Publications by authors named "Yoseph Caraco"

Article Synopsis
  • SPL84 is an antisense oligonucleotide (ASO) drug designed to treat cystic fibrosis by correcting splicing issues in the CFTR gene, which are caused by a specific mutation leading to non-functional proteins.
  • In a phase 1 clinical trial with 32 healthy individuals, SPL84 was tested for safety and tolerability compared to a placebo, without significant adverse effects observed.
  • The results indicated that SPL84 was well-tolerated, with low systemic exposure suggesting it is safe for further development in treating cystic fibrosis.
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Molnupiravir (MOV) was introduced in Israel in January 2022 during the SARS-CoV-2 Omicron surge for high-risk patients contraindicated for nirmatrelvir/ritonavir. This retrospective cohort study aimed to describe characteristics of patients offered COVID-19 antiviral treatment in Maccabi Healthcare Services (antiviral treatment-eligible cohort; = 5596) between 12 January and 28 February 2022, and the subset of these who were dispensed MOV (MOV-treated cohort; = 1147), as well as outcomes following MOV dispensation. Median (interquartile range) age in the antiviral treatment-eligible and MOV-treated cohorts were 70.

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Article Synopsis
  • FMXIN002 is a needle-free nasal spray version of epinephrine designed to treat severe allergic reactions, aiming to overcome issues of incorrect use, cost, and shelf life associated with traditional autoinjectors.
  • In a trial with 12 adults, FMXIN002 showed a quicker absorption time compared to the EpiPen, although the results were not statistically significant.
  • Both treatments were well tolerated, with FMXIN002 exhibiting only mild, self-resolving side effects, while no adverse events were reported for the EpiPen.
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Background: Binge-eating disorder) BED) is the most common eating disorder in the United-States. Daily, orally administered topiramate has shown BED treatment efficacy, with two major limitations: frequent and severe side effects and slow time-to-effect. SipNose is a novel non-invasive intranasal direct nose-to-brain drug delivery platform that delivers drugs to the central nervous system consistently and rapidly.

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Background: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells.

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ABBV-47D11 is a neutralizing monoclonal antibody that targets a mutationally conserved hydrophobic pocket distal to the ACE2 binding site of SARS-CoV-2. This first-in-human safety, pharmacokinetics, and antiviral pharmacodynamic assessment in patients with COVID-19 provide an initial evaluation of this antibody that may allow further development. This multicenter, randomized, double-blind, and placebo-controlled single ascending dose study of ABBV-47D11 (180, 600, or 2400 mg) as an intravenous infusion, was in hospitalized and non-hospitalized (confined) adults with mild to moderate COVID-19.

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Background: While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery.

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Ritonavir-boosted nirmatrelvir (RBN) has been authorized recently in several countries as an orally active anti-SARS-CoV-2 treatment for patients at high risk of progressing to severe COVID-19 disease. Nirmatrelvir is the active component against the SARS-CoV-2 virus, whereas ritonavir, a potent CYP3A inhibitor, is intended to boost the activity of nirmatrelvir by increasing its concentration in plasma to ensure persistence of antiviral concentrations during the 12-hour dosing interval. RBN is involved in many clinically important drug-drug interactions both as perpetrator and as victim, which can complicate its use in patients treated with antiseizure medications (ASMs).

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Background: CYP2C9 is a member of the cytochrome P450 (CYP) superfamily responsible for the metabolism of 16% of drugs that undergo oxidative metabolism. The activity of CYP2C9 exhibits marked inter-individual variability, which translates into prominent differences in the pharmacokinetics of CYP2C9 substrates, some of which are characterized by a narrow therapeutic window. Genetic polymorphisms in the gene encoding for CYP2C9 account for a fraction of the variability in CYP2C9 activity.

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Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity.

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The emergence of rapidly spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a major challenge to the ability of vaccines and therapeutic antibodies to provide immunity. These variants contain mutations of specific amino acids that might impede vaccine efficacy. BriLife (rVSV-ΔG-spike) is a newly developed SARS-CoV-2 vaccine candidate currently in phase II clinical trials.

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BACKGROUND: Safe and effective oral treatments are needed to improve clinical outcomes for nonhospitalized patients with Covid-19. Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug shown to inhibit replication of severe acute respiratory syndrome coronavirus 2 in vitro and in animal models. METHODS: MOVe-OUT is an ongoing, phase 2/3, randomized, placebo-controlled, double-blind study evaluating the safety, efficacy, and pharmacokinetics of molnupiravir in nonhospitalized adults.

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Background: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness.

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Introduction: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations.

Methods: This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC.

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The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism.

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The pharmacokinetics of CYP2C9 substrates is characterized by substantial interethnic variability. The objective of the study was to compare CYP2C9 activity by using Phenytoin Metabolic Ratio (PMR) between Ethiopian and non-Ethiopian Jews. PMR was derived from the ratio of p-HPPH in 24 h urine collection to plasma phenytoin, 12 h (PMR24/12) or 24 h (PMR24/24) after the administration of 300 mg phenytoin.

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Objectives: Although commercially available levodopa (LD) formulations include carbidopa (CD) or benserazide for gastrointestinal L-aromatic amino acid decarboxylase inhibition, little is known how manipulating CD delivery affects the pharmacokinetics of LD. Our research systematically evaluated the peripheral and central pharmacokinetics of LD during continuous subcutaneous CD delivery.

Methods: We conducted pharmacokinetic experiments in pigs, mice, and humans to characterize effects of continuous subcutaneous CD delivery co-administered with LD as compared with oral LD/CD administration on LD pharmacokinetics.

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Objective: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy.

Methods: UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks.

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Background: The initial rise in INR following warfarin is attributed to rapid decline in coagulation factor VII (F7). The R353Q polymorphism in F7 accounts for approximately 1/3 of the variability in F7 activity (FVIIc).

Objective: Evaluate the role of R353Q in the initial response to warfarin.

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Objectives: Prolonged activation of the β-1 adrenergic receptor (ADRB1) is associated with receptor desensitization. This process has been suggested to have important pathophysiological and clinical implications in conditions such as congestive heart failure. The contribution of genetic factors to this process is a subject of ongoing research.

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The potential of the high-affinity CXCR4 antagonist BL-8040 as a monotherapy-mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019). The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open-label phase, in which 8 subjects received a single injection of BL-8040 (1 mg/kg) and approximately 4 hours later underwent a standard leukapheresis procedure.

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Objective: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM.

Methods: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS).

Results: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described.

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Objectives: To compare 24-month outcomes of participants of a prospective randomized controlled trial (RCT) assigned to undergo a medication intervention of orally communicated recommendations based on Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) (intervention group) with outcomes of those assigned to undergo written medication review (control group).

Design: Retrospective cohort study.

Setting: Chronic care geriatric facility.

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Background: Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions.

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