Samuel E. Gilchrist

Fusidic acid and rifampicin co-loaded PLGA nanofibers for the prevention of orthopedic implant associated infections.

Implant-associated infections following invasive orthopedic surgery are a major clinical problem, and are one of the primary causes of joint failure following total joint arthroplasty. Current strategies using perioperative antibiotics have been met with little clinical success and have resulted in various systemic toxicities and the promotion of antibiotic resistant microorganisms. Here we report the development of a biodegradable localized delivery system using poly(D,L-lactic acid-co-glycolic acid) (PLGA) for the combinatorial release of fusidic acid (FA) (or its sodium salt; SF) and rifampicin (RIF) using electrospinning. The drug-loaded formulations showed good antibiotic encapsulation (~75%-100%), and a biphasic drug release profile. All dual-loaded formulations showed direct antimicrobial activity in vitro against Staphylococcus epidermidis, and two strains of methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, lead formulations containing 10% (w/w) FA/SF and 5% (w/w) RIF were able to prevent the adherence of MRSA to a titanium implant in an in vivo rodent model of subcutaneous implant-associated infection.

Intra-articular drug delivery systems: overcoming the shortcomings of joint disease therapy

Background: Intra-articular drug delivery is very useful for treating local disease flare-ups, synovitis and pain in joints. However, the effectiveness of drugs following intra-articular administration is limited by drug delivery issues. Aim: This review addresses critical drug delivery parameters that influence the biocompatibility, tolerability and efficacy of intra-articular administrations and offers an opinion on aspects of formulation design. Methods: The relevant literature was reviewed, focusing on factors influencing tissue targeting, safety and effectiveness of particulate formulations. Results/conclusion: Therapeutic applications of novel drug delivery systems for the localized treatment of joints have lagged significantly. Future innovations in the field will require the discovery of new therapeutic agents for regional delivery, combination regimens, novel biomaterials as drug carriers and targeting carriers to specific molecules.

Lactation stage-dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids

Since solute carrier (SLC) and ATP‐binding cassette (ABC) transporters play pivotal roles in the transport of both nutrients and drugs into breast milk, drug–nutrient transport interactions at the lactating mammary gland are possible. Our purpose was to characterize lactation stage‐dependent changes in transporter expression in rat mammary gland and isolated mammary epithelial organoids (MEO) to provide additional insight for the safe use of maternal medications during breastfeeding. We used quantitative reverse transcription‐polymerase chain reaction to assess the temporal expression patterns of SLC and ABC transporters in rat mammary gland and isolated MEO at different stages of lactation. In whole mammary gland five distinct patterns of expression emerged relative to late gestation: (i) decreasing throughout lactation (Mdr1a, Mdr1b, Mrp1, Octn2, Ent2, Ent3, Ncbt2, Mtx1); (ii) prominent increase in early lactation, which may remain elevated or decline with advancing lactation (Octn1, Cnt2, Cnt3, Ent1, Pept1, Pept2); (iii) constant but decreasing later in lactation (Octn3, Dmt1); (iv) increasing until mid‐to‐late lactation (Oct1, Cnt1); and (v) prominent increase late in lactation (Ncbt1). In isolated MEO (an enriched source of mammary epithelial cells) major differences in expression patterns were noted for Octn3, Ncbt1, and Mtx1, but otherwise were reasonably similar with the whole mammary gland. In conclusion our study augments existing data on transporter expression in the lactating mammary gland. These data should facilitate investigations into lactation‐stage dependent changes in drug or nutrient milk‐to‐serum concentration ratios, the potential for drug– or disease–transporter interactions, and mechanistic studies of transporter function in the lactating mammary gland.

