Single Daily Dose Research Articles

Ameliorative Effects of Moringa Oleifera on Histomorphology of Rat Testis Treated with Fluoxetine

Objective: To observe the histomorphological changes in rat testes treated with Fluoxetine, focusing on the weight of the testis along with the epithelial thickness of the seminiferous tubules and evaluating the ameliorative effects of Moringa oleifera on the same gross and histological parameters. Study Design: Laboratory-based experimental study. Place and Duration of Study: Army Medical College, National University of Medical Sciences (NUMS), with the National Institute of Health, Islamabad and Pak Emirates Military Hospital, Rawalpindi Pakistan, from Sep 2022 to Mar 2023. Methodology: Thirty male Sprague Dawley rats divided into three groups (n=10). Group-A was the Control-Group, and the rest served as the Experimental-Group. Drugs were given in a single daily dose through oral gavage for eight weeks. Group-B was given Fluoxetine, 10 mg/kg body weight. Group-C was administered Fluoxetine in the same dose and concomitant administration of Moringa powder, 50mg/30 grams body weight. After sacrifice, testes were fixed and stained with Hematoxylin and Eosin for histological study. Results: The study found a statistically significant decrease in the weight of rat testis (p-value˂0.05) and epithelial thickness of seminiferous tubules of rats treated with Fluoxetine (p-value ˂0.05). Conclusion: Fluoxetine significantly decreased the weight of the testis and epithelial thickness of the seminiferous tubules in rat testes. Moringa Oleifera administration ameliorated these effects in the short term.

Abstract C085: OPN-6602, a dual EP300/CBP bromodomain inhibitor modulates androgen-driven transcription, including MYC, in mCRPC

Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains an urgent unmet medical need despite existing therapies that target androgen receptor (AR) signaling. Disease progression is commonly a result of acquired resistance to existing anti-androgen therapies. Biological models have revealed potential resistance mechanisms of CRPC through the reactivation of the AR pathway. Transcriptional coactivators CREB-binding protein (CBP) and E1A binding protein (EP300) are high value targets in mCRPC as they mediate androgen-dependent and -independent activity of the AR pathway. EP300 and CBP proteins harbor both histone acetyltransferase (HAT)- and bromo-domains, and the HAT activity of EP300 regulates AR function. EP300 bromodomain inhibition partially blocks its HAT activity, reducing AR-mediated gene expression and tumor growth. OPN-6602 and OPN-6742 are potent, selective, and orally active small molecule dual EP300/CBP bromodomain inhibitors which abrogate persistent AR signaling in CRPC by modulating H3K27 acetylation and the recruitment of EP300, AR full length (AR-FL), and AR variant 7 (AR-v7) to AR response elements. OPN-6602 and OPN-6742 obstruct the EP300 bromodomain leading to downregulation of the AR pathway and consequent anti-tumor effects in AR-dependent CRPC. OPN-6602 and OPN-6742 are highly selective (>100-fold) against other bromodomains based on a screening panel of 40 bromodomains. Biochemical screens using AlphaScreen technology show these compounds to be equipotent against EP300 and CBP. OPN-6602 is particularly potent by Surface Plasmon Resonance analysis, displaying a KD of 0.87 nM, with a fast association rate (1.5 E+06/Ms) and a slow dissociation rate (1.3 E-03/s). Consequently, OPN-6602 displays a noteworthy residence time of 13 minutes. Both compounds show an AR-selective mode of action with anti-proliferative activity in AR-dependent prostate cancer cell lines (e.g. VCaP, LNCaP, and 22Rv-1) but are inactive against AR-negative prostate cancer cell lines (e.g. DU145). VCaP and mCRPC patient-derived xenograft (PDX) RNA profiling provides evidence of a marked, dose-dependent, pharmacodynamic response indicative of EP300/CBP inhibition. In the VCaP xenograft model, OPN-6602 and OPN-6742 show dose-dependent tumor growth inhibition and corresponding pharmacodynamic responses with prostate-specific antigen level decreases and decreased H3K27 acetylation. In the QR (AR-v7+) PDX model of CRPC (post-androgen deprivation therapy), a synergistic effect was observed between OPN-6602 and enzalutamide. This combination further modulates the expression of AR-driven transcripts such as MYC compared to single agent treatments. The pharmacokinetic profiles of OPN-6602 and OPN-6742 are favorable for oral single daily dose administration due to a high Cmax and short half-life. Due to its higher potency, OPN-6602 has been chosen as clinical candidate and a first-in-human study will start in 2024. Citation Format: Bernice Matusow, Wayne Spevak, Chao Zhang, Yan Ma, Rafe Shellooe, Peipei Li, James Tsai, Pan- Yu Chen, Parmveer Singh, Jackie Walling, Christine Nichols, Jason Halladay, Kerry Inokuchi, Gaston Habets, Gideon Bollag. OPN-6602, a dual EP300/CBP bromodomain inhibitor modulates androgen-driven transcription, including MYC, in mCRPC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C085.

