Treatment modalities for infantile spasms: current considerations and evolving strategies in clinical practice.

Infantile spasms, newly classified as infantile epileptic spasm syndrome (IESS), occur in children under 2 years of age and present as an occur as brief, symmetrical, contractions of the musculature of the neck, trunk, and extremities. When infantile spasms occur with a concomitant hypsarrhythmia on electroencephalogram (EEG) and developmental regression, it is known as West Syndrome. There is no universally accepted mainstay of treatment for this condition, but some options include synthetic adrenocorticotropic hormone (ACTH), repository corticotropin injection (RCI/Acthar Gel), corticosteroids, valproic acid, vigabatrin, and surgery. Without effective treatment, infantile spasms can cause an impairment of psychomotor development and/or cognitive and behavioral functions. The first-line treatment in the USA is ACTH related to high efficacy for cessation of infantile spasms long-term and low-cost profile. Acthar Gel is a repository corticotropin intramuscular injection that became FDA-approved for the treatment of IESS in 2010. Though it is believed that ACTH, Acthar Gel, and corticosteroids all work via a negative feedback pathway to decrease corticotropin-releasing hormone (CRH) release, their safety and efficacy profiles all vary. Vigabatrin and valproic acid are both anti-seizure medications that work by increasing GABA concentrations in the CNS and decreasing excitatory activity. Acthar Gel has been shown to have superior efficacy and a diminished side effect profile when compared with other treatment modalities.

ACTH vs steroids for the treatment of acute gout in hospitalized patients: a randomized, open label, comparative study.

The management of acute gout in the hospital setting may be challenging since most patients are elderly with multiple unstable comorbidities. However, there are no prospective clinical trials for hospitalized patients with gout to guide optimal management. Evidence indicates that steroids or adrenocorticotropic hormone (ACTH) may be effective and safe therapeutic options for these patients. This study aimed at directly comparing the efficacy and safety of ACTH vs betamethasone for the treatment of gout in hospitalized patients. This is the first prospective clinical trial for hospitalized patients with gout. We designed a randomized, open label study to assess the efficacy and safety of a single intramuscular injection of either ACTH or betamethasone in hospitalized patients with acute gout. Primary efficacy endpoints were the change in intensity of pain as recorded using a Visual Analogue Scale (VAS) at baseline compared to 24 h (ΔVAS24h), and 48 h. Moreover, we assessed safety and effects on the hypothalamic-pituitary-adrenal (HPA) axis, glucose and lipid homeostasis, bone metabolism, electrolytes and renal function. 38 patients were recruited. Both treatments were highly effective. The mean ± SE ΔVAS24h and ΔVAS48h for ACTH was 4.48 ± 0.29 and 5.58 ± 0.26, respectively. The mean ± SE ΔVAS24h and ΔVAS48h for betamethasone was 4.67 ± 0.32 and 5.67 ± 0.28, respectively. Direct comparison between the two groups at 24 h and 48 h did not show statistically significant differences. Both treatments were well tolerated and safe. The effects on all metabolic parameters were mostly minimal and transient for both treatments. However, ACTH may affect less the HPA axis and bone metabolism compared to betamethasone, thus leading to the conclusion that. ACTH and betamethasone are effective and safe for the management of acute gout in hospitalized patients but that ACTH may associate with less disturbance of the HPA axis and bone metabolism. Our data support the use of both drugs as first line treatments for hospitalized patients with gout.Clinical trial registration: ClinicalTrials.gov NCT04306653.

Risks of ACTH therapy for West syndrome following BCG vaccination.

