ABSTRACT
BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).
Subject(s)
Adrenal Hyperplasia, Congenital , Androstenedione , Glucocorticoids , Humans , Adrenal Hyperplasia, Congenital/drug therapy , Androstenedione/blood , Female , Male , Child , Child, Preschool , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Adolescent , Double-Blind Method , HydrocortisoneABSTRACT
BACKGROUND: Lidocaine is the most commonly used local anesthetic for Mohs micrographic surgery (MMS), but given its limited half-life, postoperative pain remains a significant concern for patients. Bupivacaine is used in various surgical subspecialty procedures and has demonstrated improved pain control compared with lidocaine. However, its role in MMS is insufficiently explored. OBJECTIVE: To systematically review the current literature for reports on use of bupivacaine, traditional nonliposomal and newer liposomal formulations, for MMS. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. The MEDLINE, PubMed, and EMBASE databases were queried for articles presenting original data on the use of bupivacaine for MMS. RESULTS: Of 483 potentially relevant articles, 3 studies met final inclusion criteria, capturing a total of 253 patients involved in primary investigations comparing bupivacaine to traditional local anesthesia for MMS. Bupivacaine was well-tolerated and associated with comparable or modestly reduced intraoperative and postoperative pain and opioid use. CONCLUSION: Bupivacaine may have a role in prolonging intraoperative anesthesia, reducing acute postoperative pain, and reducing postoperative opioid use after MMS. However, large, prospective studies are needed to solidify the generalizability and clinical utility of these findings.
Subject(s)
Bupivacaine , Mohs Surgery , Humans , Mohs Surgery/adverse effects , Analgesics, Opioid , Anesthetics, Local , Pain, Postoperative/etiology , Pain, Postoperative/prevention & control , LidocaineABSTRACT
BACKGROUND: Pinch grafting has experienced a resurgence in interest in recent years, stemming from its simplicity, safety, and potential in restoring tissue integrity. While historically employed for chronic nonhealing wounds, pinch grafts have shown promise following surgical procedures, particularly those involving the lower extremities. OBJECTIVE: To systematically review the literature and present an updated overview of the current applications of pinch grafting. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In collaboration with a medical reference librarian, the PubMed, Embase, Scopus, and Web of Science databases were searched for studies reporting on the use of pinch grafting from 2000 onward. The references of each included article were also screened. RESULTS: Ten articles met final inclusion criteria. In total, 300 patients underwent pinch grafting for treatment of skin ulceration, while an additional 35 cases were performed as an alternative to primary closure following skin cancer resection. Overall, pinch grafting was safe and well tolerated, with minimal adverse outcomes reported. CONCLUSION: Pinch grafting is a safe, straightforward, and effective technique to promote the healing of chronic wounds. While the procedure shows early promise in emerging applications within dermatologic surgery, only about 10% of the reported cases involved this indication, reflecting a need for further research in this area.
Subject(s)
Skin Transplantation , Wound Healing , Humans , Skin Transplantation/methods , Dermatologic Surgical Procedures/methods , Dermatologic Surgical Procedures/adverse effects , Skin Ulcer/surgery , Skin Neoplasms/surgeryABSTRACT
BACKGROUND: Hidradenocarcinoma (HAC) is a rare adnexal carcinoma. To the best of the authors' knowledge, there are no published systematic reviews on HAC. OBJECTIVE: To incorporate a case series from the authors' institution and systematically integrate reported information to provide a reference tool for optimization of diagnosis and management. METHODS: A comprehensive MEDLINE search was conducted from database inception to 2021 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This yielded 225 studies with 165 cases of HAC. References of included articles were also searched. In addition, 9 patients with HAC were identified from the authors' institution over the past 10 years. RESULTS: The mean age of HAC presentation is 60 years with a slight male predilection (60%). The head and neck is the most commonly affected region. Over 36% of cases either presented with metastatic disease or went on to metastasize. The most common treatment type was wide local excision, followed by Mohs micrographic surgery. CONCLUSION: Early detection with accurate histologic interpretation is prudent in all cases of HAC. Wide local excision is the current first-line treatment. However, Mohs micrographic surgery offers complete marginal analysis with evidence of reduced risk of metastasis and better outcomes compared with wide local excision. Currently, there are no National Comprehensive Cancer Network guidelines for the treatment of HAC, and consensus guidelines are limited to tumor and nodal metastasis staging provided by the American Joint Committee on Cancer, eighth edition. Thus, this case series and systematic review integrates important aspects of diagnosis, workup, and management of HAC.
