Principles of early drug discovery.

Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12-15 years and cost in excess of $1 billion. The idea for a target can come from a variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development.

Partner management for gonococcal and chlamydial infection: expansion of public health services to the private sector and expedited sex partner treatment through a partnership with commercial pharmacies.

BACKGROUND: Public health partner notification (PN) services currently affect only a small minority of patients with gonorrhea or chlamydial infection and new approaches to PN are needed. OBJECTIVES: To expand PN for gonorrhea and chlamydial infection to private sector patients and to assess the feasibility of treating sex partners through commercial pharmacies. METHODS: Selected patients were offered PN assistance and were randomly offered medication to deliver to their partners. RESULTS: Providers permitted the health department to contact 3613 (91%) of 3972 potentially eligible patients, and 1693 (67%) of 2531 successfully contacted patients consented to interview. Of these, 1095 (65%) reported at least one untreated partner. Most patients (90%) wished to notify partners themselves. Patients were more likely to have partners who had not yet been treated and to request PN assistance if they had more than one sex partner in the preceding 60 days or a partner they did not anticipate having sex with in the future. These two factors characterized 49% of all patients interviewed, 70% of those with a partner that was untreated 7 or more days after index patient treatment, and 83% of those accepting PN assistance. Among 458 randomly selected patients with untreated partners at time of study interview, 346 (76%) agreed to deliver treatment to a partner. Of these, most (266) chose to obtain medication for a partner at a pharmacy, of whom 223 (84%) successfully did so. CONCLUSION: A substantial minority of private sector patients have untreated partners more than 7 days after their own treatment; some need help with PN, but most will agree to deliver medication to partners themselves.

Syndromic management of STDs in pharmacies: evaluation and randomised intervention trial.

BACKGROUND: Improved clinic based syndromic management of sexually transmitted diseases (STDs) in Tanzania reduced HIV transmission. However, in many developing countries, people seek STD treatment in pharmacies. This study used standardised simulated patients (SSP) to assess STD syndromic management in pharmacies and evaluate the impact of an educational intervention. METHODS: SSP presented syndromes of urethral discharge, genital ulcer, vaginal discharge, and pelvic inflammatory disease (PID) at 180 randomly selected pharmacies in Lima, Peru. These pharmacies were then randomised to receive or not receive education on STD recognition, management, and prevention counselling, and were again visited by SSP. RESULTS: At 360 pharmacy visits before the intervention, syndromes most often recognised as STD related were genital ulcer (81%) and urethral discharge (73%) in men, followed by vaginal discharge (43%) and PID (6%) in women. Treatments offered to 82.5% of SSP rarely conformed to international or national guidelines (for urethral discharge, 1.5%; genital ulcer, 1%; vaginal discharge, 4%; and PID, none). Only 20.5% of SSP were referred to a physician and 30% received any counselling. The intervention reached 55% of pharmacies, and produced a small but significant increase in counselling; by "intent to intervene" analysis, intervention pharmacies provided post-counselling more often than did controls (40% v 27%, p = 0.01). CONCLUSION: Pharmacies usually failed to recognise STD syndromes in women, and usually provided treatment, most often with ineffective regimens. Educational interventions improved counselling. More effective interventions are needed to improve STD recognition, treatment, and referral practices.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease.

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as "definite Alzheimer's disease" (AD), "probable AD," "possible AD," and "normal brain" to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed brief, comprehensive, and reliable batteries of clinical and neuropsychological tests for assessment of patients with the clinical diagnosis of Alzheimer's disease (AD). We administered these batteries in a standardized manner to more than 350 subjects with a diagnosis of AD and 275 control subjects who were enrolled in a nationwide registry by a consortium of 16 university medical centers. The tests selected for this study measured the primary cognitive manifestations of AD across a range of severity of the disorder, and discriminated between normal subjects and those with mild and moderate dementia. The batteries also detected deterioration of language, memory, praxis, and general intellectual status in subjects returning for reassessment 1 year later. Interrater and test-retest reliabilities were substantial. Long-term observations of this cohort are in progress in an effort to validate the clinical and neuropsychological assessments and to confirm the diagnosis by postmortem examinations. Although information on validation is limited thus far, the CERAD batteries appear to fill a need for a standardized, easily administered, and reliable instrument for evaluating persons with AD in multicenter research studies as well as in clinical practice.