OBJECTIVE: Bacille de Calmette et Guérin (BCG) is a live vaccine for tuberculosis that is administered to all infants in Japan. Adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS) causes immunosuppression and may result in BCG infection after BCG vaccination. We evaluated the safety of ACTH therapy initiated shortly after BCG vaccination. METHODS: We analyzed patients with WS who received ACTH therapy between 2005 and 2018. We evaluated the interval between BCG and ACTH therapy, and the rate of BCG infection during and after ACTH therapy, by retrospective chart review. RESULTS: Seventy-nine patients were included in the analysis. Twenty-three patients received ACTH therapy prior to BCG vaccination. For the remaining 56 patients, the median interval between BCG vaccination and the start of ACTH therapy (BCG-ACTH interval) was 91.5 (range 14-280) days. The BCG-ACTH interval was shorter in patients with unknown than in those with known etiologies. It was <8 weeks in 13 patients (10 with unknown and 3 with known etiologies). The minimum BCG-ACTH interval was 14 days. Six patients with epileptic spasms received BCG vaccinations because physicians did not recognize their seizures. None of the patients developed BCG infection. CONCLUSION: No patients who received ACTH therapy after BCG, even at an interval of 8 weeks, developed BCG infection. The timing of ACTH therapy initiation should be based on the risk of BCG-related adverse events and the adverse effects of any delay.

Lipomatous atrial septal hypertrophy associated with adrenocorticotropin hormone administration in an infant with West syndrome.

We present the rare case of lipomatous atrial septal hypertrophy associated with adrenocorticotropin hormone therapy in an infant with West syndrome, highlighting their relatively benign nature and good prognosis in children, and the relevance of the differential diagnosis with more dangerous cardiac masses in order to avoid aggressive diagnostic and therapeutic interventions.

Follow-up results of myositis patients treated with H. P. Acthar gel.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by proximal muscle weakness. H. P. Acthar gel [repository corticotropin injection (RCI)] is a formulation of adrenocorticotropic hormone and has been approved by Food and Drug Administration for use in IIM; however, literature is limited. In this study, we report longitudinal follow-up of myositis patients treated with RCI. METHODS: Patients with refractory IIM who were enrolled in the prospective, open-label RCI trial were included in this study. The post-trial follow-up period was 6 months with assessments every 2 months, which included myositis core set measures including extra-muscular global, muscle and patient global disease activities, HAQ, and manual muscle testing. RESULTS: Two patients were lost to follow-up after finalization of the trial, and the remaining eight patients were enrolled in the follow-up study. One patient remained on RCI after the trial. In the follow-up period, four of eight patients had flare at on average 4.1 months after the RCI trial. Among the patients who flared, three required an increase in prednisone. One patient was restarted on RCI at 5.5 months, but had minimal improvement after 3 months. Four patients who remained stable continued to satisfy criteria for the definition of improvement through the 6-month follow-up. However, none showed any further improvement in the primary or secondary efficacy outcomes after the initial RCI trial. CONCLUSION: To our knowledge, this is the first study reporting the follow-up results of patients treated with standard dose and duration of Acthar. We believe that our study will provide the basis for the development of future randomized RCI trials in IIM.

Laboratory changes during adrenocorticotropic hormone therapy associated with renal calcified lesions.

BACKGROUND: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high-risk cases with renal calcified lesions are yet to be clarified. METHODS: In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. RESULTS: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. CONCLUSIONS: The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy.

Metabolomic signatures and microbial community profiling of depressive rat model induced by adrenocorticotrophic hormone.

