Therapeutic Index Research Articles

The Catechol O-MethyltransferaseInhibitor Entacapone in the Treatment of Parkinson's Disease: Personal Reflections on a First-in-Class Drug Development Programme 40Years On.

In the 1980s, Orion Pharma, then a mid-ranking Nordic area pharmaceutical company, established a drug development programme on the inhibition of catechol O-methyltransferase (COMT). This enzyme, which plays an important role in the inactivation of catecholamine neurotransmitters and drugs with a catechol structure, thus came under consideration as a target in the innovative translational and clinical programme we describe in this historical review. The starting point was the conjecture that a peripherally acting COMT inhibitor might improve entry of levodopa into the brain. This had potentially significant implications for the medical treatment of Parkinson's disease (PD). The rationale was that more efficient delivery of levodopa to the brain might allow the high therapeutic doses of levodopa to be reduced and the dose interval to be extended. Elucidation of structure-activity relations paved the way for the discovery and development of entacapone, a 5-nitrocatechol that was a potent and highly specific inhibitor of COMT. Experience in phaseIII clinical trials established that entacapone, used as an adjunct to regular or controlled-release levodopa preparations (also including a peripherally acting dopa-decarboxylase inhibitor), increased ON-time and reduced OFF-time and improved clinical condition in patients with PD experiencing wearing-off, often with a reduced daily levodopa dose. Several of these studies also identified that entacapone improved patients' quality of life and was cost-effective. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo®) with levodopa and carbidopa to create a flexible and convenient drug therapy for patients with PD who have end-of-dose motor fluctuations not stabilised on levodopa/dopa-decarboxylase inhibitor treatment. This review offers a historical perspective on a successful programme of drug development by researchers who played central roles in the progress from exploratory hypothesis to registered pharmaceutical product.

The Effect of Therapeutic Doses of Culinary Spices in Metabolic Syndrome: A Randomized Controlled Trial.

Non-communicable diseases (NCDs) place a significant burden on global health and the healthcare systems which support it. Metabolic syndrome is a major risk factor for a large number of NCDs; however, treatments remain limited. Previous research has shown the protective benefits of edible dietary spices on key components of metabolic syndrome. Therefore we performed a 12-week double-blind, placebo-controlled, randomized, clinical trial to evaluate the effect of ginger (Zingiber officinale), cinnamon (Cinnamomum), and black seed (Nigella sativa) consumption on blood glucose, lipid profiles, and body composition in 120 participants with, or at risk of, metabolic syndrome. Each participant consumed 3 g/day of powder (spice or placebo). Data related to different parameters were collected from participants at the baseline, midpoint, and endpoint of the intervention. Over the 12-week interventions, there was an improvement in a number of biochemical indices of metabolic syndrome, including fasting blood glucose, HbA1c, LCL, and total cholesterol associated with supplementation with the spices when compared to a placebo. This study provides evidence to support the adjunct use of supplementation for those at risk of metabolic syndrome and its sequelae.

Tipifarnib physiologically-based pharmacokinetic modeling to assess drug-drug interaction, organ impairment, and biopharmaceutics in healthy subjects and cancer patients.

A physiologically-based pharmacokinetic (PBPK) model for tipifarnib, which included mechanistic absorption, was built and verified by integrating invitro data and several clinical data in healthy subjects and cancer patients. The final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations of tipifarnib in healthy subjects and cancer patients under several dosing conditions, such as co-administration with a strong CYP3A4 inhibitor and inducer, an acid-reducing agent (proton pump inhibitor and H2 receptor antagonist), and with a high-fat meal. In addition, the model was able to accurately predict the effect of mild or moderate hepatic impairment on tipifarnib exposure. The appropriately verified model was applied to prospectively simulate the liability of tipifarnib as a victim of CYP3A4 enzyme-based drug-drug interactions (DDIs) with a moderate inhibitor and inducer as well as tipifarnib as a perpetrator of DDIs with sensitive substrates of CYP3A4, CYP2B6, CYP2D6, CYP2C9, and CYP2C19 in healthy subjects and cancer patients. The effect of a high-fat meal, acid-reducing agent, and formulation change at the therapeutic dose was simulated. Finally, the model was used to predict the effect of mild, moderate, or severe hepatic, and renal impairment on tipifarnib PK. This multipronged approach of combining the available clinical data with PBPK modeling-guided dosing recommendations for tipifarnib under several conditions. This example showcases the totality of the data approach to gain a more thorough understanding of clinical pharmacology and biopharmaceutic properties of oncology drugs in development.

