Dalal H Elsori

Bio: Dalal H Elsori is an academic researcher from Brown University. The author has contributed to research in topics: Autism & Decompensation. The author has an hindex of 1, co-authored 12 publications receiving 7 citations.

A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy

Abstract: Cystic fibrosis (CF) is a potentially fatal genetic disease that causes serious lung damage. With time, researchers have a more complete understanding of the molecular-biological defects that underlie CF. This knowledge is leading to alternative approaches regarding the treatment of this condition. Trikafta is the third FDA-approved drug that targets the F508del mutation of the CFTR gene. The drug is a combination of three individual drugs which are elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA). This trio increases the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) protein and reduces the mortality and morbidity rates in CF patients. The effectiveness of Trikafta, seen in clinical trials, outperforms currently available therapies in terms of lung function, quality of life, sweat chloride reduction, and pulmonary exacerbation reduction. The safety and efficacy of CFTR modulators in children with CF have also been studied. Continued evaluation of patient data is needed to confirm its long-term safety and efficacy. In this study, we will focus on reviewing data from clinical trials regarding the benefits of CFTR modulator therapy. We address the impact of Trikafta on lung function, pulmonary exacerbations, and quality of life. Adverse events of the different CFTR modulators are discussed.

Dose-Dependent Aripiprazole-Induced Stuttering in a Child With Mild Intellectual Disability.

Abstract: To the Editor: An 11-year-old Kuwaiti boy with mild intellectual disability (nonsyndromic, nonepileptic, verbal, 35 Kg) was referred from developmental pediatrics for behavioral dyscontrol that failed to respond to behavioral modification. No environmental or medical causes for this behavioral decompensation could be detected. He has been trialled previously on risperidone with favorable outcome but at the expense of enormous weight gain. At parents’ request, swapping to the more metabolic friendly aripiprazole was pursued. He was started on 2 mg/d for a week. The dose was uptitrated to 5 mg/d over 2 weeks with only mediocre response. At 10 mg/d after 4 weeks, parents reported a tangible response in accordance with school records (special setting). However, at that dose, parents have noticed their child beginning to stutter. Neurological examination was unrevealing. Oto-rhino-laryngological consult was summoned with negative yield. Blood levels were obtained and read 85 ng/mL (ruled out toxic levels). Electroencephalogram was performed to rule out/in a remote possibility of epileptogenicity and nothing abnormal detected. Although no other (somatic/psychic) concomitants of anxiety could be probed on mental status examination, we adopted a rather lower threshold to introduce clonazepam at 0.75 mg/d. After 2 weeks, no improvement was seen regarding stuttering, which becomes socially embarrassing. Clonazepam was discontinued. Aripiprazole dose was reduced to 5 mg/d. Stuttering, lo and behold, has totally abated over 10 days. Behavioral facets, unfortunately, re-emerged. With cautiously increasing the dose back to 10 mg, stuttering reappeared. Naranjo Adverse Drug Reaction Probability scale scored 9 (definite). Aripiprazole, as the culprit agent, was then discontinued and replaced with risperidone again at 1 mg/d. Add-on metformin 1000 mg/d was coprescribed, and a dietary advice was sought out. Two months have elapsed at time of writing this report, and the child keeps faring well on risperidone with great tolerability. No stuttering anymore. Parents’ viva voce consent to report this case anonymously was obtained beforehand. Stuttering (or stammering/DSM-5 childhood-onset fluency disorder) describes disturbance in both timing and fluency of speech inappropriate to age. This is typified with the repetition and prolongation of sounds and syllables. Cluttering is the visual analogue of stuttering. Two types of stuttering are characterized in literature; viz. as developmental and nondevelopmental (acquired). Nondevelopmental stuttering may begin suddenly at any age and may be seen rarely due to the adverse effects of drugs.1 Nondevelopmental stuttering is rare and possibly dose-dependent side effect that has been reported with antipsychotics.2 Early reports suggested that antipsychotic-induced stuttering can be envisioned as an extrapyramidal syndrome.3 This has, however, been debunked by the fact that add-on anticholinergic benztropine failed to bring about any efficacy. Some has opined that stuttering could be a harbinger of future seizure.4 By contrast, developmental stuttering, based on functional imaging studies, has been ascribed to increased hyperdopaminergic tone in striatum, and hence the robust response to antipsychotic treatment, including aripiprazole.5 Abnormal patterns of cerebral hemispheric dominance in both anterior and posterior language areas might also be contributory.6 Immune-based mechanisms were also suggested as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection).7 Aripiprazole-induced stuttering has similarly been reported previously in a 34-year-old woman with paranoid schizophrenia at 30 mg.8 In our case, stuttering developed at a relatively low dose. Intellectual disability population might have a heightened vulnerability. Mechanistically, it is difficult to explain the differential effects of risperidone, which has a potent dopaminergic D2 blockade. Aripiprazole D2 tenacity could be a factor.9 Psychotropic-induced dysarthria, including stuttering, should always alert clinicians to possible neurotoxicity. If this is ruled out, nondevelopmental stuttering might be a American Journal of Therapeutics 0, 1–2 (2020)