Efficacy of Ferrous Bis-Glycinate versus Ferrous Sulphate in Children with Iron Deficiency Anemia

Iron deficiency anemia is a common pediatric disease and oral iron supplementation is the usual treatment. Newer formulations has been developed to treat iron deficiency anemia in children. Objective: To compare the efficacy of ferrous Bis-Glycinate in children with iron deficiency anemia to the conventional therapy with ferrous sulphate. Methods: In this open labelled prospective clinical trial was performed in children with iron deficiency anemia. Two groups were made, one group was given ferrous sulphate and the other group ferrous bis-glycinate at a dose of 5 mg/kg/day, single daily dose. Patient were followed 04 weekly till 12 weeks and then baselines reviewed. Results: Out of these total 108 children, 64 (59.3%) were male while the remaining 40.7% were female, with mean age was 27.48 in months with SD of 14.1. Iron therapy succefully raised Hb by 3.49 gm/dl as a whole with in Iron Bis –glycinate group as 3.85d/dl while 3.13gm /dl in ferrous sulphate group. The frequency of gastrointestinal adverse symptoms were less in bis-glycinate group. Conclusions: It was concluded that ferrous bis-glyicante has better efficacy to ferrous sulphate in term of Hb rising and has less gastrointestinal side effects.

Gene expression levels and inhibitory effect of 7-[(7-methoxy-4,5-dihydro-1H-benzo[g]indazol-3-yl)carbonyl]-2-phenyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[4,3-d]Pyrimidin-9(1H)-one (MCL) against AP2-I and BDP1 in malaria experimental models

Resistance to antimalarial drugs leads a global recurrence of malaria, posing a significant challenge to malaria control. This study aimed to assess gene expression and resistance profiles in clinical isolates, and validate the inhibitory effect of MCL compound against PbAP2-I and PbBDP1 genes in vivo. Malaria prevalence rate throughout the clinical study period stood at 12.24%. Blood samples were obtained from 182 malaria outpatients and 30 P. berghei-infected mice treated with varying MCL concentrations. DNA and RNA were extracted. PfAP2-I, PfBDP1, PfMDR1, and PfK13 genes were amplified using Real-time qPCR and sequenced for mutation profiling. Relative gene expression of AP2-I and BDP1 genes in P. falciparum and P. berghei-treated mice was carried out by Reverse-transcription PCR. The data were analyzed using ANOVA at P<0.05 indicating a significant difference. Relative gene expression results from clinical isolates showed PfAP2-I and PfBDP1 are highly expressed in the trophozoite and schizont stages. The clinical isolates show conserved nucleotide sequences for PfAP2-I, PfBDP1, and PfK13 genes compared to the 3D7 strain. However, Asn86Tyr mutation implicated in antimalarial drug resistance and Leu1312Iso mutation not previously reported to be associated with antimalarial drug resistance were observed for the PfMDR1 gene. MCL inhibited the expression of PbAP2-I (by 4.52 and 8.08 folds) and PbBDP1 (by 37.92 and 79.07 folds) at 40µM and 50µM concentrations after a 7-day, single oral daily dose. Our findings validate MCL's inhibitory activity against AP2-I and BDP1 genes, hence representing potential new targets of antimalarial therapy for controlling malaria parasite invasion.