Repetitive mild traumatic brain injury impairs norepinephrine system function and psychostimulant responsivity

Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus coeruleus-norepinephrine (LC-NE) system is a critical regulator of arousal levels and higher executive processes affected by TBI including attention, working memory, and decision making. LC-NE axon injury and impaired signaling within the prefrontal cortex (PFC) is a potential contributor to the neuropsychiatric symptoms after single, moderate to severe TBI. The majority of TBIs are mild, yet long-term cognitive deficits and increased susceptibility for further injury can accumulate after each repetitive mild TBI. As a potential treatment for restoring cognitive function and daytime sleepiness after injury psychostimulants, including methylphenidate (MPH) that increase levels of NE within the PFC, are being prescribed “off-label”. The impact of mild and repetitive mild TBI on the LC-NE system remains limited. Therefore, we determined the extent of LC-NE and arousal dysfunction and response to therapeutic doses of MPH in rats following experimentally induced single and repetitive mild TBI. Microdialysis measures of basal NE efflux from the medial PFC and arousal measures were significantly lower after repetitive mild TBI. Females showed higher baseline PFC-NE efflux than males following single and repetitive mild TBI. In response to MPH challenge, males exhibited a blunted PFC-NE response and persistent arousal levels following repetitive mild TBI. These results provide critical insight into the role of catecholamine system dysfunction associated with cognitive deficits following repeated injury, outcome differences between sex/gender, and lack of success of MPH as an adjunctive therapy to improve cognitive function following injury.

Changes in Time in Therapeutic Range Within a Warfarin Anticoagulation Clinic Following Introduction of Direct Oral Anticoagulants.

Background: As direct oral anticoagulants (DOACs) have become widely recommended as first-line anticoagulation therapy, patients who remain on warfarin are likely those unable to afford, adhere to, or utilize DOAC therapy due to the presence of a contraindication. It is currently unknown how availability of DOACs have affected populations being managed at warfarin (VKA) anticoagulation clinics. Methods: This was a retrospective chart review assessing warfarin-treated patients at an outpatient anticoagulation clinic. The primary endpoint was the 6-month time in therapeutic range (TTR) before and after DOACs were recommended as first-line therapy by clinical guidelines. Study periods were January to June 2015, before DOACs were recommended over VKA, and January to June 2022, when DOACs were often recommended over VKA. TTR, demographic changes, and the presence of contraindications to DOAC therapy in the clinic population between the two time periods were assessed. Results: No difference in 6-month TTR was observed between study periods (59% in 2015 vs 63% in 2022; P = .45). Patient demographics did not significantly vary, which may be due to the clinic retaining 45% of patients between both time periods. Contraindications to DOAC therapy were identified in 39% of the 2015 group and 49% of the 2022 group (P = .18). The most common contraindication was indication for anticoagulation. Conclusion: Availability of DOACs did not seem to significantly affect the population or management of warfarin-treated patients at an outpatient anticoagulation clinic, however, contraindications and potential challenges to use of DOAC therapy are present in many patients.

From lab bench to hope: a review of gene therapies in clinical trials for Parkinson's disease and challenges.

Parkinson's disease (PD) is a chronic neurological disorder that is identified by a characteristic combination of symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. It is the second most common neurodegenerative disease after Alzheimer's disease and is characterized by the progressive loss of dopamine-producing neurons in the brain. Currently, available treatments for PD are symptomatic and do not prevent the disease pathology. There is growing interest in developing disease-modifying therapy that can reduce disease progression and improve patients' quality of life. One of the promising therapeutic approaches under evaluation is gene therapy utilizing a viral vector, adeno-associated virus (AAV), to deliver transgene of interest into the central nervous system (CNS). Preclinical studies in small animals and nonhuman primates model of PD have shown promising results utilizing the gene therapy that express glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), aromatic L-amino acid decarboxylase (AADC), and glutamic acid decarboxylase (GAD). This study provides a comprehensive review of the current state of the above-mentioned gene therapies in various phases of clinical trials for PD treatment. We have highlighted the rationale for the gene-therapy approach and the findings from the preclinical and nonhuman primates studies, evaluating the therapeutic effect, dose safety, and tolerability. The challenges associated with gene therapy for heterogeneous neurodegenerative diseases, such as PD, have also been described. In conclusion, the review identifies the ongoing promising gene therapy approaches in clinical trials and provides hope for patients with PD.