A Case of Prepubertal Low-Functioning Autism With Behavioral Decompensation Favorably Responding to Tianeptine.

Abstract: Copyright © maladaptive challenging behaviors. Pharmacotherapy is indicated once psychosocial and educational interventions (eg, Lovaas' applied behavior analysis) prove ineffective, inadequate, or inaccessible. A sound evidence-base supports the use of atypical antipsychotics to address these behavioral facets. This is reflected in Food and Drug Administration approval of both risperidone (5–16 years) and aripiprazole (6–17 years) to tackle severe irritability (self-injury, tantrums, and aggression). Unfortunately, these agents are plaguedwith heinous neurohormonal and cardiometabolic (diabesity) adverse effects, in this population who are at a heightened vulnerability by virtue of neurodisability and young age. These problem behaviors could interfere with acquisition of more functional and adaptive behaviors, add to caregivers' distress, and are a primary reason for referral to a child psychiatrist. These include, inter alia, attention-deficit/hyperactivity disorder symptom profile, severe irritability, aberrant sleeping and eating patterns, inappropriate sexuality, and comorbid anxiety, mood disorders, catatonia, or tics. There is then a pressing need to explore agents that are both efficacious and tolerable. Here, we report a case of essential ASD and moderate intellectual disability with a severe behavioral component that failed multiple psychotropic trials either for ineffectiveness or poor tolerability issues. Interestingly, the case has ultimately responded favorably to the atypical antidepressant, tianeptine at 25 mg/d with great tolerability. Response was well sustained over a 30-week duration at the time of writing up this report. Tianeptine is uniquely a selective serotonin reuptake enhancer antidepressant. It additionally enhances extracellular dopamine in nucleus accumbens and is a μ opiate agonist, hence possessing an abuse potential. It has also been demonstrated to normalize stress-induced glutamate excitotoxicity in

Supramaximal Dose of Ecitalopram-Associated Hematuria in an Adolescent With Obsessive-Compulsive Disorder: A Case Report.

Abstract: adding fluvoxamine would have increased the serum level of fluoxetine and norfluoxetine more significantly than by their own “autoinhibition” effect. As a limitation of our case and owing to the lack of laboratory facility, we were not able to measure serum level of fluoxetine and its metabolite. So here, the possibility of enhanced pharmacodynamics effect from the combined forces of fluvoxamine and residual norfluoxetine cannot be excluded. Although fluvoxamine was tapered over a week, potent inhibition of its metabolizer CYP2D6 by fluoxetine and norfluoxetine is crucial and has a clinically significant role in the metabolism of fluvoxamine, so it may explain the gradual reduction in prolactin level. Second, as hyperprolactinemia and galactorrhea have been reported more commonly with escitalopram than fluvoxamine, but pharmacodynamically, it is very difficult to explain why one SSRI would seem to work better for OCD than another SSRI. It shows that while having a similar mechanism of action as of other SSRIs, an individual SSRI molecule can still differ in its therapeutic and side effect profile. In such cases, it is not always possible to predict how interaction occurs and which drug is more actively inhibiting the metabolism of another drug, or vice versa, unless we have the serum levels of all drugs. Clinically, there is a potential need to find out possible confounders and significant pharmacological drug interactions. This necessitates the regular monitoring of serum level of SSRIs by keeping a watch on patients' clinical symptoms, which can help clinicians in understanding and avoiding or minimizing the potential side effects of drugs. The growing evidence toward SSRI-associated alteration in the serum prolactin level also necessitates for a large sample size study in the future to understand the pathophysiological effect of SSRIs on the hypothalamicpituitary-adrenal axis.

