim of this paper was to explore how aging influences the nail unit, its disorders and its response to treatment, and to identify some of the age-related gaps in the ungual drug delivery literature. Aging causes obvious changes to the nail, some of which are inherently due to old age, while others are due to diseases/conditions which become more prevalent as we age. Alterations in the nail plates colour, contour, thickness, fragility, surface features, cell size, chemical composition and growth rate are some of the changes, with toenails and fingernails showing different effects. With respect to disease, the incidence of onychomycosis - the most common nail disorder - is considerably higher in older people. Similarly, brittle nails become more common as we age. In contrast, the literature about aging and the incidence of nail psoriasis is inconclusive, although, it is clear that as one gets older, the negative impact of nail psoriasis on ones quality of life decreases. Pharmaceutical treatment of the diseases comprises local and systemic therapies, sometimes in combination. Systemic therapies have the inherent disadvantages of adverse systemic effects, drug interactions and the need for monitoring, disadvantages which are especially problematic for older people who are more likely to suffer from co-morbidities and be on other medications. Topical therapy avoids such disadvantages. However, the success rates of commercially available preparations are low, and older people may need help with their application. It is also proposed that regular inspection and grooming of nails should become part of routine care of older people, as these would provide opportunities to identify and treat any problems at an earlier stage.

Development of a rapid, reliable and quantitative method – “SPOTi” for testing antifungal efficacy

A reference method for the antimicrobial susceptibility testing of common fungal pathogens such as dermatophytes, is currently lacking. In this study, we report the successful adaptation of solid agar-based spot culture growth inhibition assay (SPOTi) for dermatophytes, currently being used as a gold-standard in the anti-tubercular drug discovery field. The fungal-SPOTi assay correlated with the disc-diffusion method, and is validated using mycelial plugs. We propose the fungal-SPOTi as a high-throughput alternative to the disc-diffusion and broth micro-dilution anti-fungal assays to screen novel anti-fungals.

Sex differences in excipient effects: Enhancement in ranitidine bioavailability in the presence of polyethylene glycol in male, but not female, rats.

Males and females respond differently to drugs: indeed, sex plays a crucial role in determining drug pharmacokinetics and pharmacodynamics. Excipients have also been shown to enhance the biovailability of drugs differently in men and women. The aim of this work was to investigate whether rodents are a good model in which to study sex-specific effects of polyethylene glycol 400 (PEG 400) on the bioavailability of ranitidine. Ranitidine (50mg/kg) was dissolved in water with different amounts of PEG 400-0 (control), 13, 26, 51, 77, 103, and 154mg/kg; these solutions were dosed orally by gavage to male and female Wistar rats. Blood samples were withdrawn over 480min and assayed via HPLC-UV. Individual ranitidine plasma profiles were constructed for each rat, and standard pharmacokinetic parameters were determined. In the male rats, the change in the area under the plasma ranitidine curve (AUC0-480) compared to the control group, was +18%; +49% (p<0.05); +37% (p<0.05); +31% (p<0.05); +8% and -22% (p<0.05) for PEG 400 doses of 13; 26; 51; 77; 103; and 154mg/kg respectively. On the other hand, females showed no statistically significant difference between the groups. In conclusion, low doses of PEG 400 enhanced the bioavailability of ranitidine in male, but not female, rats. These findings are in agreement with previously published human data, therefore confirming the validity of the rodent model, and highlight the unusual and clinically significant phenomenon that an excipient can influence drug bioavailability in one gender and not the other.