Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial.

Importance: Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure. Objective: To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials. Design, Setting, and Participants: Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h. Interventions: Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily. Main Outcomes and Measures: The primary end point was change in automated office systolic blood pressure from baseline to study week 8. Results: Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of -14.1, -13.2, -6.9, and -4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were -10.1 and -13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was -9.6 mm Hg (90% CI, -15.8 to -3.4 mm Hg; P = .01) for the 50-mg once-daily dose and -7.8 mm Hg (90% CI, -14.1 to -1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred. Conclusions and Relevance: Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies. Trial Registration: ClinicalTrials.gov Identifier: NCT05001945.

First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11ß-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.

Hit and lead criteria in drug discovery for infectious diseases of the developing world.

Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.

Decision-making models in Japanese psychiatry: transitions from passive to active patterns.

This study deconstructs the current dynamics of the physician-patient relationship in the treatment of minor mood disorders including depression in Japan. An in-depth qualitative investigation was conducted on psychiatrists employed at mental health clinics, university hospitals, and psychiatric hospitals. Triangulation was conducted concurrently using key informant interviews and periodic non-structured interviews with additional physicians and patients. Results revealed two patterns of omakase (entrusting) (Omakase Model) and an emerging pattern of patient participation in decision making (Participatory Model). The pattern traditionally denoted by the Omakase Model encompasses an active and passive entrusting model. The phenomenon of an emerging Participatory Model was uncovered whereby an in-depth analysis led to an understanding behind the associative physician-patient relationship, communication patterns, and a patient's level of awareness. It was found that while active participation in medical decision making is capable of raising the level of treatment efficacy, it is not only active participation in medical decision making, but also active participation in medical treatment that is valued in the physician-patient relationship. Ultimately, a patient actively participates in his or her medical treatment under either the active Omakase Model or Participatory Model, be it entrusting or participatory. Consequently, the active Omakase Model will continue to remain functional alongside the Participatory Model while the passive Omakase Model is likely to fade away in time.

Three patterns of voluntary consent in the case of adult-to-adult living related liver transplantation in Japan.

To elucidate the psychosocial aspects of the donors' decisions to engage in adult-to-adult living related liver transplantation, we interviewed a total of five institutional ethics committee members who had experience with reassessing informed consent prior to surgery. Qualitative analysis revealed several nuances of voluntary consent consisting of three patterns: "unconditional consent" is consent from the bottom of one's heart to save a family member's life; "pressured consent" describes a donor who feels implicit pressure to donate despite fear; and "ulterior-motivated consent" defines a donor who has a hidden motive. This study diverges from previous work in that it employs a qualitative approach to deconstructing the psychosocial intricacies of the informed consent process in adult-to-adult LRLT. This initial study raises several questions on the meaning of voluntary informed consent in adult-to-adult living related liver transplantation.

Straight talk with...BT Slingsby. Interviewed by Cassandra Willyard.

Japan boasts the second-largest pharmaceutical industry in the world. With its rich background in medical research, the country has turned its attention to diseases of the developing world with this year's launch of the Global Health Innovative Technology (GHIT) Fund--a new public-private partnership between five Japanese pharmaceutical companies, two government ministries and the Bill & Melinda Gates Foundation. In November, the Tokyo-based fund announced its first round of awards totaling $5.7 million. The six grants will go to partnerships aimed at developing new drugs and vaccines to fight malaria, tuberculosis and Chagas disease, a neglected disease endemic to Latin America. Leading the new $120 million, five-year initiative is BT Slingsby, a US-born scholar of the Japanese healthcare industry who most recently served as director of global partner solutions at Eisai, a Tokyo-based drugmaker. On a recent trip to New York, Slingsby, who serves as GHIT's executive director and CEO, met with Cassandra Willyard to discuss the new fund and how Japan can help drive development of medicines and vaccines for diseases of the developing world.

Accelerating the development of a therapeutic vaccine for human Chagas disease: rationale and prospects.

Chagas disease is a leading cause of heart disease affecting approximately 10 million people in Latin America and elsewhere worldwide. The two major drugs available for the treatment of Chagas disease have limited efficacy in Trypanosoma cruzi-infected adults with indeterminate (patients who have seroconverted but do not yet show signs or symptoms) and determinate (patients who have both seroconverted and have clinical disease) status; they require prolonged treatment courses and are poorly tolerated and expensive. As an alternative to chemotherapy, an injectable therapeutic Chagas disease vaccine is under development to prevent or delay Chagasic cardiomyopathy in patients with indeterminate or determinate status. The bivalent vaccine will be comprised of two recombinant T. cruzi antigens, Tc24 and TSA-1, formulated on alum together with the Toll-like receptor 4 agonist, E6020. Proof-of-concept for the efficacy of these antigens was obtained in preclinical testing at the Autonomous University of Yucatan. Here the authors discuss the potential for a therapeutic Chagas vaccine as well as the progress made towards such a vaccine, and the authors articulate a roadmap for the development of the vaccine as planned by the nonprofit Sabin Vaccine Institute Product Development Partnership and Texas Children's Hospital Center for Vaccine Development in collaboration with an international consortium of academic and industrial partners in Mexico, Germany, Japan, and the USA.

Physician strategies for addressing patient adherence to prescribed psychotropic medications in Japan: a qualitative study.

BACKGROUND AND OBJECTIVES: Effective psychiatric care requires physicians to address the problems of patient adherence to prescribed medications. The aim of this study was to understand physician-perceived barriers to, and effective strategies for, prescribing anti-depressants in Japan. METHODS: A qualitative study using semi-structured and key-informant interviews with a purposive sample of Japanese psychiatrists and key-informant physicians who had practiced in both the US and Japan. RESULTS: Japanese psychiatrists recognize patient misperceptions, social stigma and resistance to acceptance of prescribed anti-depressant medication. Physicians also recognize that selective serotonin reuptake inhibitors (SSRIs) decrease rather than reinforce patient resistance. Physicians initially underdose, employ euphemisms and accept patient decisions to decline treatment by medication. DISCUSSION: Even after the introduction of SSRI anti-depressants in 1999, Japanese psychiatrists' primary adherence strategy to initially underdose prescribed anti-depressants remains. The unstated physician strategy is to allow the pharmaceutical industry to address patient misperceptions, social stigma and the resistance to prescription therapies. CONCLUSIONS: The results of this study delineate the fundamental strategies employed by Japanese physicians to address patient adherence to prescribed psychotropic medications, primarily to reduce the initial dose rather than to stress patient education.

The placebo effect and relaxation response: neural processes and their coupling to constitutive nitric oxide.

The placebo effect appears to be a real phenomenon as is the scientifically demonstrated and examined relaxation response. Given this, we attempt to understand how these phenomena work in light of our current understanding of central and peripheral nervous system mechanisms. Central to our hypothesis is the significance of norepinephrine, nitric oxide and opioid signaling both in the central and peripheral nervous system. In this regard, we find that nitric oxide controls norepinephrine processes on many levels, including synthesis, release and actions. In closing, we conclude that enough scientific information exists to support these phenomena as actual physical processes that can be harnessed to provide better patient care.