Binary Proton Therapy of Ehrlich Carcinoma Using Targeted Gold Nanoparticles.

Proton therapy can treat tumors located in radiation-sensitive tissues. This article demonstrates the possibility of enhancing the proton therapy with targeted gold nanoparticles that selectively recognize tumor cells. Au-PEG nanoparticles at concentrations above 25 mg/L and 4 Gy proton dose caused complete death of EMT6/P cells in vitro. Binary proton therapy using targeted Au-PEG-FA nanoparticles caused an 80% tumor growth inhibition effect in vivo. The use of targeted gold nanoparticles is promising for enhancing the proton irradiation effect on tumor cells and requires further research to increase the therapeutic index of the approach.

Harnessing therapeutic deep eutectic solvents in self-emulsifying systems to improve CBD delivery

In this study, Cannabidiol crystals (CBD) were used as a BCS class II model drug to generate a novel therapeutic deep eutectic solvent (THEDES) with easy preparation using caprylic acid (CA). The hydrogen bonding interaction was confirmed by different techniques such as FT-IR and NMR, resulting in a hydrophobic system suitable for liquid formulations. The CBD-based THEDES, combined with a specific mixture of surfactants and co-surfactants, successfully formed a self-emulsifying drug delivery system (SEDDS) that generated uniform nano-sized droplets once dispersed in water. Hence, the THEDES showed compatibility with the self-emulsifying approach, offering an alternative method to load drugs at their therapeutic dosage. Physical stability concerns regarding the unconventional oily phase were addressed through stress tests using multiple and dynamic light scattering, demonstrating the robustness of the system. In addition, the formulated SEDDS proved effective in protecting CBD from the harsh acidic gastric environment for up to 2 h at pH 1.2. Furthermore, in vitro studies have confirmed the safety of the formulation and the ability of CBD to permeate Caco-2 cells when formulated. This investigation highlights the potential incorporation of THEDES in lipid-based formulations like SEDDS, expanding the avenues for innovative oral drug delivery approaches.

D.6 Neurological care and outcomes of pregnant patients with epilepsy in a Canadian tertiary care center (2014-2020)

Background: Limited data exists on neurological care and outcomes of Canadian pregnant patients with epilepsy (PPWE). This study provides Canadian data to inform practice patterns and observed outcomes for PPWE at a tertiary care center. Methods: PPWE receiving care at the University Health Network (Toronto, Canada) epilepsy clinic from January 1, 2014 to November 20 2020 were retrospectively identified with demographics and neurological data and outcomes collected. Results: A total of 195 cases were identified, with a median maternal age of 32 years (SD 4.58), a median age at first seizure of 17 years (range 1 month – 36 years old), 52% were diagnosed with genetic generalized epilepsy and 50% endorsed 6 months of seizure freedom prior to conception. In pregnancy, 93% took ASM(s) with 77% receiving therapeutic drug monitoring (TDM) and drug dose adjustments reported in 69%. Most cases (73%) maintained a stable seizure frequency. Conclusions: This study provides new Canadian data on PPWE at a tertiary care center. PPWE are overall well controlled, more likely to have young adult onset, genetic generalized epilepsy with nearly all taking ASM(s) during pregnancy. While high rates of TDM and drug dose adjustments were observed, most experienced seizure stability in pregnancy.