Phase Separation Behavior of Fusidic Acid and Rifampicin in PLGA Microspheres

The purpose of this study was to characterize the phase separation behavior of fusidic acid (FA) and rifampicin (RIF) in poly(d,l-lactic acid-co-glycolic acid) (PLGA) using a model microsphere formulation. To accomplish this, microspheres containing 20% FA with 0%, 5%, 10%, 20%, and 30% RIF and 20% RIF with 30%, 20% 10%, 5%, and 0% FA were prepared by solvent evaporation. Drug-polymer and drug-drug compatibility and miscibility were characterized using laser confocal microscopy, Raman spectroscopy, XRPD, DSC, and real-time video recordings of single-microsphere formation. The encapsulation of FA and RIF alone, or in combination, results in a liquid-liquid phase separation of solvent-and-drug-rich microdomains that are excluded from the polymer bulk during microsphere hardening, resulting in amorphous spherical drug-rich domains within the polymer bulk and on the microsphere surface. FA and RIF phase separate from PLGA at relative droplet volumes of 0.311 ± 0.014 and 0.194 ± 0.000, respectively, predictive of the incompatibility of each drug and PLGA. When coloaded, FA and RIF phase separate in a single event at the relative droplet volume 0.251 ± 0.002, intermediate between each of the monoloaded formulations and dependent on the relative contribution of FA or RIF. The release of FA and RIF from phase-separated microspheres was characterized exclusively by a burst release and was dependent on the phase exclusion of surface drug-rich domains. Phase separation results in coalescence of drug-rich microdroplets and polymer phase exclusion, and it is dependent on the compatibility between FA and RIF and PLGA. FA and RIF are mutually miscible in all proportions as an amorphous glass, and they phase separate from the polymer as such. These drug-rich domains were excluded to the surface of the microspheres, and subsequent release of both drugs from the microspheres was rapid and reflected this surface location.

Mosquirix (RTS,S): A Novel Vaccine for the Prevention of Plasmodium falciparum Malaria:

Objective: To summarize and evaluate the literature for Mosquirix (RTS,S) and provide insight into the therapeutic and economic controversies of this novel malaria vaccine candidate. Data Sources: A systematic literature search was performed using the terms Mosquirix; RTS.S; malaria; vaccine; and Plasmodium in MEDLINE (1948–November 2011), EMBASE (1980–November 2011), International Pharmaceutical Abstracts (1970-November 2011), Google, and Google Scholar. Study Selection and Data Extraction: Clinical trials describing vaccine development, pharmacology, pharmacokinetics, efficacy, and safety were reviewed. For efficacy, clinical trials were reviewed that reported acquisition of malarial disease. Information regarding study design, population, study period, baseline characteristics, clinical outcomes, results, and assessors of quality was extracted. Data Synthesis: Five randomized controlled trials and 4 follow-up extension studies were identified. In Phase 2 trials, vaccine efficacy rates were 33–65% in infants and 30–53% in children for preventing the first episode of clinic a) disease. In Phase 3 trials, vaccine efficacy was 56% in children aged 5–17 months. RTS,S reduced (he number of clinical malaria episodes and prevented severe malaria in several studies. The follow-up period for vaccine efficacy ranged from 6 to 45 months. RTS,S 25 μg is administered intramuscularly as 3 injections given 1 month apart for infants and children. RTS,S appears to be generally well tolerated. A few cases of meningitis and seizures (within 7 days of vaccination) have been reported. Conclusions: RTS,S has demonstrated efficacy and safety in Phase 1, 2, and 3 trials, and has the potential to decrease morbidity and mortality from malaria worldwide. Major challenges include determination of the duration of immunity, assessment of its cost-effectiveness, its use in special populations, and its dissemination in endemic regions. Pending further studies, RTS,S has the potential to become the benchmark as the first effective vaccine against malaria.

The solid-state characterization of fusidic acid.

PURPOSE The aim of this work was to characterize the solid-state properties of fusidic acid (FA). METHODS Solid forms of FA were prepared by solvent-mediated polymorphic transformation of commercial FA (Form III) in acetonitrile (ACN), and methanol:H(2)O (50:50), or generated by solvent recrystallization from dichloromethane (DCM). Polymorphs were characterized using, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), polarizing hot stage microscopy (HSM), and intrinsic dissolution rate (IDR). RESULTS Slurrying commercial FA (Form III) in methanol:H(2)O (50:50), yielded a metastable form (Form IV). This metastable form converts to Form I or back to Form III in ACN and H(2)O, respectively, and Form II upon recrystallization from DCM. IDR of Form IV was 0.092 mg/min/cm(2), and was statistically different (p<0.05) from the IDR of Forms I, II, and III, with IDR of 0.053, 0.043, and 0.045mg/min/cm(2), respectively. The amorphous FA had an IDR of 0.125 mg/min/cm(2), and was significantly higher (p<0.05) than any other solid form. There were no statistical differences in the IDR of Form I, II, or III. CONCLUSIONS This work provides evidence for the existence of two previously unreported polymorphic forms of FA (Forms II and IV) and an amorphate.