Extravascular Factor IX Pool Fed By Prophylaxis Is a True Hemostatic Barrier Against Bleeding

Factor IX (FIX) can bind to type-IV collagen in the endothelial basement membrane and diffuse into extravascular spaces. Previous studies in rodents have reported a large biodistribution of FIX. However, the potential hemostatic activity of extravascular FIX and its role in protecting against joint bleeds have not been demonstrated. The capacity of 4 different FIX molecules (plasma derived [pd] and recombinants) to bind type I and type IV collagen was studied here. FIX molecules were also administered intravenously at doses of 50 to 3000 IU/kg in FIX knock-out (KO) mice. A specific FIX signal was detected in immunohistochemistry in the liver as well as in muscles and knee joints with recombinant FIX molecules injected at 1000 and 3000 IU/kg but not at the usual clinical doses of 50-100 IU/kg, while pdFIX generated a FIX signal at all doses including 50 IU/kg. After five 100 IU/kg daily infusions of rFIX, a clear accumulation of FIX was seen in the liver and joints of animals having received 5-day daily FIX infusions with all FIX molecules, with a higher FIX labelling intensity compared to that observed after a single infusion of FIX 100 IU/kg or a single infusion of FIX 500 IU/kg. The extravascular procoagulant activity of FIX was assessed in saphenous vein bleeding assays performed 7 days after a single infusion of FIX 100 IU/kg. An additional group of FIX KO mice received intravenously for 5 days a single daily dose of 100 IU/Kg of one the four types of FIX concentrate in order to mimic prophylaxis. The number of clots formed in 15 minutes was significantly greater in mice having received prophylaxis during 5 days with 100 IU/kg FIX compared to untreated FIX KO mice (p=0.009) and to mice having received a single infusion of FIX 100 IU/kg (p&amp;lt;0.0001) (Figure 1). Taken together, these results show that in individuals with severe hemophilia B receiving regular prophylaxis with FIX, extravascular accumulation of FIX over time may have a significant impact on the coagulation capacity and protection towards bleeding.

Validation of a robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of VK-2019, a selective EBNA1 inhibitor.

EBNA1 is an Epstein Barr virus (EBV) protein expressed in all EBV-associated cancers. EBNA1 plays a critical role in the replication and maintenance of EBV episomes in latently infected cells. VK-2019 was developed as a highly specific inhibitor of EBNA1 DNA binding activity and is currently in phase 1 development as a treatment for EBV-associated carcinomas. A sensitive and reliable method was developed to quantify VK-2019 in human plasma using liquid chromatography with tandem mass spectrometry to perform detailed pharmacokinetic studies. VK-2019 was extracted from plasma using protein precipitation with acetonitrile. Separation of VK-2019, two purported metabolites, and the internal standard, VK-2019-d6, was achieved with a Zorbax XDB C18 column using a gradient flow over 6 min. VK-2019 was detected using a SCIEX 4500 triple quadrupole mass spectrometer operating in positive electrospray ionization mode. The assay range was 0.5-500 ng/mL and proved to be accurate and precise. Dilutions of 1:10 were accurately quantified. VK-2019 was stable in plasma at -70°C for approximately 18 months. The method was applied to assess the total plasma concentrations of VK-2019 in a patient who received a single and multiple oral daily doses of 120 mg.

Effect of safranal or candesartan on 3-nitropropionicacid-induced biochemical, behavioral and histological alterations in a rat model of Huntington's disease.

3-nitropropionic acid (3-NP) is a potent mitochondrial inhibitor mycotoxin. Systemic administration of 3-NP can induce Huntington's disease (HD)-like symptoms in experimental animals. Safranal (Safr) that is found in saffron essential oil has antioxidant, anti-inflammatory and anti-apoptotic actions. Candesartan (Cands) is an angiotensin receptor blocker that has the potential to prevent cognitive deficits. The present study aims to investigate the potential neuroprotective efficacy of Safr or Cands in 3-NP-induced rat model of HD. The experiments continued for nine consecutive days. Rats were randomly assigned into seven groups. The first group (Safr-control) was daily intraperitoneally injected with paraffin oil. The second group (Cands- and 3-NP-control) daily received an oral dose of 0.5% carboxymethylcellulose followed by an intraperitoneal injection of 0.9% saline. The third and fourth groups received a single daily dose of 50 mg/kg Safr (intraperitoneal) and 1 mg/kg Cands (oral), respectively. The sixth group was daily treated with 50 mg Safr kg/day (intraperitoneal) and was intraperitoneally injected with 20 mg 3-NP/ kg, from the 3rd till the 9th day. The seventh group was daily treated with 1 mg Cands /kg/day (oral) and was intraperitoneally injected with 20 mg 3-NP/ kg, from the 3rd till the 9th day. The present results revealed that 3-NP injection induced a considerable body weight loss, impaired memory and locomotor activity, reduced striatal monoamine levels. Furthermore, 3-NP administration remarkably increased striatal malondialdehyde and nitric oxide levels, whereas markedly decreased the total antioxidant capacity. Moreover, 3-NP significantly upregulated the activities of inducible nitric oxide synthase and caspase-3 as well as the Fas ligand, in striatum. On the contrary, Safr and Cands remarkably alleviated the above-mentioned 3-NP-induced alterations. In conclusion, Safr and Cands may prevent or delay the progression of HD and its associated impairments through their antioxidant, anti-inflammatory, anti-apoptotic and neuromodulator effects.

