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1.
J Transl Med ; 21(1): 122, 2023 Feb 14.
Article in English | MEDLINE | ID: mdl-36788520

ABSTRACT

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. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. METHODS: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 106 AstroRx® cells and 5 patients with 250 × 106 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). RESULTS: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 106 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 106 AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. CONCLUSIONS: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 106 or 250 × 106 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. TRIAL REGISTRATION: NCT03482050.


Subject(s)
Amyotrophic Lateral Sclerosis , Mesenchymal Stem Cell Transplantation , Humans , Amyotrophic Lateral Sclerosis/therapy , Astrocytes , Injections, Spinal , Mesenchymal Stem Cell Transplantation/methods
2.
Clin Pharmacokinet ; 61(9): 1219-1236, 2022 09.
Article in English | MEDLINE | ID: mdl-35895276

ABSTRACT

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). Interactions between RBN and ASMs are bidirectional. As perpetrator, RBN may increase the plasma concentration of a number of ASMs that are CYP3A4 substrates, possibly leading to toxicity. As victims, both nirmatrelvir and ritonavir are subject to metabolic induction by concomitant treatment with potent enzyme-inducing ASMs (carbamazepine, phenytoin, phenobarbital and primidone). According to US and European prescribing information, treatment with these ASMs is a contraindication to the use of RBN. Although remdesivir is a valuable alternative to RBN, it may not be readily accessible in some settings due to cost and/or need for intravenous administration. If remdesivir is not an appropriate option, either bebtelovimab or molnupiravir may be considered. However, evidence about the clinical efficacy of bebtelovimab is still limited, and molnupiravir, the only orally active alternative, is deemed to have appreciably lower efficacy than RBN and remdesivir.


Subject(s)
COVID-19 Drug Treatment , Epilepsy , Antibodies, Neutralizing , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Epilepsy/drug therapy , Humans , Ritonavir/therapeutic use , SARS-CoV-2
3.
Clin Pharmacol Ther ; 112(1): 156-163, 2022 07.
Article in English | MEDLINE | ID: mdl-35426132

ABSTRACT

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. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)-warfarin. Single 300-mg phenytoin and 20-mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)-warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin in 24-hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)-warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no-function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti-inflammatory drugs, or siponimod.


Subject(s)
Cytochrome P-450 CYP2C9 , Phenytoin , Warfarin , Alleles , Anticoagulants/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Genotype , Humans , Phenytoin/pharmacokinetics , Warfarin/pharmacokinetics
4.
BMC Pharmacol Toxicol ; 21(1): 47, 2020 06 29.
Article in English | MEDLINE | ID: mdl-32600424

ABSTRACT

BACKGROUND: In acute intoxication, carbamazepine concentration above 40 mcg/ml is associated with a risk of severe neurological consequences, including depressed consciousness, respiratory depression, cardiac conduction disorders, seizures, and death. Carbamazepine intoxication is often associated with the use of concomitant medications. However, the effect of exposure to other central-nervous-system (CNS) acting medications on the neurological manifestations of carbamazepine toxicity has not been evaluated. OBJECTIVE: To examine the effect of exposure to CNS-acting medications on the neurological effects of carbamazepine toxicity. METHODS: A retrospective nested case-control study of all patients > 18 years of age, with at least one test of carbamazepine levels > 18 mcg/ml recorded at the Hadassah Hospital Central Laboratory, between the years 2004-2016. Sociodemographic and clinical data were collected from the computerized medical records, and the characteristics of patients with and without severe neurological symptoms of carbamazepine intoxication were compared. RESULTS: Eighty patients were identified. In bivariate analyses, the odds of severe neurological symptoms was higher in patients with antidepressants use (odds ratio 8.7, 95% confidence interval: 1.8-41.2, p = 0.007), benzodiazepines use (8.6, 2.0-37.1, p = 0.004), and carbamazepine concentration above 30 mcg/ml (8.1, 1.9-33.3, p = 0.004). Multivariate models demonstrated that antidepressants and benzodiazepines were associated with severe neurological manifestations during carbamazepine intoxication, independently of carbamazepine concentration over 30 mcg/ml. ICU admission was associated in multivariate analysis with antidepressants (but not benzodiazepines) use, and with carbamazepine levels > 30 mcg/ml. CONCLUSIONS: Among patients with carbamazepine intoxication, severe neurological symptoms are associated with exposure to benzodiazepines or antidepressants and with carbamazepine levels higher than 30 mcg/ml.


Subject(s)
Anticonvulsants/toxicity , Antidepressive Agents/toxicity , Benzodiazepines/toxicity , Carbamazepine/toxicity , Neurotoxicity Syndromes/epidemiology , Adult , Case-Control Studies , Drug Interactions , Female , Humans , Male , Middle Aged
5.
CNS Drugs ; 33(12): 1223-1228, 2019 12.
Article in English | MEDLINE | ID: mdl-31686406

ABSTRACT

INTRODUCTION: Factor Xa-inhibiting direct oral anticoagulants (FXa-DOACs) undergo hepatic metabolism via cytochrome P-450 (CYP450). Concomitant use of rifampicin, an inducer of these enzymes, with FXa-DOACs, has been shown to decrease FXa-DOAC concentrations in healthy subjects. Several common antiepileptic drugs (AEDs) are known to induce CYP450 enzymes as well. However, little is known regarding the impact of this potential interaction on treatment outcomes with FXa-DOACs. METHODS: We analyzed adverse event cases submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from January 2013 to December 2018. We compared the proportion of cases reporting thromboembolic and ischemic adverse events (TAIAEs) with the concomitant use of FXa-DOACs and enzyme-inducing AEDs to the proportion of cases with FXa-DOACs and other AEDs. RESULTS: During this period, 9693 adverse event cases reported concomitant use of FXa-DOACs and AEDs. Almost all reports (> 99%) involved the use of rivaroxaban or apixaban. Compared with other AEDs, enzyme-inducing AEDs were associated with an 86% increase in the odds of reporting TAIAEs [reporting odds ratio (ROR) 1.86, 95% confidence interval (CI) 1.61-2.15; p < 0.0001]. In secondary separate analyses of rivaroxaban and apixaban, enzyme-inducing AEDs were similarly associated with increased reporting of a TAIAE (ROR 1.79, 95% CI 1.50-2.12, and ROR 1.88, 95% CI 1.41-2.48, respectively). CONCLUSION: Using real world data, we observed an increase in the odds of reporting anticoagulation treatment failure among patients treated with FXa-DOACs and concomitant enzyme-inducing AEDs compared to those treated with other AEDs.


Subject(s)
Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Anticonvulsants/adverse effects , Anticonvulsants/therapeutic use , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/therapeutic use , Ischemia/chemically induced , Administration, Oral , Adverse Drug Reaction Reporting Systems , Aged , Blood Coagulation/drug effects , Female , Humans , Male , Middle Aged , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyridones/adverse effects , Pyridones/therapeutic use , Rivaroxaban/adverse effects , Rivaroxaban/therapeutic use , United States , United States Food and Drug Administration
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