Dopamine enhances model-free credit assignment through boosting of retrospective model-based inference

Dopamine is implicated in representing model-free (MF) reward prediction errors a as well as influencing model-based (MB) credit assignment and choice. Putative cooperative interactions between MB and MF systems include a guidance of MF credit assignment by MB inference. Here, we used a double-blind, placebo-controlled, within-subjects design to test an hypothesis that enhancing dopamine levels boosts the guidance of MF credit assignment by MB inference. In line with this, we found that levodopa enhanced guidance of MF credit assignment by MB inference, without impacting MF and MB influences directly. This drug effect correlated negatively with a dopamine-dependent change in purely MB credit assignment, possibly reflecting a trade-off between these two MB components of behavioural control. Our findings of a dopamine boost in MB inference guidance of MF learning highlights a novel DA influence on MB-MF cooperative interactions.

Sepia 200cH at 1:1000 dilution ameliorates salt stress in cowpea seedlings but its medium 90% ethanol proves ineffective at the same dilution

Soil salinity severely affects crop yield all over the world. In a recent study we observed that Natrum mur 200cH, a homeopathic remedy, improved growth in germinating cowpea seeds. In the present study we have tested another remedy Sepia, which is complementary to Natrum mur, on cowpea seedlings under salt stress. Cowpea seedlings grown over moist filter paper in petridishes were divided into 4 groups: (1) control in sterile water, (2) in 50mM NaCl solution, (3) seeds pretreated with 90% ethanol diluted with water 1:100 and then transferred to 50mM NaCl solution, (4) seeds pretreated with Sepia 200cH diluted with water 1:100 and transferred to 50mM NaCl solution. In another experiment the groups were same, but the dilution of 90% ethanol and Sepia 200cH was 1:1000 instead of 1:100. The purpose was to further reduce the ethanol content in both the drug and its vehicle 90% ethanol, so that the alcohol effect is minimized or abolished. The data were analysed by ANOVA followed by t-test. Sepia 200cH at both 1:100 and 1:1000 dilutions significantly increased growth, sugar, chlorophyll, protein and water content in seedlings as compared to the untreated salt-stressed group. The effect with the1000th dilution of Sepia 200cH was more pronounced than with its 100th dilution. The vehicle 90% ethanol at 1:100 dilution produced some positive effect on the seedlings, but the 1000th dilution of the vehicle produced no such effect. It is, therefore, concluded that Sepia 200cH could ameliorate salt stress in cowpea seedlings and that the 1000th dilution is more effective than its 100th dilution. The alcohol effect is totally eliminated with the 1000th dilution of 90% ethanol. Thus the 1000th dilution could retain the drug effect and eliminate the vehicle effect.

CURRENT MEASURES AGAINST OPHTHALMIC COMPLICATIONS OF DIABETES MELLITUS-A SHORT REVIEW

Diabetes mellitus (DM) is a metabolic disorder, whose prevalence is predicted to rise shortly. The present review focuses on the various ocular complications associated with DM, and the various ophthalmic formulation approaches developed to treat the same. Diabetic macular edema (DME), diabetic retinopathy, cataracts, and glaucoma are some of the major vision-threatening complications linked to DM. The ocular route of drug delivery has undergone several advancements in recent decades, the introduction of various novel drug delivery systems (DDS), various modifications in the existing formulation approaches, development of custom-designed personalized medications, being some of the major developments introduced in the field of ocular drug delivery. Due to the application of state-of-the-art technologies in the field of innovations related to ocular DDS, patients have been immensely benefited by the current modes of ocular treatment imparting fewer side effects, enhanced penetration, sustained drug effect, and so on. The present review includes and emphasizes the gradual development that has occurred from the conventional ophthalmic dosage forms to the currently reported novel ocular drug delivery approaches along with the related clinical research works.