Live birth rate following endometrial preparation with daily versus depot GnRH agonist

Background Gonadotrophin-releasing hormone agonist (GnRHa) downregulates gonadotropin secretion in the pituitary gland. It is used both in ovulation induction protocols and in artificial endometrium preparation. Frozen—thawed embryo transfer to artificially prepared endometrium (FET-APE) is a frequent procedure in vitro fertilization (IVF) which requires GnRHa. It can be used either as a daily low-dose injection or as a single depot injection. It is unclear which of these two regimens is superior for artificial endometrium preparation. Methods We evaluated the data of 72 patients who had undergone frozen embryo transfer following the 5th day Preimplantation Genetic Test-aneuploidy (PGT-A) between 2018–2021. All embryos were genetically screened, and euploid single embryos were transferred. Group 1 (n: 36) used depot GnRHa, and Group 2 (n: 36) used single daily injections for artificial endometrial preparation. The outcomes for Beta Human Chorionic Gonadotrophin (BHCG) positivity and live birth rates (LBR) was compared. Results The BHCG positivity for Group 1 and Group 2 was 75% and 80.6%, respectively. The LBR for Group 1 and Group 2 were found to be 58.3% and 63.9%, respectively. There was no statistically significant differences between the two groups. Conclusions In artificial endometrium preparation, depot GnRHa offers cheaper and more convenient alternative to single daily dose injections, particularly in busy clinical settings.

SAT595 A Successful Long-time Experience Of A Dose-finding Approach For The Treatment Of Central Adrenal Insufficiency (CAI) With Prednisone

Abstract Disclosure: P.F. Santos-Neto: None. S.R. Correa-Silva: None. B.M. Mascarenhas Nakano: None. J. Abucham: None. Introduction: In patients with CAI, hydrocortisone (HC) is considered the preferred treatment. Recommended daily doses are based on estimates of daily cortisol production which have recently been decreased. Doses in the upper part of the previously suggested range have been associated with higher cardiovascular morbimortality. Currently recommended HC replacement doses have been reduced. In our country, HC has never been commercially available in tablets, but prednisone, an intermediate action glucocorticoid available in 5mg and 20mg tablets (lower doses are available elsewhere) is easily found, at low cost, and doesn't need prescription. Aim: To analyze our experience with prednisone in patients with CAI using the same dose-finding protocol established four decades ago. Patients: Data were extracted from electronic files. After applying inclusion/exclusion criteria, 72 out of 96 patients entered the study. Inclusion criteria: &amp;gt;18y, last consultation &amp;lt;2y, stable and same daily doses of prednisone, stable replacement of thyroid and sex hormone deficits in the last year. Exclusion criteria: Cushing´s disease, alternating prednisone doses, non-controlled acromegaly, intestinal malabsortion, other diseases requiring glucocorticoid, hepatic insufficiency. Dose-finding Protocol: Starting doses of prednisone in outpatients are usually 2.5mg or 5.0mg. Thereafter, dose adjustments are done according to clinical signs and symptoms and a pre-defined minimal dose of 2.5mg is attempted in all patients. Patients requiring &amp;gt;2.5mg are changed to 5.0mg, and then suggested to decrease to 3.75mg (3/4 of a 5.0mg tablet). If 3.75mg doses are judged insufficient, we return to 5.0mg; if unpractical, we suggest to alternate doses or to return to 5.0mg. Statistical Analysis: Patients were divided in two groups according to the prednisone daily dose. Group comparisons: Student´s t-test and Fisher´s exact test. P&amp;lt;0.05 was set as significant. Results: Fifty-four patients were on 2.5mg (75%) and 18 patients were on 5.0mg (25%) of prednisone. None was on GH replacement. The 5mg group tended to be younger (P=0.06). No significant differences (0.10&amp;lt;P&amp;lt;1.0) were found in relation to sex, treatment duration, BMI (both at diagnosis and last visit), other hormone deficiencies, IGF-1 levels, diabetes mellitus, dyslipidemia, and hypertension between the two groups. Conclusions: Adult patients with CAI are successfully treated with a single daily morning dose of prednisone determined by a dose-finding approach. In the absence of GH replacement, most patients stay at 2.5mg and the remaining ones at 5.0mg. The lack of difference between doses in parameters of excessive glucocorticoid exposure indicates that our approach is able to adjust prednisone doses close to individual requirements. A broader range of doses from &amp;lt;2.5mg including intermediate doses &amp;lt;5mg should be tried if low dose tablets are available. Presentation: Saturday, June 17, 2023

The role of opicapone in the management of Parkinson's disease: an Italian consensus through a combined Nominal Group Technique and Delphi approach.

Opicapone (OPC) is a third-generation peripheral catechol-O-methyl transferase inhibitor (COMT-i) approved as add-on therapy to levodopa/DOPA decarboxylase inhibitors (DDCI) combinations in Parkinson's disease (PD) patients with end-of-dose motor fluctuations. While the OPC effectiveness on motor symptoms is well known, there is still uncertainty about the timing of introduction, the management of levodopa dose, and the efficacy on non-motor symptoms (NMS). A group of PD experts participated in a consensus activity composed of the Nominal Group Technique (NGT) and the Delphi method to better define the role of OPC. A list of statements was defined with the NGT and voted on through an online Delphi process by a panel of 85 Italian clinicians. 24 statements were selected for the Delphi voting. Most statements (n=15, 62%) reached a consensus. A wide agreement was reached about the efficacy of OPC in treating motor fluctuations, including early morning akinesia and nocturnal akinesia. The panel widely agreed about the effectiveness of OPC in early fluctuating patients. The long-lasting inhibitory effect of OPC was recognized as an advantage over other COMT-i, resulting in a single daily dose and greater ease of introduction into the levodopa therapeutic regimen. The efficacy of OPC observed in the clinical trials for the management of PD patients with motor fluctuations is also experienced in clinical practice. The review of the current positioning of OPC from the late to early stages of the disease may represent an important step in the evolution of the PD therapeutic approach.

Histopathological Effects of Supercypermethrin in Liver of Albino rats

Histopathological alterations histochemistry and Biochemical parameters were used to assess the toxicity of the commercial pesticide (cypermethrin) on the liver tissue of male albino rats. 48 rats were used in this study. Each set of six rats was separated into four groups in the acute experiment. The control group was subcutaneously injected with distilled water, while the other three were injected subcutaneously with the insecticide at different concentrations (0.050, 0.025, 0.10). At these different concentrations, acute toxicity was assessed. A)er 24 hours, the mortality rate and poisoning signs increased with the increase in the concentration of the pesticide. As for the subacute toxicity experiment, 4 groups were used in this experiment with 6 animals in each. a control group injected with distilled water only, and another group injected with 0.025 as a single daily dose for 10, 20, and 30 days, respectively. This pesticide In the three separate times, caused some histopathological and biochemical changes in the treated groups in liver tissues and some biochemical changes in liver function were recorded, including Alanine Transaminase(ALT), Aspartate Transaminase (AST), and the levels of protein were measured in the serum. The researchers determined that cypermethrin has acute and subacute toxic effects, which manifested as alterations in serum enzymes and histopathological abnormalities in liver tissue.

Novel, non-colonizing, single-strain live biotherapeutic product ADS024 protects against Clostridioides difficile infection challenge in vivo.