BACKGROUND: Adrenocorticotrophic hormone (ACTH)-treatment rat model has been utilized as a widely accepted model of treatment-resistant depression. Metabolomic signatures represent the pathophysiological phenotype of diseases. Recent studies in gut microbiota and metabolomics analysis revealed the dramatic role of microbiome in psychoneurological system diseases, but still, the mechanisms underlying gut microbiome-host interaction remain unclear. METHODS: Male Wistar rats were s.c. injection of ACTH fragment 1-24 for 14 days to induce treatment-resistant depression. Depression-related behavioral tests, analysis of serum monoamine neurotransmitters and hypothalamic-pituitary-adrenal (HPA) axis-related hormones were determined for assessment of ACTH-induced depression rat model. A gas chromatography-time-of-flight mass spectrometer based urinary metabolomic signatures integrated 16S rRNA sequence analysis based gut microbial profiling was performed, as well as Spearman's correlation coefficient analysis was used to manifest the covariation between the differential urinary metabolites and gut microbiota of genus level. RESULTS: Chronic injection of ACTH-induced depression-like phenotype (increased immobility time in forced swimming test and tail suspension test) was accompanied by peripheral serotonin down-regulation and HPA axis overactivation (ACTH and corticosterone up-regulation). Urinary metabolomics analysis indicated that pyruvic acid, L-threonine, mannitol, D-gluconic acid, 4-hydroxybenzoic acid, D-arabitol, myo-inositol and ascorbic acid levels were reduced in ACTH-treated rats' urine, while hippurate level was elevated. In addition, microbial community profiling revealed bacterial enrichment (e.g. Ruminococcus, Klebsiella) and reduction (e.g. Akkermansia, Lactobacillus) in the ACTH-induced depression rat model. Correlation analysis showed that Akkermansia and Lactobacillus were closely relevant to metabolites myo-inositol and hippurate, which were included in host inositol phosphate metabolism, and phenylalanine, tyrosine and tryptophan biosynthesis. CONCLUSIONS: Depression rat model induced by ACTH is associated with disturbance of pyruvate metabolism, ascorbate and aldarate metabolism, inositol phosphate metabolism, glycine, serine and threonine metabolism, and glycolysis or gluconeogenesis, as well as changes in microbial community structure. Gut microbiota may participate in the mediation of systemic metabolomic changes in ACTH-induced depression model. Therefore, integrated metabolomic signatures and gut microbial community profiling would provide a basis for further studies on the pathogenesis of depression.

Efficacy and tolerability of the ketogenic diet versus high-dose adrenocorticotropic hormone for infantile spasms: A single-center parallel-cohort randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of the ketogenic diet (KD) with standard adrenocorticotropic hormone (ACTH) treatment in infants with West syndrome. METHODS: In this parallel-cohort (PC) randomized controlled trial (RCT), infants were randomly allocated to KD or high-dose ACTH. Those who could not be randomized were followed in a PC. Primary end point was electroclinical remission at day 28. Secondary end points were time to electroclinical remission, relapse after initial response, seizure freedom at last follow-up, adverse effects, and developmental progress. RESULTS: One hundred one infants were included: 32 in the RCT (16 KD; 16 ACTH) and 69 in the PC (37 KD; 32 ACTH). Electroclinical remission at day 28 was similar between KD and ACTH (RCT: 62% vs 69%; PC: 41% vs 38%; combined cohort: 47% vs 48%; KD vs ACTH, respectively). In the combined cohort, time to electroclinical remission was similar between both treatments (14 days for KD, 16 days for ACTH). However, relapse rates were 16% (KD) and 43% (ACTH, P = 0.09), and seizure freedom at last follow-up was 40% (KD) and 27% (ACTH, P = 0.18). Adverse effects needing acute medical intervention occurred more often with ACTH (30% with KD, 94% with ACTH, P < 0.001). Age-appropriate psychomotor development and adaptive behavior were similar. Without prior vigabatrin (VGB) treatment, remission at day 28 was 47% (KD) and 80% (ACTH, P = 0.02); relapse rates were 29% (KD) and 56% (ACTH, P = 0.13). Consequently, seizure freedom at last follow-up was similar. In infants with prior VGB, seizure freedom at last follow-up was 48% (KD) and 21% (ACTH, P = 0.05). SIGNIFICANCE: The study is underpowered; therefore, its results should be interpreted with caution. KD is as effective as ACTH in the long term but is better tolerated. Without prior VGB treatment, ACTH remains the first choice to achieve short-term remission. However, with prior VGB, KD was at least as effective as ACTH in the short term and was associated with lower relapse rates in the long term; therefore, it represents an appropriate second-line treatment after VGB.

Adrenal Suppression in Infants Treated with Topical Ocular Glucocorticoids.