Molecular Structures Reveal Synergistic Rescue of Δ508 CFTR by Trikafta Modulators

Abstract: The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo–electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function. Description How three drugs restore function Cystic fibrosis is caused by defects in a chloride channel crucial for proper fluid balance and secretion. Deletion of a single amino acid, phenylalanine 508 (Δ508), is the most common mutation and leads to misfolding and degradation of the protein before it can reach cell surfaces. Fiedorczuk and Chen determined the structures of the Δ508 channel bound to three drugs that are given in combination therapy to correct folding and potentiate the channel. They uncovered a binding site for one of the drugs, a dual function corrector and potentiator, that was not previously known. The structures showed only a partial correction of folding when only one corrector was provided, but full correction was achieved when type I and III correctors were bound. —MAF Molecular structures reveal how three drugs rectify the effects of the most common CFTR mutant in cystic fibrosis.

Safety and tolerability of antipsychotic agents in neurodevelopmental disorders: a systematic review.

Abstract: Neurodevelopmental disorders (NDDs) are a group of complex and heterogeneous disorders, caused by the disruption of normal brain development. Antipsychotic agents are frequently used in these disor...

Impact of CFTR Modulators on Beta-Cell Function in Children and Young Adults with Cystic Fibrosis

Abstract: Background: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). Methods: In this study, 21 CF patients aged 10–25 underwent oral glucose tolerance test (OGTT) before and after 12–18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. β-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between β-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. Results: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. Conclusions: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

Elexacaftor-Tezacaftor-Ivacaftor as a Final Frontier in the Treatment of Cystic Fibrosis: Definition of the Clinical and Microbiological Implications in a Case-Control Study

Abstract: The use of modulator drugs that target the Cystic Fibrosis transmembrane conductance regulator (CFTR) is the final frontier in the treatment of Cystic Fibrosis (CF), a genetic multiorgan disease. F508del is the most common mutation causing defective formation and function of CFTR. Elexacaftor-tezacaftor-ivacaftor is the first triple combination of CFTR modulators. Herein, we report on a one-year case-control study that involved 26 patients with at least one F508del mutation. Patients were assigned to two similar groups, and patients with the worse clinical condition received treatment with the triple combination therapy. The study aimed to define the clinical and especially microbiological implications of treatment administration. The treatment provided significant clinical benefits in terms of respiratory, pancreatic, and sweat function. After one year of therapy, airway infection rates decreased and pulmonary exacerbations were dramatically reduced. Finally, treated patients reported a surprising improvement in their quality of life. The use of triple combination therapy has become essential in most CF people carrying the F508del mutation. Although the clinical and instrumental benefits of treatment are thoroughly known, further investigations are needed to properly define its microbiological respiratory implications and establish the real advantage of life-long treatment with elexacaftor-tezacaftor-ivacaftor.

Cystic Fibrosis Patients with F508del/Minimal Function Genotype: Laboratory and Nutritional Evaluations after One Year of Elexacaftor/Tezacaftor/Ivacaftor Treatment

Abstract: The last ten years have been characterized by an enormous step forward in the therapy and management of patients with Cystic Fibrosis (CF), thanks to the development and combination of Cystic Fibrosis Transmembrane Receptor (CFTR) correctors and potentiators. Specifically, the last approved triple combination elexacaftor/tezacaftor/ivacaftor has been demonstrated to improve lung function in CF patients with both homozygous Phe508del and Phe508del/minimal function genotypes. Here we have assessed the effect of elexacaftor/tezacaftor/ivacaftor in patients carrying the Phe508del/minimal function genotype (n = 20) after one year of treatments on liver function and nutrient absorption with a focus on lipid metabolism. We show that weight, BMI, and albumin significantly increase, suggesting a positive impact of the treatment on nutrient absorption. Furthermore, cholesterol levels as a biomarker of lipid metabolism increased significantly after one year of treatment. Most importantly, we suggest that these results were not dependent on the diet composition, possibly indicating that the drug improves the hepatic synthesis and secretion of proteins and cholesterol.