Subject(s)
Mohs Surgery , Sweat Gland Neoplasms , Female , Humans , Male , Middle Aged , Acrospiroma/pathology , Acrospiroma/diagnosis , Acrospiroma/surgery , Sweat Gland Neoplasms/pathology , Sweat Gland Neoplasms/surgery , Sweat Gland Neoplasms/diagnosis , Sweat Gland Neoplasms/therapyABSTRACT
BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
Subject(s)
Achondroplasia/drug therapy , Growth/drug effects , Natriuretic Peptide, C-Type/analogs & derivatives , Osteogenesis/drug effects , Achondroplasia/physiopathology , Adolescent , Biomarkers/analysis , Body Height/drug effects , Child , Child, Preschool , Collagen/blood , Cyclic GMP/urine , Dose-Response Relationship, Drug , Female , Growth Charts , Humans , Injections, Subcutaneous , Male , Natriuretic Peptide, C-Type/administration & dosage , Natriuretic Peptide, C-Type/adverse effects , Natriuretic Peptide, C-Type/therapeutic useABSTRACT
PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.
Subject(s)
Achondroplasia , Child , Male , Female , Humans , Child, Preschool , Prospective Studies , Achondroplasia/epidemiology , Achondroplasia/genetics , Achondroplasia/diagnosis , Body HeightABSTRACT
PURPOSE OF REVIEW: Therapeutic use, misuse, abuse, and diversion of controlled substances in managing chronic non-cancer pain remain a major concern for physicians, the government, payers, and patients. The challenge remains finding effective diagnostic tools that can be clinically validated to eliminate or substantially reduce the abuse of controlled prescription drugs, while still assuring the proper treatment of those patients in pain. Urine drug testing still remains an important means of adherence monitoring, but questions arise as to its relevance and effectiveness. This review examines the role of UDT, determines its utility in current clinical practice, and investigates its relevance in current chronic pain management. RECENT FINDINGS: A review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Literature was searched from year 2000 to present examining the relevance and role of UDT in monitoring chronic opioid therapy along with reliability and accuracy, appropriate use, overuse, misuse, and abuse. There are only a limited number of reviews and investigations on UDT, despite the fact that clinicians who prescribe controlled medications for chronic states commonly are expected to utilize UDT. Therefore, despite highly prevalent use, there is a limited publication base from which to draw in this present study. Regardless of experience or training background, physicians and healthcare providers can much more adequately assess opioid therapy with the aid of UDT, which often requires confirmatory testing by a laboratory for clinical and therapeutic prescribing decisions. It has become a strongly recommended aspect of pain care with controlled substances locally, regionally, and nationally. Incorporating UDT for all patients in whom chronic opioid therapy is undertaken is consistent with state and national guidelines and best practice strategies. Practice standards vary as to the frequency of UDT locally, regionally, and nationally, however.
Subject(s)
Analgesics, Opioid/therapeutic use , Analgesics, Opioid/urine , Chronic Pain/drug therapy , Chronic Pain/urine , Substance Abuse Detection/methods , Humans , Substance Abuse Detection/standardsABSTRACT
PURPOSE OF REVIEW: Acute postoperative pain reduction is a major target against the opioid crisis. While opioids have traditionally been the mainstay for postoperative analgesia, current practice has focused on a multimodal approach to pain control, including ultrasound-guided blocks with longer acting local anesthetic agents. RECENT FINDINGS: Non-steroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, are an important class of medications utilized to manage pain in the perioperative period. An additional treatment used in perioperative or postoperative pain relief is Exparel, a bupivacaine (sodium channel blocker) liposomal injectable suspension with a 3-4-day duration of action. The long-acting mechanism and formulation of Exparel consistently has demonstrated decreased opioid use and pain scores in patients undergoing many different surgical procedures. A concern is that pH negatively alters the efficacy of bupivacaine, as in cases of inflamed tissue and acidic fluid pH. For this reason, a combination medication with both meloxicam and bupivacaine has been developed, which normalizes pH and has anti-inflammatory and anti-pain conduction properties. Clinical studies demonstrate that this combination agent can be extremely beneficial in treating postoperative pain. This manuscript summarizes the newest developments with regard to liposomal bupivacaine and the non-steroidal meloxicam, their roles in effective treatment of postoperative pain, contraindications, special considerations of using these medications, and future considerations. HTX-011 pairs up a new extended-release formulation of the local anesthetic bupivacaine with meloxicam, a well-established non-steroidal anti-inflammatory drug (NSAID).
