Roderick B. Walker

The role of percutaneous penetration enhancers

It is clear that scientists are now only beginning to comprehend the complexity of transdermal drug delivery. Elucidation of the biochemical composition and functioning of the intrinsic diffusional barrier of the stratum corneum has prompted investigation of chemical and physical means of enhancing the percutaneous penetration of poorly absorbed drugs. Chemical enhancers that aid absorption of co-administered moieties are currently believed to improve solubility within the stratum corneum or increase lipid fluidity of the intracellular bilayers. Alternatively, the use of ionto- or phonophoresis may facilitate the absorption of some drug molecules by physical alteration of the barrier. The role of penetration enhancer inclusion in topical formulations has been well documented and will undoubtedly, in the future, permit the delivery of broader classes of drugs through the stratum corneum.

Analysis of macrolide antibiotics

The following macrolide antibiotics have been covered in this review: erythromycin and its related substances, azithromycin, clarithromycin, dirithromycin, roxithromycin, flurithromycin, josamycin, rokitamycin, kitasamycin, mycinamycin, mirosamycin, oleandomycin, rosaramicin, spiramycin and tylosin. The application of various thin-layer chromatography, paper chromatography, gas chromatography, high-performance liquid chromatography and capillary zone electrophoresis procedures for their analysis are described. These techniques have been applied to the separation and quantitative analysis of the macrolides in fermentation media, purity assessment of raw materials, assay of pharmaceutical dosage forms and the measurement of clinically useful macrolide antibiotics in biological samples such as blood, plasma, serum, urine and tissues. Data relating to the chromatographic behaviour of some macrolide antibiotics as well as the various detection methods used, such as bioautography, UV spectrophotometry, fluorometry, electrochemical detection, chemiluminescence and mass spectrometry techniques are also included.

Should active recruitment of health workers from sub-Saharan Africa be viewed as a crime?

Shortages of health-care staff are endemic in sub-Saharan Africa (table). Overall, there is one physician for every 8000 people in the region. In the worst affected countries, such as Malawi, the physician-to-population ratio is just 0·02 for every 1000 (one per 50 000). There are also huge disparities between rural and urban areas: rural parts of South Africa have 14 times fewer doctors than the national average. These numbers are very different to those in developed countries: the UK, for example, has over 100 times more physicians per population than Malawi. Furthermore, almost one in ten doctors working in the UK are from Africa. The insufficiency of health staff to provide even basic services is one of the most pressing impediments to health-care delivery in resource-poor settings. The consequences are clearly shown by the inverse relation that exists between health-care worker density and mortality.

The identification of the UV degradants of melatonin and their ability to scavenge free radicals

Ultraviolet (UV) light is known to induce the generation of free radicals in biological tissues such as skin. Of these free radicals, the O2–· and particularly the ·OH radical can induce cellular damage including lipid peroxidation. Thus, the use of antioxidants to prevent such damage induced by UV irradiation has received much attention recently. One such antioxidant, which has the potential to be incorporated into sunscreens, is the pineal secretory product melatonin. One of the concerns of using melatonin in sunscreens is its photostability. In the present study, we investigated the photostability of melatonin subjected to UV irradiation. In addition, we used liquid chromatography mass spectrometry (LC‐MS) to identify the degradants and we also assessed the ability of the degradants to inhibit O2–· generation as well as lipid peroxidation in rat brain homogenate. The results show that UV irradiation of melatonin (0.1 mg/mL) using a 400‐W lamp for 2 hr caused a significant decline of melatonin to 18% of its original concentration after 20 min, with the decline continuing until the melatonin concentration reaches zero at 120 min. The LC‐MS results show that the degradants of melatonin are 6‐hydroxymelatonin and N1‐acetyl‐N2‐formyl‐5‐methoxykynurenamine (AFMK). These degradants were able to provide equipotent activity against potassium cyanide (KCN)‐induced superoxide generation compared to non‐irradiated melatonin. Thus, the study shows that although melatonin is rapidly degraded by UV irradiation, the degradants retain antioxidant activity, making melatonin a likely candidate for inclusion in sunscreens.