523. Use of Immune-Viral Dynamics Modeling to Understand Molnupiravir Drug Effect for COVID-19

Background Molnupiravir (MOV) is an orally administered ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) against SARS-CoV-2. Here we present viral dynamics analysis of Phase 2 clinical virology data to inform MOV Phase 3 study design and development strategy. Methods An Immune-Viral Dynamics Model (IVDM) was developed with mechanisms of SARS-CoV-2 infection, replication, and induced immunity, which together describe the dynamics of viral load (VL) during disease progression. Longitudinal virology data from ferret studies (Cox, et al. Nat. Microbiol 2021:6-11) were used to inform IVDM, which was further translated to human by adjusting parameter values to capture clinical data from MOVe-IN/MOVe-OUT studies. Different placements of drug effects (on viral infectivity vs. productivity) and representations of immune response were explored to identify the best ones to describe data. A simplified 95% drug effect was implemented to represent a highly effective dose of MOV. Results IVDM showed data were best described when MOV acts on viral infectivity, consistent with the error catastrophe mechanism of action. A cascade of innate and adaptive immune response and a basal level activation enabled durable immunity and continued viral decay after treatment end. IVDM reasonably describes VL and viral titer data from animals and humans. Influence of MOV start time was explored using simulations. Consistent with the ferret studies, simulations showed when treatment is started within the first week post infection, MOV reduces viral growth, resulting in a lower and shortened duration of detectable VL. When started later (e.g. >7 days since symptom onset), the magnitude of drug effect is substantially diminished in a typical patient with an effective immune response which reduces VL prior to treatment start. Further work is needed to model response in patients with longer term infection, where MOV drug effects may have more persistent utility. Conclusion A COVID-19 IVDM developed using multiscale MOV virology data supports drug action on viral infectivity and importance of interplay of treatment and immune response and can describe infection time course and drug effect. IVDM provided mechanistic interpretations for VL drug effect in clinical studies. Disclosures Youfang Cao, PhD, Merck & Co. (Employee) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Ruthie Birger, PhD, Merck (Employee) Julie Stone, PhD, Merck & Co., Inc. (Employee, Shareholder)

Sulfasalazine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) with concomitant acute chikungunya virus infection: possible role of new viral trigger

Drug reaction with eosinophilia and systemic symptoms (DRESS) is designated as a potentially lethal adverse drug effect with characteristic signs and symptoms such as skin rash, fever, leucocytosis with eosinophilia or atypical lymphocytes, lymphadenopathy and liver or renal dysfunction. In addition to most commonly implicated drug category (aromatic anticonvulsants), lamotrigine, sulfonamides, dapsone and abacavir may also induce this syndrome. We describe here a case a sulfasalazine-induced DRESS with coexisting chikungunya fever. The shared presentation of fever with rash in both conditions made it a challenging diagnosis. Sulfasalazine hypersensitivity manifesting as DRESS has rarely been reported. Furthermore, we document chikungunya virus (CV) as a possible triggering agent for DRESS. To the best of our knowledge, CV as a viral aetiology in DRESS has not been reported previously in the literature.

