Academic literature on the topic 'Stiripentol'

Introduction: This work is concerned with the stability-indicating method development and validation of Stiripentol in a bulk drug and formulation by high-performance thin-layer chromatographic method (HPTLC). Materials and Methods:The pre-coated silica gel 60 F254 aluminum plate was selected as the stationary phase, and the solvent system consisted of Ethyl acetate: Dichloromethane: Toluene (2:2:6 v/v) used as developing solvents. Analysis of Stiripentol was carried out at 301 nm with Stiripentol being detected at an R(f) of 0.63. The developed method was validated for linearity, accuracy, precision, limit of detection (LoD), limit of quantitation (LoQ), robustness parameters, and stability are determined by force degradation study. Results and Discussion: The correlation coefficient of Stiripentol was 0.994 observed. The calibration plot was linear between 50–300 ng/band, respectively. The average percentage recovery of Stiripentol was found to be 100.25 %. Intra and inter-day precision measured as %RSD was less than 2%. Hence stability study of Stiripentol, it was found to degrade in acidic condition(8.52% - 0.1N HCL for 30 minutes at room temperature), alkali condition(7.47%- 0.1 N NaOH for 30min at room temperature), Hydrolytic condition(4.73%– dist. Water for 30min at room temperature), thermal condition(7.69%-40°C for 30min ), oxidative condition(7.55% - 3% H2O2 for 30min at room temperature) and photolytic UV condition(7.54% -24hr UV radiation) respectively. Stiripentol was unstable in acidic condition and stable in normal dist. Water hydrolytic condition. Conclusion: The proposed method was found to be very sensitive and accurate for the determination of Stiripentol in bulk and formulation.

Bone structure abnormalities are increasingly observed in patients chronically treated with antiepileptic drugs (AEDs). The majority of the available data concern older conventional AEDs, while the amount of information regarding newer AEDs, including stiripentol, is limited. The aim of the study was to assess the effect of stiripentol on bones. For 24 weeks, male Wistar rats, received 0.9% sodium chloride (control group) or stiripentol (200 mg/kg/day) (STP group). In the 16th week of the study, we detected lower serum PINP levels in the STP group compared to the control group. In the 24th week, a statistically significant lower 1,25-dihydroxyvitamin D3 level, higher inorganic phosphate level and higher neutrophil gelatinase-associated lipocalin (NGAL) levels in serum were found in the STP group compared to the control. Micro X-ray computed tomography of the tibias demonstrated lower bone volume fraction, lower trabecular thickness, higher trabecular pattern factor and a higher structure model index in the stiripentol group. Considering the results of this experiment on rats which suggests that long-term administration of stiripentol may impair the cancellous bone microarchitecture, further prospective human studies seem to be justified. However, monitoring plasma vitamin D, calcium, inorganic phosphate and kidney function in patients on long-term stiripentol therapy may be suggested.

Objective: To describe the pharmacology, efficacy, and safety of stiripentol in the treatment of refractory seizures in patients with Dravet syndrome. Data Sources: A search of the English language literature was conducted using PubMed and MEDLINE (1978 to April 2019) with the search terms stiripentol, Dravet syndrome, and refractory epilepsy. Other resources included article bibliographies, prescribing information, and relevant trials at https://clinicaltrials.gov/ . Study Selection and Data Extraction: All phase 1, 2, or 3 trials; observational studies; and retrospective studies were analyzed. Data Synthesis: In controlled studies, stiripentol has been shown to reduce seizure frequency by 50% or more in 40% to 70% of patients with Dravet syndrome. Reductions in seizure duration and episodes of status epilepticus have also been documented. Common adverse effects include somnolence and anorexia. Stiripentol inhibits the metabolism of clobazam and valproate, often requiring dose adjustment. Relevance to Patient Care and Clinical Practice: Stiripentol, a direct allosteric modulator of GABAA receptors, offers a novel approach to treatment in patients with Dravet syndrome, both with and without pathogenic variants of the sodium channel α-1 subunit gene, and potentially other refractory seizures. Although available outside the United States for a decade, it was only recently approved by the Food and Drug Administration for patients 2 years of age and older with Dravet syndrome taking clobazam. Conclusions: Stiripentol is an effective adjunctive therapy for reducing the frequency and duration of refractory seizures in patients with Dravet syndrome. Its role in the treatment of other refractory epilepsies requires further study.

