Implementing Algorithm-Guided Warfarin Dosing in an Ethnically Diverse Patient Population Using Electronic Health Records and Preemptive CYP2C9 and VKORC1 Genetic Testing.

Implementation of pharmacogenetic-guided warfarin dosing has been hindered by inconsistent results from reported clinical trials and a lack of available algorithms that include alleles prevalent in non-white populations. However, current evidence indicates that algorithm-guided dosing is more accurate than empirical dosing. To facilitate multiethnic algorithm-guided warfarin dosing using preemptive genetic testing, we developed a strategy that accounts for the complexity of race and leverages electronic health records for algorithm variables and deploying point-of-care dose recommendations.

Determining the effects and challenges of incorporating genetic testing into primary care management of hypertensive patients with African ancestry.

People of African ancestry (Blacks) have increased risk of kidney failure due to numerous socioeconomic, environmental, and clinical factors. Two variants in the APOL1 gene are now thought to account for much of the racial disparity associated with hypertensive kidney failure in Blacks. However, this knowledge has not been translated into clinical care to help improve patient outcomes and address disparities. GUARDD is a randomized trial to evaluate the effects and challenges of incorporating genetic risk information into primary care. Hypertensive, non-diabetic, adults with self-reported African ancestry, without kidney dysfunction, are recruited from diverse clinical settings and randomized to undergo APOL1 genetic testing at baseline (intervention) or at one year (waitlist control). Providers are educated about genomics and APOL1. Guided by a genetic counselor, trained staff return APOL1 results to patients and provide low-literacy educational materials. Real-time clinical decision support tools alert clinicians of their patients' APOL1 results and associated risk status at the point of care. Our academic-community-clinical partnership designed a study to generate information about the impact of genetic risk information on patient care (blood pressure and renal surveillance) and on patient and provider knowledge, attitudes, beliefs, and behaviors. GUARDD will help establish the effective implementation of APOL1 risk-informed management of hypertensive patients at high risk of CKD, and will provide a robust framework for future endeavors to implement genomic medicine in diverse clinical practices. It will also add to the important dialog about factors that contribute to and may help eliminate racial disparities in kidney disease.

Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists.

BACKGROUND AND PURPOSE: Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception. EXPERIMENTAL APPROACH: Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a delta-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats. KEY RESULTS: Both micro and delta antagonists augmented analgesia produced by a sub-maximal (5 microg) or maximal (15 microg) dose of morphine. Administration of the antagonists with morphine (15 microg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency. CONCLUSIONS AND IMPLICATIONS: Combining ultralow doses of micro- or delta-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of micro- and delta-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity.