Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production. In a placebo-controlled clinical study, these same endpoints were evaluated in healthy volunteers that were treated with a cumulative dose of 2400 mg HCQ over 5 days. In vitro, HCQ inhibited TLR responses with IC50s > 100 ng/mL and reaching 100% inhibition. In the clinical study, maximal HCQ plasma concentrations ranged from 75 to 200 ng/mL. No ex vivo HCQ effects were found on RIG-I-mediated cytokine release, but there was significant suppression of TLR7 responses and mild suppression of TLR3 and TLR9 responses. Moreover, HCQ treatment did not affect B cell and T cell proliferation. These investigations show that HCQ has clear immunosuppressive effects on human PBMCs, but the effective concentrations exceed the circulating HCQ concentrations under conventional clinical use. Of note, based on HCQ’s physicochemical properties, tissue drug concentrations may be higher, potentially resulting in significant local immunosuppression. This trial is registered in the International Clinical Trials Registry Platform (ICTRP) under study number NL8726.
Soluble guanylate cyclase (sGC) and its product, cyclic guanosine monophosphate, play a role in learning and memory formation. Zagociguat (CY6463) is a novel stimulator of sGC being developed for the treatment of neurodegenerative disease. Single zagociguat doses of 0.3, 1, 3, 10, 20, 30, and 50 mg were administered once to healthy participants in a single‐ascending‐dose phase; then zagociguat 2, 5, 10, and 15 mg was administered q.d. for 14 days in a multiple‐ascending‐dose phase; and, finally, zagociguat 10 mg was administered once in both fed and fasted state in a food‐interaction phase. Safety of zagociguat was evaluated by monitoring treatment‐emergent adverse events, suicide risk, vital signs, electrocardiography, and laboratory tests. Pharmacokinetics of zagociguat were assessed through blood, urine, and cerebrospinal fluid sampling. Pharmacodynamic effects of zagociguat were evaluated with central nervous system (CNS) tests and pharmaco‐electroencephalography. Zagociguat was well‐tolerated across all doses evaluated. Zagociguat exposures increased in a dose‐proportional manner. Median time to maximum concentration ranged from 0.8 to 5 h and mean terminal half‐life from 52.8 to 67.1 h. CNS penetration of the compound was confirmed by cerebrospinal fluid sampling. Zagociguat induced up to 6.1 mmHg reduction in mean systolic and up to 7.5 mmHg reduction in mean diastolic blood pressure. No consistent pharmacodynamic (PD) effects on neurocognitive function were observed. Zagociguat was well‐tolerated, CNS‐penetrant, and demonstrated PD activity consistent with other sGC stimulators. The results of this study support further development of zagociguat.
Aim Dysfunction of nitric oxide (NO) – soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) signalling is implicated in the pathophysiology of cognitive impairment and dementia. Zagociguat is a central nervous system-(CNS-) penetrant sGC stimulator designed to amplify NO-cGMP signalling in the CNS. This article reports on a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. Methods In this randomized crossover study, 24 healthy participants ≥65 years of age were planned to receive 15 mg zagociguat or placebo once daily for two 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms, and laboratory tests to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and CSF. Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement, and biomarkers in blood, cerebrospinal fluid, and brain. Results Twenty-four participants were enrolled and 12 participants completed both treatment periods, while 12 participants completed only one treatment period. Zagociguat was well tolerated and penetrated the blood-brain barrier. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. Conclusion Zagociguat was well tolerated and induced modest systemic blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected, perhaps due to optimal CNS function in healthy participants. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound.
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