Safety pharmacology of acute LSD administration in healthy subjects

Rationale Lysergic acid diethylamide (LSD) is used in psychiatric and psychological research and investigated as a potential treatment for medical and psychiatric disorders, including depression, anxiety, and cluster headache. Objectives Safety data on clinical safety are available from small studies but not from larger samples. We report safety pharmacology data from a large pooled study sample on acute effects of LSD in healthy subjects. Methods We conducted a pooled analysis of four double-blind, randomized, placebo-controlled, crossover studies that included a total of 83 healthy subjects and 131 single-dose administrations of LSD. LSD administrations were matched to dose groups according to measured LSD peak plasma concentrations to adjust for uncertainties in the correct LSD dose in some studies. Single doses were 25, 50, 100, and 200 µg of LSD base. We investigated subjective effects (self-rated any drug effect, good drug effect, bad drug effect, and anxiety), blood pressure, heart rate, body temperature, duration of the acute LSD response, acute (12 h) and subacute (24 h) adverse effects, reports of flashbacks, and liver and kidney function before and after the studies. Results LSD dose-dependently increased subjective, physiologic, and adverse effects. The dose–response curves for the proportions of subjects with a certain amount of a subjective effect were steeper and reached a higher maximum for positive acute subjective effects compared with negative acute subjective effects. Maximal ratings of > 50% good drug effects were reached in 37%, 91%, 96%, and 91% of the LSD administrations at 25, 50, 100, and 200 µg. Maximal ratings of > 50% bad drug effects were reached in 0%, 9%, 27%, 31% at 25, 50, 100, and 200 µg, respectively. Mean ratings of Oceanic Boundlessness were 10%, 25%, 41%, and 44%, and mean ratings of Anxious Ego-Dissolution were 3.4%, 13%, 20%, and 22% at 25, 50, 100, and 200 µg, respectively. The physiologic effects of LSD were moderate. None of the subjects had systolic blood pressure > 180 mmHg at any time. Peak heart rate > 100 beats/min was observed in 0%, 6%, 20%, and 25% of the subjects at 25, 50, 100, and 200 µg, respectively. Maximal heart rates of 129 and 121 beats/min were observed in one subject at the 50 and 200 µg doses, respectively. Peak body temperature > 38° was observed in 0%, 11%, 7%, and 34% at 25, 50, 100, and 200 µg, respectively. Mean acute adverse effect scores on the List of Complaints were 5.6, 9.2, 12, and 13 at 25, 50, 100, and 200 µg, respectively. Kidney and liver function parameters were unaltered. Six subjects reported transient flashback phenomena. Conclusions The single-dose administration of LSD is safe in regard to acute psychological and physical harm in healthy subjects in a controlled research setting.

Carbamazepine drug effect simulating biochemical central hypothyroidism in a patient with Bardet-Biedl syndrome

Carbamazepine (CBZ) is a medication used commonly in epilepsy. Decreases in free T4 levels simulating central hypothyroidism have been reported, although the clinical significance is still unclear. We present a 24-year-old man with Bardet-Biedl syndrome (BBS) who was found to have isolated biochemical central hypothyroidism. BBS is a ciliopathy occasionally associated with anterior pituitary dysfunction. While taking CBZ for epilepsy, his TSH was 1.73 mIU/L (reference range: 0.20–4.00 mIU/L) with a low free T4 of 6.6 pmol/L (reference range: 10.0–26.0 pmol/L). Pituitary MRI was normal. Although treated with levothyroxine initially, his apparent biochemical central hypothyroidism was later recognised as secondary to CBZ drug effect. This was confirmed with a normal free T4 of 12.2 pmol/L while he was off CBZ and levothyroxine. Despite the association between CBZ and biochemical central hypothyroidism, nearly all patients remain clinically euthyroid. This effect is reversible and recognition could lead to reductions in unnecessary thyroid replacement therapy if CBZ is discontinued.

Clinical connectivity map for drug repurposing: using laboratory results to bridge drugs and diseases

Background Drug repurposing, the process of identifying additional therapeutic uses for existing drugs, has attracted increasing attention from both the pharmaceutical industry and the research community. Many existing computational drug repurposing methods rely on preclinical data (e.g., chemical structures, drug targets), resulting in translational problems for clinical trials. Results In this study, we propose a novel framework based on clinical connectivity mapping for drug repurposing to analyze therapeutic effects of drugs on diseases. We firstly establish clinical drug effect vectors (i.e., drug-laboratory results associations) by applying a continuous self-controlled case series model on a longitudinal electronic health record data, then establish clinical disease sign vectors (i.e., disease-laboratory results associations) by applying a Wilcoxon rank sum test on a large-scale national survey data. Eventually, a repurposing possibility score for each drug-disease pair is computed by applying a dot product-based scoring function on clinical disease sign vectors and clinical drug effect vectors. During the experiment, we comprehensively evaluate 392 drugs for 6 important chronic diseases (include asthma, coronary heart disease, congestive heart failure, heart attack, type 2 diabetes, and stroke). The experiment results not only reflect known associations between diseases and drugs, but also include some hidden drug-disease associations. The code for this paper is available at: https://github.com/HoytWen/CCMDR Conclusions The proposed clinical connectivity map framework uses laboratory results found from electronic clinical information to bridge drugs and diseases, which make their relations explainable and has better translational power than existing computational methods. Experimental results demonstrate the effectiveness of our proposed framework, further case analysis also proves our method can be used to repurposing existing drugs opportunities.