Investigation of the effect of the dual orexin receptor antagonist almorexant on ophthalmological, spermatogenic, and hormonal variables in healthy male subjects.

BACKGROUND/AIMS: The aim of this single-center, double-blind study was to investigate the effect of a 4-week once daily administration of 200 mg almorexant on tear film break-up time, spermatogenesis, hormone levels, and pancreatic elastase in stool in healthy male subjects. METHODS: Almorexant 200 mg or matching placebo was administered in the evening for 4 weeks once daily to 56 healthy male subjects. Changes in ophthalmological variables, sperm composition, hormone levels, and pancreatic elastase levels in stool were evaluated periodically up to 8 weeks after discontinuation of drug administration. Blood samples for pharmacokinetic measurements were taken after 4 weeks to confirm compliance to study drug intake. RESULTS: The results of this study revealed no treatment effects of almorexant, neither on tear film break-up time nor on other ophthalmological variables investigated during this study. Furthermore, spermatogenesis, hormones of the hypothalamic-pituitary-adrenal and -gonadal axes, and endocrine pancreatic secretion were shown to be not affected by a 4-week once daily administration of almorexant. CONCLUSION: Almorexant was well tolerated and had no effect on the spectrum of pharmacodynamic variables assessed. Ophthalmology and testicular findings detected in preclinical studies were not observed in this clinical study. Therefore, these preclinical findings appear not to be relevant for humans and do not prevent from conducting larger clinical trials with either healthy subjects or patients.

Unforeseen ethical/legal complications with screening tests in the capitation model of medical aid schemes.

In the South African health care system patients/consumers are divided into those who can afford private care and those who rely on state medical assistance. The system is under pressure to fund delivery of medical care to its beneficiaries. We consider the effects of different funding models on medicolegal liability of health professionals serving the private sector. Medical reasons should determine the service rendered. However, financial implications of services rendered and defensive practice of medicine also contribute to treatment received by a patient and its remuneration. Practitioners who commit to delivering a predetermined set of services within a particular time for a predetermined 'lump sum' are only paid for the service specifically requested. Should disease be found other than those contracted for, we argue that inaction with regard to that disease would be deemed to be negligent or unethical according to legal and ethical considerations.

Clinical, legal and ethical implications of the intra-ocular (off-label) use of bevacizumab (avastin)--a South African perspective.

Choroidal neovascularisation is a potentially visually devastating element of various forms of eye pathology. Recent research has focused on neurovascular age-related macular degeneration (AMD) as a cause. AMD can be classified as being exudative (wet) or atrophic (dry). Wet AMD is characterised by a pathological process in which new blood vessels develop in the choroids, causing leakage of fluid and haemorrhage under the retina and leading to localised serous detachment and loss of central vision. Vascular endothelial growth factor (VEGF) stimulates growth of neovascular membranes. Treatments have until recently yielded disappointing results. Ophthalmologists are using intra-ocular injections of bevacizumab (Avastin), an anti-VEGF, to treat AMD. Avastin appears to be safe and effective in the short term, but its intra-ocular administration is entirely off-label. Avastin is registered for treating metastatic colorectal and breast cancer. The off-label use of medication is an important part of mainstream, legitimate medical practice worldwide. Lawyers representing plaintiffs injured by drugs increasingly encounter off-label use claims. From a legal/ethical point of view the off-label use of medication represents a delicate balance between the statutory regulation of medication and a physician's prerogative to prescribe medication that in his or her medical opinion will be beneficial to the patient. The main reason for the controversy created by the off-label use of Avastin is that there are anti-VEGF drugs on the market that have formal approval for the treatment of AMD (and other eye conditions). Lucentis, for example, is extremely expensive, with treatment cost approximately 50 times that of Avastin. Many patients suffering from AMD and macular oedema cannot afford the registered product. The off-label use of Avastin has passed the innovative or experimental stages, as ophthalmologists have used it regularly and openly for a long time, with good success. Such use therefore cannot be considered careless, imprudent or unprofessional. We submit that an ophthalmologist who omits to inform a patient of the availability of Avastin for this form of treatment may be found to be negligent. Protocols developed by the South African Vitreoretinal Society and endorsed by the Ophthalmological Society of South Africa for administering Avastin and other intra-ocular medication intravitreally should be strictly adhered to.