A rapid, simple, sensitive, and accurate isocratic reversed-phase stability-indicating high performance liquid chromatography method has been developed and validated for the determination of stiripentol and its degradation product in its bulk form and pharmaceutical dosage form. Chromatographic separation was achieved on a Symmetry C18 column and quantification was achieved using photodiode array detector (DAD). The method was validated in accordance with the ICH requirements showing specificity, linearity (r2=0.9996, range of 1–25 μg/mL), precision (relative standard deviation lower than 2%), accuracy (mean recovery100.08±1.73), limits of detection and quantitation (LOD = 0.024 and LOQ = 0.081 μg/mL), and robustness. Stiripentol was subjected to various stress conditions and it has shown marked stability under alkaline hydrolytic stress conditions, thermal, oxidative, and photolytic conditions. Stiripentol degraded only under acidic conditions, forming a single degradation product which was well resolved from the pure drug with significantly different retention time values. This degradation product was characterized by1H-NMR and13C-NMR spectroscopy as well as ion trap mass spectrometry. The results demonstrated that the method would have a great value when applied in quality control and stability studies for stiripentol.

ZusammenfassungIn den vergangenen sechs Jahren wurden in Deutschland sechs neue Antikonvulsiva zugelassen: Pregabalin, Rufinamid, Zonisamid, Lacosamid, Stiripentol und Eslicarbazepin-acetat. Teilweise handelt es sich um Substanzen, die über neue Mechanismen ihre erregungshemmende Wirkung entfalten, teilweise um die Weiterentwicklung bestehender Antikonvulsiva. Diese neuen Medikamente sind bislang entweder nur bei Erwachsenen oder als sogenannte Orphan Drugs nur sehr eingeschränkt zugelassen.Im Folgenden werden die genannten neuen Antikonvulsiva hinsichtlich ihrer Zulassungen, Wirkmechanismen und Nebenwirkungsprofile kurz charakterisiert. Die vor allem für Kinder und Jugendliche relevanten bisherigen Studiendaten werden genannt.Diese neuesten Antikonvulsiva dürften vor allem als Zusatztherapie auch in der Pädiatrie künftig vielversprechende Therapieoptionen bieten.