The Centers for Disease Control and Prevention estimate that Clostridioides difficile (C. difficile) causes half a million infections (CDI) annually and is a major cause of total infectious disease death in the United States, causing inflammation of the colon and potentially deadly diarrhea. We recently reported the isolation of ADS024, a Bacillus velezensis (B. velezensis) strain, which demonstrated direct in vitro bactericidal activity against C. difficile, with minimal collateral impact on other members of the gut microbiota. In this study, we hypothesized that in vitro activities of ADS024 will translate in vivo to protect against CDI challenge in mouse models. To investigate the in vivo efficacy of B. velezensis ADS024 in protecting against CDI challenge in mouse models. To mimic disruption of the gut microbiota, the mice were exposed to vancomycin prior to dosing with ADS024. For the mouse single-dose study, the recovery of ADS024 was assessed via microbiological analysis of intestinal and fecal samples at 4 h, 8 h, and 24 h after a single oral dose of 5 × 108 colony-forming units (CFU)/mouse of freshly grown ADS024. The single-dose study in miniature swine included groups that had been pre-dosed with vancomycin and that had been exposed to a dose range of ADS024, and a group that was not pre-dosed with vancomycin and received a single dose of ADS024. The ADS024 colonies [assessed by quantitative polymerase chain reaction (qPCR) using ADS024-specific primers] were counted on agar plates. For the 28-d miniature swine study, qPCR was used to measure ADS024 levels from fecal samples after oral administration of ADS024 capsules containing 5 × 109 CFU for 28 consecutive days, followed by MiSeq compositional sequencing and bioinformatic analyses to measure the impact of ADS024 on microbiota. Two studies were performed to determine the efficacy of ADS024 in a mouse model of CDI: Study 1 to determine the effects of fresh ADS024 culture and ADS024 spore preparations on the clinical manifestations of CDI in mice, and Study 2 to compare the efficacy of single daily doses vs dosing 3 times per day with fresh ADS024. C. difficile challenge was performed 24 h after the start of ADS024 exposure. To model the human distal colon, an anerobic fecal fermentation system was used. MiSeq compositional sequencing and bioinformatic analyses were performed to measure microbiota diversity changes following ADS024 treatment. To assess the potential of ADS024 to be a source of antibiotic resistance, its susceptibility to 18 different antibiotics was tested. In a mouse model of CDI challenge, single daily doses of ADS024 were as efficacious as multiple daily doses in protecting against subsequent challenge by C. difficile pathogen-induced disease. ADS024 showed no evidence of colonization based on the observation that the ADS024 colonies were not recovered 24 h after single doses in mice or 72 h after single doses in miniature swine. In a 28-d repeat-dose study in miniature swine, ADS024 was not detected in fecal samples using plating and qPCR methods. Phylogenetic analysis performed in the human distal colon model showed that ADS024 had a selective impact on the healthy human colonic microbiota, similarly to the in vivo studies performed in miniature swine. Safety assessments indicated that ADS024 was susceptible to all the antibiotics tested, while in silico testing revealed a low potential for off-target activity or virulence and antibiotic-resistance mechanisms. Our findings, demonstrating in vivo efficacy of ADS024 in protecting against CDI challenge in mouse models, support the use of ADS024 in preventing recurrent CDI following standard antibiotic treatment.

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease

Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations. To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations. RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial. Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks. The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period. A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P < .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%). In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently. ClinicalTrials.gov Identifier: NCT03670953.

Clozapine dosing patterns and clinical outcomes in patients with treatment resistant schizophrenia

Clozapine is the only medication found to be effective for patients with treatment resistant schizophrenia-spectrum disorders (TRS) and its prescription patterns may impact on their outcomes. The study aims to explore the impact of clozapine dosing frequency, dose level and presence of pharmacological augmentation on the clinical, social and cognitive outcomes in patients with TRS. Patients with TRS and on clozapine were interviewed. Daily defined dose (DDD) and anticholinergic burden were calculated. Patients were categorized in three ways: the single daily dose (SDD) and multiple daily dose (MDD), ≤300 mg/day (LD) and >300 mg/day (HD) of clozapine, and clozapine monotherapy (MT) and augmentation therapy (AT). The impact of these clozapine prescription patterns and their interaction on patient outcomes were examined with ANOVA. Of 124 patients on clozapine, 98 patients (79%) had SDD, 59 patients (47.6%) received LD, and 58 patients (46.8%) had MT. Patients in the LD group had significantly better cognitive functions. Though no significant effect of clozapine dosing frequency on outcomes, among patients on LD, those on MDD had better processing speed, short-term and visual memory. Patients with MT had better motivation. Among patients on HD, those with MT had better motivation and vocational functioning. These results provide guidance to the clozapine prescription in a naturalistic setting to achieve optimizing outcomes for patients with TRS in social and cognitive functions. Further longitudinal studies are needed to verify the results.

Comparing therapeutic effects of alternate day versus daily oral iron in women with iron deficiency anemia: A retrospective cohort study.