Modern problems of preclinical studying feed additives for animals and ways to solve them

Resource-saving technology in agriculture is the use of stimulating additives in animal feeding rations that promote better absorption of feed. One of the measures to prevent toxicosis in industrial livestock and poultry farming is to determine the toxicity of feed. The variety of existing methods makes it possible to determine the level and class of drug toxicity at the initial stage. In the developed classification for veterinary drugs, the cumulation coefficient, therapeutic breadth index and dose level of toxic effect are used, which makes it possible to predict the nature and degree of their danger at the stage of preclinical study of feed additives. To determine the listed indicators, it is necessary to establish LD50and the cumulation coefficient. Since feed additives are introduced into the body through the digestive tract, during preclinical studies they are studied and classified according to their hepatotoxic effect. Bilirubin, albumin, and enzyme activity contained in the blood (glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and the ratio of alanine aminotransferase to alkaline phosphatase) are used as markers. It is necessary to determine the de Ritis, Schmidt coefficient and the R index. This will minimize the intake of toxic feed additives into the animals’ bodies and will contribute to an increase in their productivity.

Programming Probiotics: Diet-Responsive Gene Expression and Colonization Control in Engineered S. boulardii.

Saccharomyces boulardii (Sb) is an emerging probiotic chassis for delivering biomolecules to the mammalian gut, offering unique advantages as the only eukaryotic probiotic. However, precise control over gene expression and gut residence time in Sb have remained challenging. To address this, we developed five ligand-responsive gene expression systems and repaired galactose metabolism in Sb, enabling inducible gene expression in this strain. Engineering these systems allowed us to construct AND logic gates, control the surface display of proteins, and turn on protein production in the mouse gut in response to dietary sugar. Additionally, repairing galactose metabolism expanded Sb's habitat within the intestines and resulted in galactose-responsive control over gut residence time. This work opens new avenues for precise dosing of therapeutics by Sb via control over its in vivo gene expression levels and localization within the gastrointestinal tract.

#430 Risk factors for major bleeding in patients with non-valvular atrial fibrillation and CKD G3-G5D on oral anticoagulants

Abstract Background and Aims We previously published a register-based cohort study comparing direct oral anticoagulants (DOAC) and warfarin in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) GFR category 3-5 (G3-G5) including patients on dialysis (G5D) (1). This study showed that DOAC was associated with lower risk of major bleeding but similar risk of ischemic stroke compared to warfarin. Bleedings were however more common than strokes, especially in advanced CKD (G5-G5D) where the risk of major bleeding was up to 10 times higher than the risk of stroke. Subsequently, the stroke- and bleeding risk in patients with AF and advanced CKD must be carefully evaluated when deciding on whether to prescribe oral anticoagulants (OAC) or not. Available stroke- and bleeding scoring systems do not perform well in CKD (2, 3). This study aims to present risk factors associated with major bleeding in a Swedish cohort of OAC-treated patients with CKD G3-G5D. Method Data was collected from high quality Swedish healthcare registers including Swedish Renal Registry and Auricula, a register for atrial fibrillation and oral anticoagulants and the National Patient Register. Patients with eGFR<60 ml/min/1.73m2 and non-valvular atrial fibrillation and either DOAC (apixaban, rivaroxaban, edoxaban and dabigatran) or warfarin treatment between 2009-2018 where included. DOAC treatment periods were collected from the Swedish Prescribed Drug Register (PDR), starting from dispense date covering assumed standard pill use and an additional 30 days grace period. Warfarin treatment periods were collected directly from Auricula. An undefined treatment was a period of no OAC or a period of warfarin from PDR not matching a treatment period in Auricula. All periods of OAC treatment with either DOAC or warfarin were evaluated in a multivariate Cox regression model regarding the risk of major bleeding requiring inpatient care. Time-dependent covariates adjusted for in the model were age, sex, years from study start, GFR category, congestive heart failure, diabetes mellitus, hypertension, excessive alcohol use, liver disease, vascular disease, previous gastrointestinal bleeding, intracranial bleeding, other bleeding, ischemic stroke/ transient ischemic attack (TIA), myocardial infarction, PCI and exposures (DOAC, warfarin and periods of undefined treatment). Results Of 2453 included patients, 59% had warfarin (time in therapeutic range, TTR, 67%) and 41% DOAC at inclusion, predominantly apixaban (81% of DOAC users). The mean age was 77 years, 28.3% had G3, 45.4% G4, 9.1% G5 and 17.3% G5D (Table 1). Mean follow up was 2.2 years. During follow up 424 major bleedings occurred yielding 8.9 (95% confidence interval 8.1-9.8) bleedings per 100 patient-years. Table 2 shows effect estimates of each covariate on the outcome major bleeding. Covariates, besides warfarin, associated with increased risk of major bleeding were GFR category, G5/5D versus G3, hazard ratio 1.92 (95% CI 1.43-2.56), previous GI bleeding, 1.77 (1.39-2.25) and previous other bleeding 1.33 (1.09-1.62). Other factors associated with major bleeding were congestive heart failure 1.36 (1.11-1.68), male sex 1.28 (1.03-1.60) and vascular disease, 1.35 (1.01-1.79). Conclusion Patients with non-valvular atrial fibrillation and CKD G3-G5D on OAC are at high risk of major bleeding. Previous major bleeding and kidney failure are strongly associated with major bleeding, this reiterates the results of many previous studies. The present study also shows an association between OAC-associated major bleeding in CKD and male sex, congestive heart failure and vascular disease. Similar associations have been showed in non-CKD cohorts previously but is inadequately studied in CKD. Knowledge about risk factors for major bleeding on OAC in advanced CKD is essential when deciding on when to anticoagulate or not.