Trois études observationnelles chez des patients épileptiques (6 mois-18 ans) ont été réalisées respectivement pour le levetiracetam (KEPPRAPOP), le stiripentol (STIPOP), et le valproate de sodium sous forme de microgranules (VAPOP). Par une approche de population, utilisant le logiciel NONMEM, les covariables pouvant expliquer une part de la variabilité interindividuelle des paramètres PKs ont été analysés. L’étude de la PK du lévétiracetam a mis en évidence l’absence d’interaction médicamenteuse significative, que le poids corporel était la seule covariable retrouvée comme pouvant expliquer la variabilité interindividuelle de la clairance du médicament ainsi que de son volume de distribution (Vd) et qu’une dose de 10 mg/kg 2 fois par jour chez l’enfant correspond, en terme d’AUC, à 500 mg 2 fois par jour chez l’adulte. L’étude de la PK du stiripentol a été réalisée, en condition réelle d’utilisation, c’est à dire en association au valproate de sodium et au clobazam, dans le syndrome de Dravet. Il est apparu au cours de cette étude que la clairance et le Vd du stiripentol étaient liés au poids. En revanche, le sexe et le génotype CYP2C19 n’avaient aucune influence sur la cinétique du stiripentol. L’étude PK du valproate de sodium (microgranules) a montré que la clairance et le Vd variaient selon le poids et que la clairance dépendait également de la dose journalière. Des recommandations de posologie ont pu être établies pour les AUCs similaires obtenus avec les autres formes galéniques de valproate. Ces études PKs de population a permis de minimiser le nombre de prélèvements soulignant ainsi son intérêt pour évaluer la PK des médicaments dans une population pédiatrique
Three observational pharmacokinetic studies in children with epilepsy (6 months-18 years) were performed for levetiracetam (KEPPRAPOP), stiripentol (STIPOP), and valproate sodium (microspheres) (VAPOP), by using a population approach. The levetiracetam study has highlighted the lack of significant drug-drug interactions. The body weight was found the sole covariate that may explain the interindividual variability of drug clearance and its volume of distribution (Vd). A dose of 10 mg per kg twice a day in children is equivalent to 500 mg twice a day in adults, in terms of AUC. The stiripentol study was carried out under clinical practice, i. E in combination with valproate and clobazam in Dravet children. The stiripentol clearance and Vd were related to bodyweight. In contrast, the covariates sex and CYP2C19 genotype had no influence on the stiripentol PK. The valproate study showed that clearance and Vd varied with bodyweight and clearance was also dependent on the daily dose. Dosage recommendations have been established to reach the same AUC obtained with the other valproate pharmaceutical forms. These population PK studies could minimize the number of samples and confirmed their interest in the evaluation of the drugs PK used in a pediatric population

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2018