In order to replenish iron stores and bring hemoglobin (Hb) levels back to normal, oral iron is the primary treatment option for women with iron deficiency anemia (IDA). This study investigated the efficacy and side effects of daily versus alternate-day, given single doses versus double doses oral iron supplementation for treating IDA. A retrospective cohort study was performed between 2021 and 2022, including 120 patients. Study group were divided into 4 age-sex-matched groups; Group I (n = 30) and Group II (n = 30) which were received ferrous sulphate tablets daily in single or double doses, respectively, containing 60 mg of elemental iron each. Groups III (n = 30) and IV (n = 30) were received a single and double dose on alternate days, respectively. The primary outcome was the mean difference in Hb from baseline at week 4. Gastrointestinal (GI) side effects were accepted as a secondary outcome. The daily single dose and alternate day double dose groups had median Hb changes of 2.3 (2.1) and 2.6 (1.8) g/dL. The differences in Hb between Groups I and II, I and III, and Groups IV and II, IV and III were significant (P < .001, P = .001, P < .001, and P < .001, respectively). There is no significant difference between groups regarding improving iron parameters such as serum iron, total iron binding capacity, transferrin saturation, and ferritin. The incidence of GI side effects were greater in double doses than in single doses of daily or alternate-day therapies (43.3% and 30% vs 10% and 3.3%). Daily or alternate-day double dose resulted in more side effects but less therapeutic efficacy in women with IDA. To find the best supplementation method, randomized controlled trials with a larger sample of participants, longer study lengths, and various iron doses may be helpful.

4’-fluorouridine as a potential COVID-19 oral drug?: a review

The available antiviral drugs against coronavirus disease 2019 (COVID-19) are limited. Oral drugs that can be prescribed to non-hospitalized patients are required. The 4′-fluoruridine, a nucleoside analog similar to remdesivir, is one of the promising candidates for COVID-19 oral therapy due to its ability to stall viral RdRp. Available data suggested that 4'-fluorouridine has antiviral activity against the respiratory syncytial virus, hepatitis C virus, lymphocytic choriomeningitis virus, and other RNA viruses, including SARS-CoV-2. In vivo study revealed that SARS-CoV-2 is highly susceptible to 4'-fluorouridine and was effective with a single daily dose versus molnupiravir administered twice daily. Although 4'-fluorouridine is considered as strong candidates, further studies are required to determine its efficacy in the patients and it’s genetic effects on humans. In this review, we the antiviral activity of 4′-fluorouridine is reviewed and compared it to other drugs currently in development. The current literature on 4′-fluorouridine's antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is compiled and discussed.

Beneficial Effects of Daily Consumption of Garlic and Onion Extract Concentrate on Infectious Respiratory Diseases in Elderly Resident Volunteers.

Aging is a biological process with high susceptibility to several infections. This risk increases in older patients in residential care facilities (RCF). Thus, there is a clear demand for developing preventive interventions with new therapeutic compounds that combine efficacy and safety. This could be the case of compounds derived from plants of the genus Allium spp. The purpose of this study was to evaluate the impact of a combination of a garlic and onion extract concentrate standardized in organosulfur compounds derived from propiin on the incidence of respiratory tract infections in elderly patients of RCF. Sixty-five volunteers were selected at random to receive a placebo or a single daily dose of the extract for thirty-six weeks. Different clinical visits were performed to evaluate the main respiratory diseases with an infectious origin, as well as the associated symptoms and their duration. The extract showed a clinical safety profile and significantly reduced the incidence of respiratory infections. Moreover, the treatment decreased the number and duration of the associated symptoms compared with the placebo group. For the first time, we demonstrated the protective effect of Alliaceae extract in respiratory infectious diseases in elderly healthy volunteers, which could be used prophylactically against the most common infectious respiratory diseases.

Alpha-Mangostin ameliorates acute kidney injury via modifying levels of circulating TNF-α and IL-6 in glycerol-induced rhabdomyolysis animal model.