#2823 High doses and levels of cholecalciferol for secondary hyperparathyroidism in hemodialysis patients

Abstract Background and Aims Vitamin D is crucial for musculoskeletal and general health. Low levels are associated with an increased risk of death and morbidity, including cancer, cardiovascular, autoimmune diseases and infections. In hemodialysis (HD) patients vitamin D deficiency plays additionally an important role in the pathogenesis of Chronic Kidney Disease–Mineral And Bone Disorder (CKD-MBD), including the development of secondary hyperparathyroidism (SHP). Determination of 25(OH)D levels in CKD patients and the administration of cholecalciferol according to the guidelines for the general population is recommended. The literature data show that therapy even with high doses of cholecalciferol appear to be safe and sufficient to increase 25(OH)D level > 30 ng/ml in HD patients. However, the prevailing opinion is that PTH lowering with cholecalciferol in CKD is unproven and clinically insignificant. The aim of the study was to evaluate the efficacy (including PTH concentration) and safety of increasing vitamin D levels from the recommended 30 ng/mL to >75 ng/mL in HD patients treated with high doses of cholecalciferol. Method 22 HD patients (16 M, 6 F)), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration 30–50 ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session) to reach the target serum 25(OH)D level > 75 ng/mL, but not longer than for 24 weeks. The baseline data on calcium, phosphate, 1,84 PTH, 25(OH)D and 1,25(OH)2D serum levels were compared with the data when 25(OH)D > 75 ng/mL was achieved or when the highest 25(OH)D levels were noted. Results A significant decrease in 1,84 PTH levels was observed during the study (542.36 ± 420.87 vs 230.99 ± 386.22 pg/mL; p < 0.005). No significant effect on calcium (8.91 ± 0.57 vs 9.03 ± 0.63 mg/dL; p = 0.23) and phosphate (4.6 ± 1.06 vs 4.81 ± 1.06 mg/dL; p = 0.93) concentrations was shown. There was also significant increase in 25(OH)D and 1,25(OH)2D levels (35.52 ± 8.26 vs 79.83 ± 21.38 ng/mL; p < 0.005, and 13.38 ± 7.26 vs 25.56 ± 12.80 pg/mL; p < 0.005, respectively). In the range of 25(OH)D levels 30-50 ng/mL 25(OH)D correlated positively with 1,25(OH)2D levels, r = 0.305. When 25(OH)D levels exceeded 50 ng/mL, there was negative correlation with 1,25(OH)2D levels (r = –0 .177 for 25(OH)D 50-75 ng/mL, and r = –0.262 for 25(OH)D >75 ng/mL). Conclusion Our study showed that the administration of high therapeutic doses of cholecalciferol to achieve 25(OH)D levels >75 ng/mL was safe, without the risk of hypercalcemia and hyperphosphatemia. Raising of 25(OH)D levels to the upper limit of the laboratory norm resulted in significant decrease in PTH levels. Cholecalciferol may be useful in the treatment of SHP in HD patients, but higher 25(OH)D levels seem to be crucial.

