Phase 0 - Microdosing strategy in clinical trials

Drug development is an activity that is long, complex and expensive. In 2004, attrition in the drug development paradigm prompted the US Food and Drug Administration (FDA) to introduce its ′Critical Path′ document, which highlighted the serious discordance between major scientific advances and limited drug development process. One issue addressed was that of microdosing. The concept of microdosing involves the use of extremely low, nonpharmacologically active doses of a drug to define the pharmacokinetic profile of the medication in human subjects. Microdosing, thus, appears as a new viable concept in the ′toolbox′ of the drug development activity. It appears that microdosing strategy could complement standard animal-to-human scaling, redefining the existing concept of phase I clinical research. In future, when research methods and technology involved in Phase 0 studies become more sophisticated, human microdosing may be applied to a number of drugs developed subsequently

Non-invasive evaluation of arterial stiffness in patients with increased risk of cardiovascular morbidity: A cross-sectional study

Objectives: Cardiovascular disease (CVD) is associated with a generalized atherosclerotic process that begins in the large arteries, representing vascular pathology leading to increased cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a simple, accurate, reproducible and a good prognostic marker of arterial stiffness. Testing arterial stiffness with non-invasive techniques provides an opportunity to evaluate large patient populations with cardiovascular risk. Therefore, the aim of the present study was to evaluate non-invasively the arterial stiffness (AS) in patients with high cardiovascular risk. Materials and Methods: Totally 3969 subjects [CAD - 845, DM - 973, ESRD - 942, RA - 221 and 988 age-matched healthy controls] were enrolled in the study approved by the IEC, NIMS; and all the subjects gave written informed consent to participate. Pulse wave velocity was determined non-invasively by PeriScope (M/S Genesis Medical Systems, Hyderabad, India). Results: In patients with CAD, DM, ESRD and RA, heart rate (HR), blood pressure (BP) and PP were significantly more than healthy controls. Peripheral and central arteries′ PWVs were higher in these patients′ group. The mean HR was maximum in RA patient, while systolic blood pressure (SBP) was highest in ESRD patient. There was a good correlation between ba PWV and PP in all patients′ group and healthy controls except RA patients. Conclusion: Our study findings emphasize the importance of the PWV in identifying the vascular damage in patients with high CV risk. Increased PWV was found to be a good independent predictor of cardiovascular morbidity

Educational Forum - Recent trends in the nitrergic nervous system

The late 20th century witnessed the novel discovery of "Nitrergic" or "Nitroxidergic" innervation of the vascular smooth muscles, their role as a vasodilator in cerebral, ocular and penile vasculature, as well as their reciprocal action to adrenergic vasoconstriction. The identification of this nerve as a postganglionic parasympathetic nerve, the discovery of autonomic efferent nerves where Nitric oxide (NO) is the neurotransmitter (NTM) to blood vessels, its physiological role in the control of smooth muscle tone, and the pharmacological implications of NO have been reviewed. This will aid an in-depth analysis of vascular dysfunctions and the development of strategic pharmacotherapeutic interventions with time