O Síndrome Dravet (SD) é uma doença rara que tipicamente se manifesta no primeiro ano de vida numa criança saudável como uma crise convulsiva prolongada, febril ou afebril, focal ou generalizada. A SD na maioria dos estudos é uma doença grave e sub-diagnosticada. O diagnóstico tardio compromete o prognóstico pois retarda a instituição de terapêutica dirigida. Para além da recorrência das crises epilépticas, há compromisso do desenvolvimento psicomotor (DPM), e a perturbação de desenvolvimento intelectual é característica. Além destes problemas fundamentais acrescem-se outros secundários, como malformações ortopédicas, alterações na marcha, dificuldades na alimentação e alterações do comportamento. A SD é causada por uma mutação no gene SCN1A em pelo menos 70% dos casos. Outros genes podem estar na origem desta síndrome, embora com fenótipos ligeiramente diferentes. A epilepsia é habitualmente refractária à terapêutica e a politerapia é quase sempre necessária. Os fármacos mais eficazes são valproato de sódio, clobazam e stiripentol. Este último fármaco é o único que demonstrou a sua eficácia num estudo cego randomizado controlado por placebo dirigido a doentes com SD. Os autores apresentam um estudo multicêntrico retrospectico que inclui 54 doentes diagnosticados com SD. Foram analisados um conjunto de características clínicas e demográficas, exames complementares de diagnóstico e terapêutica. A primeira crise foi febril em 74% dos casos. Crises tónico-clónicas generalizadas são as mais comuns tanto no primeiro ano de vida como nos seguintes. 60% dos doentes sofria de atraso global grave do desenvolvimento. Os fármacos mais prescritos foram valproato, clobazam e stiripentol (86%, 59% e 59%, respectivamente). Um quarto dos doentes não teve crises nos últimos 6 meses. A grande maioria (91%) dos doentes a quem foi feito o estudo genético tinha mutação no gene SCN1A. Mais nenhuma mutação foi identificada. Um atraso do desenvolvimento psicomotor grave não foi correlacionado com maior frequência das crises nos últimos 6 meses (c2 = 0.2911, P = 0.590).
Dravet Syndrome (DS) is a rare disease that typically presents in the first year of life in a healthy child with prolonged, febrile or afebrile, focal or generalized convulsive seizure. The disease progresses with many febrile and afebrile seizures. DS is a severe and under-diagnosed disease. Late diagnosis compromises prognosis since postpones institution of directed therapeutics. Besides the recurrent epileptic seizures, there is a psychomotor delay and severe global retardation is characteristic. Beyond these fundamental problems adds some secondary ones such as orthopaedic malformations, gait disturbances, eating and behaviour disorders. DS is caused by a mutation in the SCN1A gene in at least 70% of cases. Other genes can be at the origin of this syndrome, but with slightly different phenotypes. Epilepsy is usually therapeutic refractory and polytherapy is almost always necessary. The most effective drugs are Sodium Valproate, Clobazam and Stiripentol. The latter is the only one with efficacy demonstrated by a randomized double-blind placebocontrolled trial directed to DS patients. The authors present a multicentric retrospective study which includes 54 patients diagnosed with DS. A range of clinical and demographic characteristics, complementary studies and therapeutics data was analysed. The first seizure was febrile in 74% of the cases. Tonic-clonic generalized seizures are the most common, either on the first year of life or on the next ones. 60% of the patients suffered from severe global retardation. The most prescribed drugs were Sodium Valproate, Clobazam and Stiripentol (86%, 59% e 59%, respectively). A quarter of the patients hadn't had any crisis in the last six months. The great majority (91%) of patients which whom was made genetic study had a mutation in the SCN1A gene. Any other mutation was identified. A severe psychomotor delay was not associated with greater frequency of seizures in the last 6 months. (c2 = 0.2911, P = 0.590)