Utility of TTR-INR guided warfarin adjustment protocol to improve time in therapeutic range in patients with atrial fibrillation receiving warfarin

Warfarin remains the most prescribed oral anticoagulant of choice in atrial fibrillation (AF) patient in resource-limited settings. Despite evidence linking Time in Therapeutic Range (TTR) to patient outcomes, its use in clinical practice is not widespread. This prospective study explores the impact of a TTR-INR guided Warfarin adjustment protocol on TTR in AF patients. Conducted at the Warfarin clinic of King Chulalongkorn Memorial Hospital. TTR was calculated using the Rosendaal linear interpolation method at baseline, and then at 6 and 12 months post-protocol implementation. The primary outcome was the improvement in TTR following the protocol’s implementation. The study analyzed 57 patients, with a mean age of 72 years and an even gender distribution. At baseline, 53% of patients had a TTR of less than 65%. However, TTR significantly improved from 65% at baseline to 80% after 12 months of protocol implementation (p < 0.001). Furthermore, there was a significant increase in the proportion of patients with a TTR of 65% or more, from 47 to 88% (p < 0.001). During the follow-up period in the first 12 months, three patients died, but no ischemic or major bleeding events occurred. The significant improvement in TTR after 12 months of protocol implementation suggests that this strategy could provide additional value in improving TTR and outcomes in AF patients receiving Warfarin.

Investigating the Functional Performance of Plantago Ovate Plant as a Drug Carrier in a Targeted Drug Delivery System

The drug delivery systems that were used in the past were done without any control over the time, place and speed of drug release, and this caused the amount of drug released in the blood to fluctuate, that is, the concentration of the drug in the blood could vary from The therapeutic range will be exceeded and its side effects will also increase. Therefore, with targeted medicine, it is possible to control the place of drug release, its speed and time, and minimize the side effects caused by the drug. In this regard, in this research, the natural hydrogel extracted from the Plantago ovate plant as one of the drug carriers in the body environment in order to increase the efficiency and reduce the degradation of the drug, prevent the side effects caused by the use of the drug and increase the access to the drug and improve Its effect was investigated at the lesion site. In this context, after extracting the natural hydrogel from Plantago ovate plant, the swelling rate of Plantago ovate gel powder was investigated at different pH, the FT-IR spectrum obtained from Plantago ovate hydrogel and the swelling rate of Plantago ovate mucilage at different pH were investigated. Therefore, the obtained results indicate that natural polysaccharides can be used as a natural drug carrier in drug delivery systems due to their high biocompatibility in the body environment, non-toxicity and cheapness.

Impulse control disorders and use of dopamine agonists in early onset Parkinson's disease.

Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists. Current data on ICDs in patients with early-onset Parkinson's disease (EOPD) is lacking. In this study we aim to assess the frequency of use of dopamine agonists, the prevalence of ICDs, and to explore potential factors associated with their development in patients with EOPD. We used the Mayo Clinic Data Explorer system to investigate a population-based cohort of EOPD patients between 1990 and 2022 at Mayo Clinic, Rochester, MN. We used ICD coding for parkinsonism; then, we reviewed all the clinical records and included only those patients with a clinical diagnosis of PD with symptoms onset at or before the age of 50, and who developed ICDs after using therapeutic doses of dopamine agonists. A total of 831 (513 males and 318 females) patients with EOPD were included with a median age at symptom onset of 42 years of age (CI: 37-46). Dopamine agonists were used in 49.7% of all patients; of these, only 14.5% developed symptoms of one or more ICDs. Hypersexuality was the most commonly observed ICD (38.3%), and the only one having a statistically significant male predominance (p = 0.011). ICDs are common in EOPD, particularly when associated with the use of dopamine agonists.