Selection and characterization of suitable lipid excipients for use in the manufacture of didanosine-loaded solid lipid nanoparticles and nanostructured lipid carriers

This research aimed to evaluate the suitability of lipids for the manufacture of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) loaded with the hydrophilic drug, didanosine (DDI). The crystalline state and polymorphism of lipids with the best-solubulizing potential for DDI was investigated using differential scanning calorimetry (DSC) and wide-angle X-ray scattering (WAXS). DSC and WAXS were also used to determine potential interactions between the bulk lipids and DDI. Precirol® ATO 5 and Transcutol® HP showed the best-solubilizing potential for DDI. Precirol® ATO 5 exists in the β-modification before heating; however, a mixture of both α- and β-modifications were detected following heating. Addition of Transcutol® HP to Precirol® ATO 5 changes the polymorphism of the latter from the β-modification to a form that exhibits coexistence of the α- and β-modifications. DDI exists in a crystalline state when dispersed at 5% (w/w) in Precirol® ATO 5 or in a Precirol® ATO 5/Transcutol® HP mixture. DSC and WAXS profiles of DDI/bulk lipids mixture obtained before and after exposure to heat revealed no interactions between DDI and the lipids. Precirol® ATO 5 and a mixture of Precirol® ATO 5 and Transcutol® HP may be used to manufacture DDI-loaded SLN and NLC, respectively.

Evaluation of the proposed FDA pilot dose-response methodology for topical corticosteroid bioequivalence testing

AbstractPurpose. The American FDA has recently released a Guidance document for topical corticosteroid bioequivalence testing. The purpose of this study was to evaluate the recommendations of this document for appropriateness. The new specifications require a dose-vasoconstriction response estimation by the use of a Minolta chromameter in a preliminary pilot study to determine the parameters for use in a pivotal bioequivalence study. Methods. The visually-assessed human skin blanching assay methodology routinely practiced in our laboratories was modified to comply with the requirements of the pilot study so that visual and chromameter data could be compared. Two different cream formulations, each containing 0.12% betamethasone 17-valerate, were used for this comparison. Results. Visual data showed the expected rank order of AUC values for most dose durations whereas the chromameter data did not show similar results. The expected rank order of AUC values for both chromameter and visual data was not observed at very short dose durations. In fitting the data to pharmacodynamic models, equivalent goodness of fit criteria were obtained when several different parameter estimates were used in the model definition, however the visual data were best described by the sigmoid Emax model while the chromameter data were best described by the simple Emax model. Conclusions. The Emax values predicted by the models were close to the observed values for both data sets and, in addition, excellent correlation between the AUC values and the maximum blanching response (Rmax) (r > 0.95) was noted for both methods of assessment. The chromameter ED50 values determined in this study were approximately 2 hours for both preparations. At this dose duration the instrument would not be sensitive enough to distinguish between weak blanching responses and normal skin for bioequivalence assessment purposes.

Cyanide-Induced Free Radical Production and Lipid Peroxidation in Rat Brain Homogenate is Reduced by Aspirin

The neuroprotective properties of aspirin were investigated using cyanide-induced neurotoxicity as model. Cyanide, a known neurotoxic agent significantly increased lipid peroxidation and superoxide anion levels in rat brain homogenate in a concentration-dependent manner (0.25–1.0 mM). When homogenate, containing 1.0 mM KCN was cotreated with aspirin (1.0 mM) there was a significant decrease in lipid peroxidation. Aspirin (0.5 mM and 1.0 mM) also significantly reduced KCN-induced superoxide anion generation. The results of the present report therefore indicate a neuroprotective role for aspirin.