Alpha mangostin (AM), isolated from G. mangostana, showed beneficial effects in several disorders due to its antioxidant and anti-inflammatory properties. Acute kidney injury (AKI) due to different etiologies can develop into severe complications, resulting in high mortality rates. In this work, AM is tested for its ability to alleviate AKI in glycerol-induced AKI rat model, where 30 Male Sprague-Dawley rats were assigned to a healthy group, glycerol-treated group and AM-treated group. Glycerol- and AM groups received a single dose of glycerol (per IM, 50% glycerol in saline, 8 ml/kg), whereas control group was injected with saline. AM treatment (a single daily dose, per IP, 175mg/kg) was accomplished for three days. Animals were executed to collect blood samples and kidney tissue for biochemical and histological examination. It was found that glycerol induced increase in serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, serum magnesium, TNF-α and IL-6. It also induced renal edema and hypocalcemia along with histopathological renal damage. AM treatment improved renal histological features and alleviated increase in serum creatinine, BUN, serum magnesium, TNF-α and IL-6 levels, as well as renal edema and lipid peroxidation but did not affect serum calcium levels. This suggests AM as a potential therapeutic agent for treating AKI mainly via its antioxidant and anti-inflammatory properties.

The Effect of Metformin and Biological Therapy on Insulin Resistance in Iraqi Psoriatic Patients

Psoriasis refers to a medical condition involving long-term infl ammation, high insulin resistance, obesity and a likelihood of cardiovascular disease. Objective: This paper attempts to fi nd out if the addition of metformin to biological therapy has the benefi cial eff ect of increasing insulin sensitivity in moderate to severe Iraqi psoriatic patients. Subjects and Methods: The experimental group comprises 24 patients suff ering from moderate to severe psoriasis. They were randomly selected into two groups: group A comprises 13 psoriatic patients treated with 40 mg of adalimumab twice monthly for 12 weeks. While group B contains 11 psoriatic patients treated with 40 mg of adalimumab twice monthly and a single daily dose of 850 mg of metformin for 12 weeks. The psoriasis area and severity index (PASI), glycosylated hemoglobin (HbA1c), body mass index (BMI), as well as insulin-resistance parameters, which include fasting blood glucose (FBG) and fasting serum insulin (FSI) are estimated for each patient before and after completion of therapy. Results: The two groups showed a signifi cant reduction in insulin resistance. Nonetheless, group B showed greater reduction. Furthermore, the PASI score of the two groups exhibited improvement, but group B exhibited a higher percentage improvement than group A, and the diff erence was signifi cant (p &lt;0.05). Conclusion: This study demonstrates that adding a single daily dose of 850 mg of metformin has a more benefi cial eff ect on insulin resistance (IR) in psoriasis patients than using only biological therapy.

Myeloproliferative Neoplasms and Aspirin: Does Increased Platelet Turnover Matter?

Platelet aggregation tests and the analysis of thromboxane A2 metabolites [serum thromboxane B2 (TXB2) and urine 11-dehydro TXB2] are used to evaluate the efficacy of aspirin. In myeloproliferative neoplasms (MPNs), the immature platelet fraction (IPF) rises due to enhanced platelet turnover, and this has been thought to reduce the efficacy of aspirin. This phenomenon is overcome by the recommendation of aspirin intake in divided doses. We aimed to evaluate aspirin efficacy in patients who were receiving aspirin treatment of 100 mg/day. Thirty-eight MPN patients and 30 control patients (non-MPN patients who received a single daily dose of aspirin at 100 mg for nonhematological conditions) were enrolled. IPF, serum TXB2, and urine 11-dehydro TXB2 levels were measured and aggregation tests with arachidonic acid and adenosine diphosphate were performed by light transmission aggregometry (LTA). Mean IPF and TXB2 levels were higher in the MPN group (p=0.008 and p=0.003, respectively). IPF levels were lower in patients on cytoreductive therapy in the MPN group (p=0.001), but these values were similar between patients on hydroxyurea and the non-MPN group (p=0.72). TXB2 levels did not differ according to hydroxyurea treatment status but were higher in the MPN group compared to non-MPN patients (23.63 ng/mL and 19.78 ng/mL, respectively; p=0.04). TXB2 values were higher in patients with essential thrombocythemia and a history of thrombotic events (p=0.031). No difference was observed in LTA between the MPN and non-MPN patient groups (p=0.513). Higher levels of IPF and TXB2 in the MPN patient group indicated platelets that could not be inhibited by aspirin. It was observed that patients under cytoreductive therapy had lower IPF values, but the expected decrease in TXB2 levels was not observed. These findings suggest that a lack of response to aspirin may be due to additional intrinsic factors rather than increased platelet turnover.