Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

Skin problems after a tsunami

BACKGROUND: On December 26, 2004, the biggest earthquake for 40 years, measuring 9.0 on the Richter scale, triggered a tsunami that pounded the coastal areas of South Asia and East Africa. The effects of the tsunami on skin conditions have not been evaluated. OBJECTIVE: To determine the influence of the tsunami on skin conditions by evaluating the skin problems of patients presenting at hospitals after the tsunami. METHODS: Between 5 and 25 January 2005, two dermatologists evaluated patients who complained of skin problems at an outpatient clinic and emergency room of a general hospital in Banda Aceh, Aceh Province, Indonesia. RESULTS: The total number of patients that presented during the study period was 235 (131 males and 104 females), and they had a total of 265 skin problems. In terms of age distribution, most subjects were in their fourth decade (23.0%), followed by the third (22.6%) and fifth decade (16.6%). The most prevalent skin problems were infections-infestations (32.5%), followed by eczemas (29.8%) and traumatic skin disorders (29.4%). In males, traumatic skin disorders were most common. The great majority of infection-infestation cases involved superficial fungal infections. Contact dermatitis accounted for three-quarters of eczema cases, and mainly involved the arms (40.0%) and legs (27.1%). The majority of traumatic skin disorders were lacerations, punctures and penetrations, and the feet (44.7%) and hands (18.8%) were most frequently affected. CONCLUSIONS: Unhygienic conditions, exposure to a hazardous environment and contact with various objects during and after the tsunami probably increased the prevalence of infections-infestations, traumatic skin disorders and contact dermatitis. To prevent these problems and associated secondary bacterial infections, health-related education and early medical management are required.     

Pesticide assessment: Protecting public health on the home turf

Pesticide regulation is examined in the context of Health Canada’s Pest Management Regulatory Agency’s assessment of the chlorophenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) for turf. 2,4-D is the most common herbicide used to kill weeds in grass.The medical literature does not uniformly indicate harms from herbicides. However, the balance of epidemiological research suggests that 2,4-D can be persuasively linked to cancers, neurological impairment and reproductive problems. These may arise from 2,4-D itself, from breakdown products or dioxin contamination, or from a combination of chemicals.Regulators rely largely on toxicology, but experiments may not replicate exposures from 2,4-D application to lawns because environmental breakdown products (eg, 2,4-dichlorophenol) may not accumulate and selected herbicides are possibly less contaminated. Dioxins are bioaccumulative chemicals that may cause cancer, harm neurological development, impair reproduction, disrupt the endocrine system and alter immune function. No dioxin analyses were submitted to the Pest Management Regulatory Agency, and the principal contaminants of 2,4-D are not among the 17 congeners covered in pesticide regulation. Independent assessment of all dioxins is needed, in tissues and in the environment.The 2,4-D assessment does not approach standards for ethics, rigour or transparency in medical research. Canada needs a stronger regulator for pesticides. Potentially toxic chemicals should not be registered when more benign solutions exist, risks are not clearly quantifiable or potential risks outweigh benefits. Until landscaping pesticides are curtailed nationally, local bylaws and Quebec’s Pesticide Code are prudent measures to protect public health. Physicians have a role in public education regarding pesticides.     

Verruciform xanthoma]

BACKGROUND: Verruciform xanthoma (VX), a rare, benign lesion of the skin and mucosa, is slow-growing, asymptomatic and characterized by a granular (verruciform) surface. It is yellowish-red or grey in color and up to 2 cm in diameter. Histologically, a papillary and/or verrucous proliferation of the squamous epithelium with hyperparakeratosis and numerous foam cells is present. These cells are predominantly located within the papillae of the lamina propria. For differential diagnosis, other papillomatous and verrucous lesions such as verrucous carcinomas or squamous cell carcinomas need to be ruled out. CASE REPORT: A 46-year-old patient with VX located on the alveolar process regio 26-28 is presented. Clinically, a 2 x 2 cm granular, oral mucosa surface lesion extending onto the palate occurred in regio 26-28. Biopsy was characterized light microscopically by the presence of swollen, elongated cells in the submucosa, an indication of VX alterations. Transmission electron microscopy demonstrated foam cells in the subepithelium containing numerous membrane-bound vesicles similar in diameter and showing a wide variation in electron density. Morphologically, these cells resembled macrophage-related cells. The lesion was excised in total with no evidence of recurrence after 9 months. DISCUSSION: The pathogenesis of VX is still unclear. The characteristic xanthoma cells may play a major role in VX. Microscopic analysis of the morphology of the foam cells indicated that they may represent a differentiated form of macrophages. Lipid vesicles inside these cells differed in their electron density indicating a heterogeneous biochemistry or different states of maturation.     

Fumonisin B1 dosimetry in relation to cancer initiation in rat liver

The wrong EDL values were given in the thirteenth line of theAbstract. The complete sentence should read: Over a period of 14 days the amount of FB₁ required for cancerinitiation is 23.3 < EDL < 33.3 mg FB₁/100 g body wt.