Subject(s)
Anesthetics, Local/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Bupivacaine/administration & dosage , Meloxicam/administration & dosage , Pain Management/methods , Pain, Postoperative/drug therapy , Delayed-Action Preparations/administration & dosage , Drug Therapy, Combination/methods , Humans , LiposomesABSTRACT
PURPOSE: Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI. METHODS: We documented the clinical features and molecular diagnoses of 9 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes. RESULTS: Molecular diagnoses of KS were established by identification of pathogenic variants in KMT2D (n = 5) and KDM6A (n = 4). Among the 100 infants with HI of unknown genetic etiology, a KS diagnosis was uncovered in one patient. CONCLUSIONS: The incidence of HI among patients with KS may be higher than previously reported, and KS may account for as much as 1% of patients diagnosed with HI. As the recognition of dysmorphic features associated with KS is challenging in the neonatal period, we propose KS should be considered in the differential diagnosis of HI. Since HI in patients with KS is well managed medically, a timely recognition of hyperinsulinemic episodes will improve outcomes, and prevent aggravation of the preexisting mild to moderate intellectual disability in KS.
Subject(s)
Abnormalities, Multiple/genetics , Congenital Hyperinsulinism/genetics , DNA-Binding Proteins/genetics , Face/abnormalities , Hematologic Diseases/genetics , Histone Demethylases/genetics , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Vestibular Diseases/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/physiopathology , Child, Preschool , Congenital Hyperinsulinism/complications , Congenital Hyperinsulinism/diagnosis , Congenital Hyperinsulinism/physiopathology , Face/physiopathology , Female , Genetic Predisposition to Disease , Hematologic Diseases/complications , Hematologic Diseases/diagnosis , Hematologic Diseases/physiopathology , Humans , Infant , Intellectual Disability/complications , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Male , Mutation , Pathology, Molecular , Retrospective Studies , Vestibular Diseases/complications , Vestibular Diseases/diagnosis , Vestibular Diseases/physiopathologyABSTRACT
The author Diva D. De Leon was incorrectly listed as instead of Diva D. De Leó-Critchlow in the original version of this paper.
Subject(s)
Carcinoma, Basal Cell , Carcinoma, Merkel Cell , Carcinoma, Squamous Cell , Incidental Findings , Mohs Surgery , Skin Neoplasms , Humans , Carcinoma, Merkel Cell/surgery , Carcinoma, Merkel Cell/pathology , Carcinoma, Merkel Cell/diagnosis , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Skin Neoplasms/diagnosis , Carcinoma, Basal Cell/surgery , Carcinoma, Basal Cell/pathology , Carcinoma, Squamous Cell/surgery , Carcinoma, Squamous Cell/pathology , Male , Carcinoma in Situ/surgery , Carcinoma in Situ/pathology , Aged , Aged, 80 and overSubject(s)
Cicatrix , Mohs Surgery , Surgical Wound , Timolol , Humans , Mohs Surgery/adverse effects , Timolol/administration & dosage , Timolol/therapeutic use , Female , Male , Cicatrix/prevention & control , Cicatrix/etiology , Aged , Surgical Wound/surgery , Middle Aged , Adrenergic beta-Antagonists/therapeutic use , Adrenergic beta-Antagonists/administration & dosage , Skin Neoplasms/surgery , Wound Healing/drug effects , Aged, 80 and over , Treatment OutcomeABSTRACT
At the 2024 American Academy of Dermatology annual meeting in San Diego, California, attendees explored the latest advancements in clinical and surgical dermatology and physician well-being. Key takeaways for residents included enhancing surgical experiences, adapting ergonomic practices, and prioritizing both patient and physician well-being. The meeting underscored the importance of combining technical proficiency with compassionate patient care and continuous learning in dermatology.
Subject(s)
Dermatology , Humans , United States , Societies, Medical , Dermatologic Surgical ProceduresABSTRACT
Basal cell carcinoma (BCC) of the ear may have aggressive histologic subtypes and a greater propensity for subclinical spread than BCC in other anatomic locations. In this retrospective analysis, we evaluated recurrence rates of BCC of the ear in 102 patients who underwent treatment with Mohs micrographic surgery (MMS) or radiation therapy (RT) at a single institution between January 2017 and December 2019. Data on patient demographics, tumor characteristics, treatment modality, and recurrence rates were collected from medical records. Recurrence rates were assessed over a mean follow-up time of 2.8 years. Although MMS is the gold standard for treatment of BCC of the ear, RT may be a suitable alternative for nonsurgical candidates.