A review of the pharmacokinetic implications of schistosomiasis.

Schistosomiasis is a common parasitic disease, with over 230 million people requiring treatment annually. The worldwide increase in medication access poses risks for patients living in regions endemic for schistosomiasis because of the potential impact of pharmacokinetic changes on clinical outcomes. Thus, the objective of this review is to summarize and evaluate the published literature reporting pharmacokinetic parameters of medications in patients with schistosomiasis and to assess associated clinical implications. Thirteen articles that described the pharmacokinetics of a total of 9 different medications (cefoperazone, propranolol, praziquantel, theophylline, metronidazole, acetaminophen/paracetamol, antipyrine, oxamniquine, and oral contraceptives) in patients with schistosomiasis were included in the review. The major finding is that pharmacokinetic changes occur in patients infected with schistosomiasis but to varying degrees depending on the extent of disease (e.g., varying stages of fibrosis, with or without signs and/or symptoms of liver disease) and medication being administered. Affected patients may consequently be at risk of adverse clinical outcomes. In general, drugs with high extraction ratios demonstrate increased bioavailability in patients with schistosomiasis compared to controls. For example, propranolol and praziquantel, respectively, show an association with increased clinical and toxic effects in patients with schistosomiasis. Conversely, the pharmacokinetics of low hepatic clearance drugs (such as metronidazole and oxamniquine) are largely unchanged unless patients present with liver disease (as in the case of antipyrine, the prototypical low clearance drug). Limitations of studies included the very small numbers of patients, being primarily single-dose studies, and the high inter-individual variability. Future clinical studies should include pharmacokinetic outcomes to further clarify dosing and administration strategies for target medications, especially those that primarily undergo metabolism and are associated with significant adverse effects. Until the results of these future studies are available, clinicians should be acutely aware of complications from schistosomiasis and carefully screen patients for signs and symptoms of liver disease prior to prescribing, dispensing, or administering potentially harmful medications.

Effect of the UGT1A1*28 Allele on Unconjugated Hyperbilirubinemia in HIV-Positive Patients Receiving Atazanavir: A Systematic Review

OBJECTIVE To systematically examine the literature assessing the effect of uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1*28 genetic polymorphisms on atazanavir-associated hyperbilirubinemia. DATA SOURCES MEDLINE (1948–November 2012), EMBASE (1980–November 2012), International Pharmaceutical Abstracts (1970–November 2012), Google, and Google Scholar were searched using combinations of the following terms: glucuronosyltransferase, glucuronosyltransferase 1A1, atazanavir, atazanavir plus ritonavir, or polymorph

The application of layered double hydroxide clay (LDH)-poly(lactide-co-glycolic acid) (PLGA) film composites for the controlled release of antibiotics.

. The reference lists of all identified articles were manually searched. STUDY SELECTION AND DATA EXTRACTION Studies were included if at least 1 group of patients received atazanavir therapy and assessed the effect of UGT1A1*28 variants on bilirubin concentrations or atazanavir discontinuation rates. The quality of each study was ranked according to the US Preventive Services Task Force 1996 classification system. Information extracted included study design, baseline characteristics, treatment regimens, UGT1A1*28 genotype frequencies, bilirubin concentrations, incidence of hyperbilirubinemia, and atazanavir discontinuation rates. DATA SYNTHESIS Our search produced 12 studies, of which 9 were included (6 full manuscripts [level II-2], 2 abstracts, and 1 letter to the editor [level III]). Reported UGT1A1*28 homozygote genotype frequencies (0.8–23.8%) were in general agreement with the literature for the diverse ethnic population captured in the 9 studies. An association between the incidence of hyperbilirubinemia and UGT1A1*28 genotype (homozygotes > heterozygotes > wild-type) was demonstrated in all studies that reported such data (6 of 9 studies). However, the calculated positive predictive value for homozygosity and hyperbilirubinemia from pooled data was low (40.3%). Only 2 studies (levels II-2 and III) reported rates of atazanavir discontinuation due to hyperbilirubinemia and showed some positive correlation with presence of the UGT1A1*28 allele. CONCLUSIONS Based on the available evidence, homozygosity of the UGT1A1*28 allele does not strongly predict the incidence of severe hyperbilirubinemia. Thus, until large, prospective trials demonstrate otherwise, UGT1A1*28 testing does not appear to provide additional information to aid clinical decision-making when initiating atazanavir treatment in HIV-infected patients.