Biochemical parameters, oxidative stress biomarkers, and anatomopathological changes in Wistar rats treated with 3′-demethoxy-6-O-demethylisoguaiacin and norisoguaiacin

Artemisia cina (Ac) is a plant with anthelmintic compounds such as 3′-demethoxy-6-O-demethylisoguaiacin (D) and norisoguaiacin (N). Three major objectives were proposed: (1) To evaluate biochemical parameters in blood (2) to determine the tissue oxidative stress by biomarkers as TBARS and glutathione peroxidase activity, and (3) to evaluate anatomopathological changes in organs such as the brain, liver, kidney, and lung after oral administration of n-hexane extract of Ac and D and N. D and N were administrated following the OECD guides for acute oral toxicity evaluation (Guide 420). Fifty Wistar rats were distributed into ten groups as follows: Group 1 (G1): 4 mg/Kg; G2: 40 mg/Kg; G3: 240 mg/Kg; G4: 1600 mg/Kg of n-hexane extract of Ac. G5: 2 mg/Kg; G6: 20 mg/Kg; G7: 120 mg/Kg; G8: 800 mg/Kg of D and N, G9: water and G10: polyvinylpyrrolidone at 2000 mg/Kg. At 14 days, the rats were euthanized, and the blood, liver, brain, kidney, and lung were taken for biochemical analysis, anatomopathological changes, and TBARS and GSH evaluation. Glucose, cholesterol, and phosphorus were altered. Histopathological analysis showed multifocal neuronal degeneration in the brain (G2). The kidney and lungs had changes in G7. The GSH and TBARS increased in G6 and G7. The TBARS activity was higher in G1 and G2. In conclusion, extract and D and N of Ac did not have damage at therapeutic doses. D, N, and n-hexane extract of A. cina do not cause histopathological damage at pharmaceutical doses. Still, the brain, kidney, and liver are related to biochemical parameters at higher doses. However, compounds are proposed as antioxidant agents.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis

Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype onparoxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P=0.03 and P=0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

The reverse transcriptase inhibitor 3TC modulates hippocampal transcriptome signatures of inflammation in tauopathy model mice

Reducing neuroinflammation, a key contributor to brain aging and neurodegenerative diseases, is a promising strategy for improving cognitive function in these settings. The FDA-approved nucleoside reverse transcriptase inhibitor 3TC (Lamivudine) has been reported to improve cognitive function in old wild-type mice and multiple mouse models of neurodegenerative disease, but its effects on the brain have not been comprehensively investigated. In the current study, we used transcriptomics to broadly characterize the effects of long-term supplementation with a human-equivalent therapeutic dose of 3TC on the hippocampal transcriptome in male and female rTg4510 mice (a commonly studied model of tauopathy-associated neurodegeneration). We found that tauopathy increased hippocampal transcriptomic signatures of neuroinflammation/immune activation, but 3TC treatment reversed some of these effects. We also found that 3TC mitigated tauopathy-associated activation of key transcription factors that contribute to neuroinflammation and immune activation, and these changes were related to improved recognition memory performance. Collectively, our findings suggest that 3TC exerts protective effects against tauopathy in the hippocampus by modulating inflammation and immune activation, and they may provide helpful insight for ongoing clinical efforts to determine if 3TC and/or related therapeutics hold promise for treating neurodegeneration.

Warfarin in the Emergency Service: Drug Interactions and Clinical Considerations

Drug-drug interactions (DDIs) are common occurrences where one drug influences the blood concentrations or efficacy of another. Warfarin, known for its narrow therapeutic index, carries a heightened risk of severe drug interactions. We retrospectively analyzed the records of 211 patients using warfarin at the Emergency Health Services clinic of Kırklareli Training and Research Hospital from January 1, 2020, to December 31, 2020. Patient demographics and drug regimens were documented, and drug interaction assessments were conducted using the drugs.com database. Among the 211 patients, 17 exhibited signs of bleeding, including 5 with major bleeding and 12 with minor bleeding. Of these, 129 had INR values exceeding 2.5, while 82 had INR values below 2.5. Notably, 11 of the 17 bleeding patients had INR values above 2.5, with an average INR of 3.69. Analysis revealed that the 211 patients collectively used 111 different drugs, with an average of 3.81 drugs per prescription. Intriguingly, 33 of these drugs exhibited major, moderate, or minor inter-actions and were prescribed to 174 patients. In conclusion, cautious and selective prescription of medications is warranted for patients receiving warfarin due to the potential for significant drug interactions