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Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.

Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells. [ABSTRACT FROM AUTHOR]

The reviews in Volume 64 of the Annual Review of Pharmacology and Toxicology cover diverse topics. A common theme in many of the reviews is the interindividual variability in the clinical response to drugs. Highlighted areas include emerging developments in pharmacogenomics that can predict the personal risk for drug inefficacy and/or adverse drug reactions. Other reviews focus on the use of circulating biomarkers to define drug metabolism phenotypes and the effect of circadian regulation on drug response. Another emerging technology, digital twins that model individual patients, is used to generate computational simulations of drug effects and identify optimal personalized treatments. Another variable that may affect clinical outcomes, the nocebo response (an adverse reaction to a placebo), complicates clinical trials. These reviews further document that pharmacological individuality is an essential component of the concepts of personalized medicine and precision medicine and will likely have an important impact on patient care. [ABSTRACT FROM AUTHOR]

Background Timely, accurate adherence data may support oral pre-exposure prophylaxis (PrEP) success and inform prophylaxis choice. We evaluated a Food and Drug Administration (FDA)-approved digital health feedback system (DHFS) with ingestible-sensor-enabled (IS) tenofovir-disoproxil-fumarate plus emtricitabine (Truvada®) in persons starting oral PrEP. Methods Human immunodeficiency virus (HIV)-negative adults were prescribed IS-Truvada® with DHFS for 12 weeks to observe medication taking behavior. Baseline demographics, urine toxicology, and self-report questionnaires were obtained. Positive detection accuracy and adverse events were computed as percentages, with Kaplan Meier Estimate for persistence-of-use. In participants persisting ≥28 days, adherence patterns (taking and timing) were analyzed, and mixed-effects logistic regression modeled characteristics associated with treatment adherence. Results Seventy-one participants were enrolled, mean age 37.6 years (range 18–69), 90.1% male, 77.5% White, 33.8% Hispanic, 95.8% housed, and 74.6% employed. Sixty-three participants (88.7%) persisted ≥28 days, generating 4987 observation days, average 79.2 (29–105). Total confirmed doses were 86.2% (95% confidence interval [CI] 82.5, 89.4), decreasing over time, odds ratio (OR) 0.899 (95% CI.876,.923) per week, P <.001; 79.4% (95% CI 66.7%, 87.3%) of participants had ≥80% adherence. Pattern analysis showed days without confirmed doses clustered (P =.003); regular dose timing was higher among participants with ≥80% confirmed doses (0.828, 95% CI.796 to.859) than among those with <80% (0.542, 95% CI95.405 to.679) P <.001. In multi-predictor models, better adherence was associated with older age, OR 1.060 (95% CI 1.033, 1.091) per year, P <.001; negative vs positive methamphetamine screen, OR 5.051 (95% CI 2.252, 11.494), P <.001. Conclusions DHFS with IS-Truvada® distinguished adherent persons from those potentially at risk of prophylactic failure. Ongoing methamphetamine substance use may impact oral PrEP success. [ABSTRACT FROM AUTHOR]

Introduction: Successful population-level antiretroviral therapy (ART) adherence will be necessary to realize both the clinical and prevention benefits of antiretroviral scale-up and, ultimately, the end of AIDS. Although many people living with HIV are adhering well, others struggle and most are likely to experience challenges in adherence that may threaten virologic suppression at some point during lifelong therapy. Despite the importance of ART adherence, supportive interventions have generally not been implemented at scale. The objective of this review is to summarize the recommendations of clinical, research, and public health experts for scalable ART adherence interventions in resource-limited settings. Methods: In July 2015, the Bill and Melinda Gates Foundation convened a meeting to discuss the most promising ART adherence interventions for use at scale in resource-limited settings. This article summarizes that discussion with recent updates. It is not a systematic review, but rather provides practical considerations for programme implementation based on evidence from individual studies, systematic reviews, meta-analyses, and the World Health Organization Consolidated Guidelines for HIV, which include evidence from randomized controlled trials in low- and middle-income countries. Interventions are categorized broadly as education and counselling; information and communication technology-enhanced solutions; healthcare delivery restructuring; and economic incentives and social protection interventions. Each category is discussed, including descriptions of interventions, current evidence for effectiveness, and what appears promising for the near future. Approaches to intervention implementation and impact assessment are then described. Results and discussion: The evidence base is promising for currently available, effective, and scalable ART adherence interventions for resource-limited settings. Numerous interventions build on existing health care infrastructure and leverage available resources. Those most widely studied and implemented to date involve peer counselling, adherence clubs, and short message service (SMS). Many additional interventions could have an important impact on ART adherence with further development, including standardized counselling through multi-media technology, electronic dose monitoring, decentralized and differentiated models of care, and livelihood interventions. Optimal targeting and tailoring of interventions will require improved adherence measurement. Conclusions: The opportunity exists today to address and resolve many of the challenges to effective ART adherence, so that they do not limit the potential of ART to help bring about the end of AIDS. Keywords: HIV; antiretroviral therapy adherence; interventions; resource-limited settings, Introduction Antiretroviral therapy (ART) has transformed HIV infection from a terminal disease into a manageable chronic illness [1]. ART can also reduce viral load (i.e. HIV RNA levels) and the [...]

Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune inflammatory conditions that primarily target the optic nerves, spinal cord, brainstem, and occasionally the cerebrum. NMOSD is characterized by recurrent attacks of visual, motor, and/or sensory dysfunction that often result in severe neurological deficits. In recent years, there has been a significant progress in relapse treatment and prevention but the residual disability per attack remains high. Although symptomatic and restorative research has been limited in NMOSD, some therapeutic approaches can be inferred from published case series and evidence from multiple sclerosis literature. In this review, we will discuss established and emerging therapeutic options for symptomatic treatment and restoration of function in NMOSD. We highlight NMOSD-specific considerations and identify potential areas for future research. The review covers pharmacologic, non-pharmacologic, and neuromodulatory approaches to neuropathic pain, tonic spasms, muscle tone abnormalities, sphincter dysfunction, motor and visual impairment, fatigue, sleep disorders, and neuropsychological symptoms. In addition, we briefly discuss remyelinating agents and mesenchymal stem cell transplantation in NMOSD. [ABSTRACT FROM AUTHOR]

The elderly have a lower ability to reabsorb plasma potassium into muscles, which may have detrimental effects during prolonged exercise. The rate of increase and maximum concentration of plasma potassium (K+) for young men, non-athletic older men and a group of elderly master athletes was measured while subjects exercised to exhaustion on stationary bicycles. Although the older men showed faster rates of K+ increase, their peak concentrations did not rise as high as that of the younger subjects, because the elder group exercised for a shorter time.

Aging is associated with diminished [beta]-adrenergic responsiveness in a variety of tissues. Desentisization of tissues secondary to age-associated increase in sympathetic nervous system activity has been proposed as a potential explanation for diminished [beta]-adrenergic responsiveness. If this hypothesis correct, then [beta]-blockade in older people might be expected to reverse the blunted [beta]-adrenergic responses of tissues having deminished chronotropic responses to bolus isoproterenol (ISO) doses and ISO-induced venous smooth muscle dilatation in superficial hand veins were examined in 8 young (26.2 [+ or -] 2.6 years) and 9 elderly (68.0 [+ or -] 2.2 yrs) healthy subjects before, during, and 3 and 7 days following 2 weeks of treatment with propanolol. Baseline cardiac chronotropic responsiveness, CD25, was 1.55 [+ or -] 0.77 mcg in the young and 5.97 (+ or -] 2.77 mcg in the elderly subjects (p < .01), increasing to 84 [+ or -] 56 mcg and 194 [+ or -] 172 mcg during treatment with propanolol. At 3 and 7 days following withdrawal of propranolol, CD25s were respectively 1.24 [+ or -] 0.79 (p = .04) and 1.10 [+ or -] in the young and 5.63 [+ or -] 2.34 (p = .31) and 4.85 [+ or -] 2.37 (p = .05) in the elderly subjects. In contrast, there was no decrease in the ED50 or increase in Emax for ISO-induced venodilation of hand veins following propanolol withdrawal. These results demonstrate that both young and elderly subjects to have similar increases in cardiac chronotropic responsiveness following discontinuation of [beta]-blockade and do not support the concept that desensitization is responsible for the diminished [beta]-adrenergic responsiveness seen with aging.

The urgent global public health need presented by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) has brought scientists from diverse backgrounds together in an unprecedented international effort to rapidly identify interventions. There is a pressing need to apply clinical pharmacology principles and this has already been recognized by several other groups. However, one area that warrants additional specific consideration relates to plasma and tissue protein binding that broadly influences pharmacokinetics and pharmacodynamics. The principles of free drug theory have been forged and applied across drug development but are not currently being routinely applied for SARS‐CoV‐2 antiviral drugs. Consideration of protein binding is of critical importance to candidate selection but requires correct interpretation, in a drug‐specific manner, to avoid either underinterpretation or overinterpretation of its consequences. This paper represents a consensus from international researchers seeking to apply historical knowledge, which has underpinned highly successful antiviral drug development for other viruses, such as HIV and hepatitis C virus for decades. [ABSTRACT FROM AUTHOR]