ABSTRACT INTRODUCTION. Epilepsy is one of the most common chronic neurological disorders characterized by the presence of spontaneous and recurrent seizures and it affects 1% of the population worldwide. Up to 30% of patients continue to have seizures despite an adequate and well-tolerated treatment with antiepileptic drugs (ASMs), used singularly or in combination. These individuals are regarded as having refractory or drug- resistant epilepsy. In 2010, an Internationally accepted definition of refractory epilepsy was proposed by a Task Force of International League Against Epilepsy (ILAE) as “failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules to achieve sustained seizure freedom”. Regardless of the advances in the field of epilepsy and the acquisition of new antiepileptic drugs, the proportion of drug-resistant patients remain unchanged. Dravet syndrome (DS) is a rare, drug-resistant, developmental epileptic encephalopathy with onset in infancy characterized by multiple types of frequent, disabling epileptic seizures, developmental delay/cognitive impairment and an increased risk of sudden unexpected death in epilepsy (SUDEP). In more than 80% of patients, a sodium voltage-gated channel alpha subunit 1 gene (SCN1A) genetic variant can be demonstrated, although diagnosis is based on clinical criteria. Idiopathic generalized epilepsies (IGEs) are the most common group of epilepsies in children and adolescents and include four well-characterized epilepsy syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and IGE with generalized tonic–clonic seizures only. Distinctive features of IGE syndromes are typical age of onset, specific generalized seizures type, normal background EEG activity and interictal generalized spike-and-wave (GSW) discharges in the absence of any brain lesion and with normal developmental skills. Lacosamide (LCM) is a third generation ASM approved by European Medicines Agency (EMA) and US Food and Drug Administration (FDA) as both monotherapy and adjunctive therapy in treatment of focal seizures, with or without bilateral tonic-clonic seizures, in patient older than 16 (EMA) or 17 (FDA) years old. Stiripentol (STP) is a third generation ASM indicated as adjunctive therapy in Dravet syndrome, whose seizures are not adequately controlled with clobazam and valproate. Fenfluramine (FFA) Hydrochloride is fourth generation ASMs, recently noticed as effective for the treatment of convulsive seizures and non-convulsive SE in DS. In the 2019, Zogenix supported an EAP of FFA in patients with a clinical diagnosis of DS, without echocardiographic signs of cardiac valve disfunction and pulmonary arterial hypertension and in June 2020 FDA approved FFA for the treatment of seizures in DS. Levetiracetam (LEV) is one of the most widely used ASMs for both adults and children. It is approved by EMA and FDA as adjunctive therapy in IGEs with myoclonic or tonic-clonic seizures in patients >12 years, as monotherapy in focal seizures in patients >16 years and as add-on therapy in focal or focal to bilateral tonic- clonic seizures in children and adults. AIM OF THE STUDY. To evaluate efficacy, long-term efficacy and tolerability of LCM, STP, FFA, or LEV in a cohort of children, adolescents and young adults with different types of refractory epilepsies, including focal and generalized forms and epileptic encephalopathies such as DS. METHODS. Patients treated with Study Drugs as therapy for different, refractory, types of epilepsy and seen at the Neuroscience Center of Excellence-Meyer Children Hospital in different period time were included in our studies. Data were retrospectively reviewed. Responder rate, relapse free survival and retention rate were calculated. Tolerability was assessed by reporting adverse events. RESULTS. Lacosamide: A total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add-on LCM treatment for refractory epilepsy. Thirty-four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure-free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow-up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add-on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11). Stiripentol first study: A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with DS. The median follow-up was 14.8 months (range=4 months-18 years, interquartile range=25.72). Twenty-nine individuals (22%) received more than two ASMs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals. Stiripentol second study: We expanded our analysis to a larger cohort of 196 patients with long-term follow-up. We observed a responder rate of 53% including seizure freedom in 9%. Etiology was associated with sustained response over time, with DS being the etiology with the highest responder rate (64%) at 48 months compared with syndromes with other genetic causes (13%) or unknown etiology (38%). A higher responder rate over time was also observed in patients with generalized (44%) and combined focal and generalized epilepsies (28%) than in patients with focal epilepsies (20%). The highest relapse free-survival was observed when STP was initiated at the youngest age (0-4 years) or in adulthood. Fenfluramine: Levetiracetam: A total of 88 patients with IGEs aged from 3.4 to 33.8 years, started LEV as monotherapy or add-on therapy. The median follow-up was 7.3 months (range=0.5-106 months). Thirty-four individuals (46.6%) received more than two ASMs. Thirty-five patients (39.8%) were responders, and 26 of them (29.5%) were seizure-free. The median time to LEV failure was 42 months and the median retention time was 10 months in all 88 individuals. A higher retention time was observed in patient older than 14 years. Fifty- Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. seven patients changed their therapy regimen by replacing LEV with another ASMs. Fourty-two (73.4%) remained responders at the last evaluation. About patients that replaced LEV with VPA or ETS, 23/27 (85.2%) or 9/12 (75%) were responders, respectively (p=0.19). neurological/psychiatric (17/18). CONCLUSIONS. Lacosamide: This study documents a real-world progressive and significant loss Stiripentol: suggest that STP is an effective and well-tolerated therapeutic option not only in DS but also in other epilepsy syndromes with or without an established genetic etiology, with sustained response over time. Fenfluramine: Levetiracetam: This study suggests that LEV did not result in a satisfactory clinical response in IGEs, considering their known good prognosis The most frequent adverse events were of LCM efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of LCM efficacy over time. These studies In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated. Further confirmations based on prospectively or controlled designed studies with larger population are required to confirm our data.