Subject(s)
Carcinoma, Basal Cell , Ear Neoplasms , Mohs Surgery , Neoplasm Recurrence, Local , Skin Neoplasms , Humans , Carcinoma, Basal Cell/surgery , Carcinoma, Basal Cell/pathology , Carcinoma, Basal Cell/radiotherapy , Male , Female , Retrospective Studies , Neoplasm Recurrence, Local/epidemiology , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Skin Neoplasms/radiotherapy , Aged , Middle Aged , Ear Neoplasms/radiotherapy , Ear Neoplasms/surgery , Ear Neoplasms/pathology , Aged, 80 and over , AdultABSTRACT
Food protein-induced allergic proctocolitis (FPIAP) is a non-IgE-mediated allergic condition that presents with hematochezia in otherwise healthy infants. It is most commonly induced by cow's milk protein via breast milk or formula. The prognosis for FPIAP is generally considered favorable with most infants achieving symptomatic resolution after diet modification. Most infants go on to tolerate the offending foods by 1-3 years of age. Over 8 years at our institution, five patients were identified and noted to have FPIAP to cow's milk during infancy with subsequent development of IgE-mediated allergic reaction to cow's milk and other foods. All five cases developed other atopic disorders (atopic dermatitis in four cases). IgE-mediated cow's milk allergy has persisted beyond the preschool years in at least two patients (currently 8 and 16 years old). For three of the patients, the IgE-mediated reaction to cow's milk was severe with development of anaphylaxis or angioedema. In addition, three patients experienced anaphylaxis or angioedema to allergens other than milk. While FPIAP is a non-IgE-mediated process traditionally thought not to progress past the first year of life, some infants with FPIAP develop severe, persistent IgE-mediated cow's milk allergy. To our knowledge, this is the first detailed clinical description of such patients.
ABSTRACT
BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 µg/kg for infants aged 0-23 months; 15·0 µg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. FINDINGS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). INTERPRETATION: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. FUNDING: BioMarin Pharmaceutical.
Subject(s)
Achondroplasia , Gastroenteritis , Female , Humans , Infant , Male , Achondroplasia/drug therapy , Double-Blind Method , Natriuretic Peptide, C-Type/therapeutic use , Child, PreschoolABSTRACT
CONTEXT: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. METHODS: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. RESULTS: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. CONCLUSION: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.
Subject(s)
Adrenal Hyperplasia, Congenital , Androgens , Male , Adult , Humans , Female , Adolescent , Adrenal Hyperplasia, Congenital/drug therapy , Androstenedione , 17-alpha-Hydroxyprogesterone , Testosterone , Adrenocorticotropic HormoneABSTRACT
INTRODUCTION: The procedure of nasotracheal intubation (NI) has long been performed utilizing the Magill forceps as developed by Sir Ivan Magill in the 1920s. While used for nearly a century, several serious patient safety concerns remain including torn tube cuffs, vocal cord trauma, and inefficient tube placement. The Tylke forceps have been developed as a modification to the largely unchanged form of Magill forceps. METHODS: In the present investigation we compared the efficacy, number of clasps, and muscle activation involved in NI using the Tylke forceps versus the Magill forceps in previously untrained individuals. RESULTS: Tylke forceps showed faster successful NI over the standard Magill forceps at an average intubation time of 6.54s vs. 13.73s, respectively. Tylke forceps also had fewer clasps per intubation over the Magill. The trapezius, deltoid, and brachioradialis muscle activation was also compared in Tylke vs Magill forceps intubation trials. Tylke forceps required less lower muscle activation in the brachioradialis and trapezius over the Magill forceps with Tylke forceps resulting in higher deltoid muscle activation. CONCLUSION: Tylke forceps were more efficacious and reduced the number of clasps over the Magill forceps when used in successful NI with different muscle activation patterns.
ABSTRACT
BACKGROUND AND OBJECTIVE: Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5-14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5-18 years randomized to receive daily subcutaneous injections for 52 weeks). METHODS: Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. RESULTS: The exposure-response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 µg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 µg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 µg/kg to patients with achondroplasia aged 5-18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. CONCLUSIONS: The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. CLINICAL TRIALS REGISTRATION: NCT02055157, NCT03197766, and NCT01603095.