6-Hydroxymelatonin protects against cyanide induced oxidative stress in rat brain homogenates

Both 6-hydroxymelatonin and N-acetyl-N-formyl-5-methoxykynurenamine are photodegradants and enzymatic metabolites of melatonin and are known to retain equipotent activity against potassium cyanide-induced superoxide generation compared to melatonin. It is not clear whether one or both of these metabolites is responsible for this effect. The present study therefore investigates the possible manner in which 6-hydroxymelatonin protects against oxidative stress induced by cyanide in rat brain homogenates. We examined the ability of 6-hydroxymelatonin to scavenge KCN-induced superoxide anion generation as well as lipid peroxidation. In addition, we also examined the effect of this indole on lactate dehydrogenase activity (LDH) as well as mitochondrial electron transport using dichlorophenol-indophenol as an electron acceptor. The results of this study show that 6-hydroxymelatonin significantly reduces KCN-induced superoxide anion generation, which is accompanied by a commensurate reduction in lipid peroxidation. Partial reversal of the KCN-induced reduction in mitochondrial electron transport is accompanied by a similar reversal of mitochondrial LDH activity blunted by KCN. It can thus be proposed that 6-hydroxymelatonin is potentially neuroprotective against KCN-induced neurotoxicity.

A sensitive and reliable method for the detection of lipid peroxidation in biological tissues

A simple, accurate and cost effective method has been designed for the determination of lipid peroxidation in biological tissue samples. The method was a modification and improvement on existing methods available for lipid peroxidation determination. Solid‐phase extraction was used to separate the thiobarbituric acid‐malondialdehyde complex from thiobarbituric acid‐reactive substances and HPLC was performed using a C18 (Waters Spherisorb, 5μm, 250 × 4.6 mm i.d.) column to achieve isolation of the complex. The procedure was validated with respect to linearity of calibration (0.998), precision, sensitivity and limits of quantitation (1 nmol mL−1) and detection (0.5 nmol mL‐1). Resorcinol was used as an external standard. The method was tested by inducing free radical generation with a known free radical generator, quinolinic acid, in rat brain homogenate. The results showed that the method presented allowed detection of lipid peroxidation products at concentrations in the nanomolar (nM) range compared with the micromolar (μM) range detected by other methods, thus rendering it suitable for use with biological samples. In addition, the modified method allowed for detection of the purified lipid peroxidation products, thus eliminating the possibility of simultaneous detection of impurities that absorb at the same wavelength.

Formulation development and in vitro evaluation of didanosine-loaded nanostructured lipid carriers for the potential treatment of AIDS dementia complex

The purpose of this article was to investigate the feasibility of incorporating didanosine (DDI) into nanostructured lipid carriers (NLC) for potential treatment of AIDS dementia complex. Aqueous DDI-free and DDI-loaded NLC were manufactured using hot high-pressure homogenization. The lipid matrix contained a mixture of Precirol ® ATO 5 and Transcutol ® HP. Photon correlation spectroscopy revealed that the mean particle size for all formulations was below 250 nm with narrow polydispersity indices. In addition, the d99% values for all formulations determined using laser diffractometry were below 400 nm with the span values ranging from 0.84 to 1.0. The zeta potential values ranged from −18.4 to −11.4 mV and the encapsulation efficiency of NLC for DDI ranged from 33.02% to 78.34%. These parameters remained relatively constant for all formulations tested following storage for 2 months at 25°C indicating that all the formulations were relatively stable. Differential scanning calorimetry revealed a decrease in the degree of crystallinity of NLC in all formulations developed relative to the bulk lipid material. In addition, wide-angle X-ray scattering showed that NLC in all formulations tested existed in a single β-modification form and that DDI that had been incorporated into the NLC appeared to be molecularly dispersed in the lipid matrices. Images of the NLC formulations obtained using transmission electron microscopy revealed that all formulations contained a mixture of spherical and nonspherical particles irrespective of the amount of DDI that was added during the manufacture of the formulations.