Glucose is transported into neurons and used as an energy source. It is also transported into astrocytes, a type of glial cell, and converted to lactate, which is then released to neurons and used as another energy source. The latter is called the astrocyte-neuron lactate shuttle. Although the lactate shuttle is a metabolic pathway, it also plays important roles in neuronal activities and brain functions. We recently reported that this metabolic pathway is involved in the antiepileptic effects of the ketogenic diet. Lactate dehydrogenase (LDH) is a metabolic enzyme that mediates the lactate shuttle, and its inhibition hyperpolarizes neurons and suppresses seizures. This enzyme is also a molecular target of stiripentol, a clinically used antiepileptic drug for Dravet syndrome. This review provides an overview of electrical regulation by the astrocyte-neuron lactate shuttle, and then introduces LDH as a metabolic target against epilepsy.

Background: Epilepsy is a complex neurological disorder, that affects 0.5 to 1% of the population, with a diversified etiology, but with emphasis on its relation with genetics. Despite there are several therapies to treat it, in some cases, this variety is still insuficiente, featuring refractory epilepsy, frequent in people with intelectual disabilities (ID). Objectives: To analyze the scientific production about refractory epilepsy and ID. Methods: Integrative literature review that searched for international articles in the Virtual Health Library (VHL), using the keywords “Intellectual disability” AND “Refractory epilepsy” with the filter: “full text”. Results: From the 27 articles found, 2 were excluded for escaping the theme, having 25 articles as a final corpus and 2 thematic axes identified: (I) Genetic aspects related to ID and refractory epilepsy and (II) Therapeutic interventions in these patients. According to studies, refractory epilepsy in people with ID is related to mutations in some genes, such as: PCDH19, FMR1, TDP2, GABRB2 and SLC9A6. As for therapies for these patients, drugs such as stiripentol, lacosamide and benzodiazepines have been used, in addition to other interventions such as vagus nerve therapies, responsive neural stimulation, ketogenic diet, immunotherapy and resection surgery. Conclusions: The ID association with refractory epilepsy is strongly linked to genetic mutations, being essencial the genetic diagnosid to individualize the treatment and overcome insuficiente therapies for this epilepsy, especially in patients with associated ID, who tend to have a reduced life quality, having as primary objective the improvement of it.

Objectives. Uncontrolled seizures in children 1 to 36 months old have serious short-term health risks and may be associated with substantial developmental, behavioral, and psychological impairments. We evaluated the effectiveness, comparative effectiveness, and harms of pharmacologic, dietary, surgical, neuromodulation, and gene therapy treatments for infantile epilepsies. Data sources. We searched Embase®, MEDLINE®, PubMed®, the Cochrane Library, and gray literature for studies published from January 1, 1999, to August 19, 2021. Review methods. Using standard Evidence-based Practice Center methods, we refined the scope and applied a priori inclusion criteria to the >10,000 articles identified. We ordered full text of any pediatric epilepsy articles to determine if they reported any data on those age 1 month to <36 months. We extracted key information from each included study, rated risk of bias, and rated the strength of evidence. We summarized the studies and outcomes narratively. Results. Forty-one studies (44 articles) met inclusion criteria. For pharmacotherapy, levetiracetam may cause seizure freedom in some patients (strength of evidence [SOE]: low), but data on other medications (topiramate, lamotrigine, phenytoin, vigabatrin, rufinamide, stiripentol) were insufficient to permit conclusions. Both ketogenic diet and the modified Atkins diet may reduce seizure frequency (SOE: low for both). In addition, the ketogenic diet may cause seizure freedom in some infants (SOE: low) and may be more likely than the modified Atkins diet to reduce seizure frequency (SOE: low). Both hemispherectomy/hemispherotomy and non-hemispheric surgical procedures may cause seizure freedom in some infants (SOE: low for both), but the precise proportion is too variable to estimate. For three medications (levetiracetam, topiramate, and lamotrigine), adverse effects may rarely be severe enough to warrant discontinuation (SOE: low). For topiramate, non-severe adverse effects include loss of appetite and upper respiratory tract infection (SOE: moderate). Harms of diets were sparsely reported. For surgical interventions, surgical mortality is rare for functional hemispherectomy/hemispherotomy and non-hemispheric procedures (SOE: low), but evidence was insufficient to permit quantitative estimates of mortality or morbidity risk. Hydrocephalus requiring shunt placement after multilobar, lobar, or focal resection is uncommon (SOE: low). No studies assessed neuromodulation or gene therapy. Conclusions. Levetiracetam, ketogenic diet, modified Atkins diet, and surgery all appear to be effective for some infants. However, the strength of the evidence is low for all of these modalities due to lack of control groups, low patient enrollment, and inconsistent reporting. Future studies should compare different pharmacologic treatments and compare pharmacotherapy with dietary therapy. Critical outcomes underrepresented in the literature include quality of life, sleep outcomes, and long-term development.