PURPOSE: To analyze the incidence of adrenal suppression and the glucocorticoid (GC) dose per kilogram body weight given in infants treated with standard protocol for topical ophthalmic GCs after congenital cataract surgery. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: All children younger than 2 years of age who underwent operation for congenital cataract between January 2011 and May 2015 in 1 center. METHODS: Patient charts were reviewed to collect data on results and timing of a standard corticotropin (adrenocorticotropic hormone [ACTH]) stimulation test and GC dose per kilogram body weight. MAIN OUTCOME MEASURES: Incidence of adrenal suppression in children tested on GC treatment. Glucocorticoid dose per kilogram body weight. RESULTS: Among 26 consecutive infants, 15 (58%) were tested while they were still on GC treatment. Ten of these 15 infants (67%) had adrenal suppression, 2 of whom had obvious clinical signs of Cushing's syndrome and 1 of whom had signs of Addisonian crises during general anesthesia. Eleven of the 26 infants (42%) were tested at a median time of 21 days (range, 6-89) after treatment cessation, and they all had normal test results. Children with suppressed adrenal function had received cumulative GC doses per body weight that were significantly higher the last 5 days before testing compared with children with normal test results. Infants with adrenal suppression were treated with hydrocortisone replacement therapy. Adrenal function recovered after a median of 3.1 months (range, 2.3 months to 2.3 years). CONCLUSIONS: Two thirds of the infants tested during treatment with a standard GC protocol after congenital cataract surgery showed adrenal suppression. There was a significant association between the cumulative daily dose of GCs and the test result. Because adrenal suppression is a serious but treatable condition, we recommend a systematic assessment of adrenal function in infants treated with doses of topical ocular GCs comparable to our regimen and careful evaluations of other treatment regimens.

Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline.

BACKGROUND: Gout is a common type of inflammatory arthritis in patients seen by primary care physicians. PURPOSE: To review evidence about treatment of acute gout attacks, management of hyperuricemia to prevent attacks, and discontinuation of medications for chronic gout in adults. DATA SOURCES: Multiple electronic databases from January 2010 to March 2016, reference mining, and pharmaceutical manufacturers. STUDY SELECTION: Studies of drugs approved by the U.S. Food and Drug Administration and commonly prescribed by primary care physicians, randomized trials for effectiveness, and trials and observational studies for adverse events. DATA EXTRACTION: Data extraction was performed by one reviewer and checked by a second reviewer. Study quality was assessed by 2 independent reviewers. Strength-of-evidence assessment was done by group discussion. DATA SYNTHESIS: High-strength evidence from 28 trials (only 3 of which were placebo-controlled) shows that colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids reduce pain in patients with acute gout. Moderate-strength evidence suggests that low-dose colchicine is as effective as high-dose colchicine and causes fewer gastrointestinal adverse events. Moderate-strength evidence suggests that urate-lowering therapy (allopurinol or febuxostat) reduces long-term risk for acute gout attacks after 1 year or more. High-strength evidence shows that prophylaxis with daily colchicine or NSAIDs reduces the risk for acute gout attacks by at least half in patients starting urate-lowering therapy, and moderate-strength evidence indicates that duration of prophylaxis should be longer than 8 weeks. Although lower urate levels reduce risk for recurrent acute attacks, treatment to a specific target level has not been tested. LIMITATION: Few studies of acute gout treatments, no placebo-controlled trials of management of hyperuricemia lasting longer than 6 months, and few studies in primary care populations. CONCLUSION: Colchicine, NSAIDs, and corticosteroids relieve pain in adults with acute gout. Urate-lowering therapy decreases serum urate levels and reduces risk for acute gout attacks. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (Protocol registration: http://effectivehealth-care.ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-141103.pdf).

Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians.

Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the management of gout. Methods: Using the ACP grading system, the committee based these recommendations on a systematic review of randomized, controlled trials; systematic reviews; and large observational studies published between January 2010 and March 2016. Clinical outcomes evaluated included pain, joint swelling and tenderness, activities of daily living, patient global assessment, recurrence, intermediate outcomes of serum urate levels, and harms. Target Audience and Patient Population: The target audience for this guideline includes all clinicians, and the target patient population includes adults with acute or recurrent gout. Recommendation 1: ACP recommends that clinicians choose corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine to treat patients with acute gout. (Grade: strong recommendation, high-quality evidence). Recommendation 2: ACP recommends that clinicians use low-dose colchicine when using colchicine to treat acute gout. (Grade: strong recommendation, moderate-quality evidence). Recommendation 3: ACP recommends against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks. (Grade: strong recommendation, moderate-quality evidence). Recommendation 4: ACP recommends that clinicians discuss benefits, harms, costs, and individual preferences with patients before initiating urate-lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).

Legionella pneumophila Pneumonia in Two Infants Treated with Adrenocorticotropic Hormone.

Patients with infantile spasms, an intractable epileptic disorder, often are treated with adrenocorticotropic hormone. Legionella pneumophila is a rare cause of pneumonia in children. We describe 2 infants with Legionella pneumonia whose infection occurred within 1 month after starting adrenocorticotropic hormone.

Repository corticotropin for Chronic Pulmonary Sarcoidosis.

PURPOSE: The dose of repository corticotropin (RCI) and need for a loading dose in sarcoidosis patients receiving chronic corticosteroids are unclear. We performed a single-blind prospective study, comparing two doses of RCI in sarcoidosis. METHODS: Chronic pulmonary sarcoidosis patients receiving prednisone therapy with deterioration by 5% in FVC in the previous year were studied. RCI was administered subcutaneously at a loading dose of 80 units RCI for 10 days. Patients were randomized at day 14 to receive either 40- or 80-unit RCI twice a week. The dose of prednisone was modified by the clinician who was blinded to the patient's dosage of RCI. RESULTS: Sixteen patients completed the full 24 weeks of the study. At week 24, there was a decrease in the dose of prednisone, and improvements in DLCO, King's Sarcoidosis Questionnaire health status and fatigue score. There was no significant change in FVC % predicted. For the PET scan, there was a significant fall in the standard uptake value (SUV) of the lung lesions. Only 3/8 patients remained on 80 units RCI for full 24 weeks. There was no significant difference in the response to therapy for those treated with 40- versus 80-unit RCI. CONCLUSIONS: Repository corticotropin treatment was prednisone-sparing and associated with significant improvement in DLCO, PET scan, and patient-reported outcome measures. A dose of 40-unit RCI twice a week was as effective as 80-unit RCI and was better tolerated.

Effectiveness of once-daily high-dose ACTH for infantile spasms.

There is insufficient evidence to recommend a specific protocol for treatment of infantile spasms (IS) and a lack of standardization among, and even within, institutions. Twice-daily dosing (for the first two weeks) of high-dose natural ACTH for IS is used by many centers and recommended by the National Infantile Spasms Consortium (NISC). Conversely, it is our practice to use once-daily dosing of high-dose natural ACTH for IS. In order to determine the effectiveness of our center's practice, we retrospectively reviewed 57 cases over the past four years at Boston Children's Hospital (BCH). We found that 70% of infants were spasm-free at 14days from ACTH initiation and 54% continued to be spasm-free at 3-month follow-up. Electroencephalogram showed resolution of hypsarrhythmia (when present on the pretreatment EEG) in all responders. Additionally, once-daily dosing of ACTH was well tolerated. We performed a meta-analysis to compare our results against the reports of published literature using twice-daily high-dose ACTH for treatment of IS. The meta-analysis revealed that our results were comparable to previously published outcomes using twice-daily ACTH administration for IS treatment. Our experience shows that once-daily dosing of ACTH is effective for treatment of IS. If larger prospective trials can confirm our findings, it would obviate the need for additional painful injections, simplify the schedule, and support a universal standardized protocol.

[Study of the efficacy of low-dose synthetic ACTH therapy without tapering to treat West syndrome].

OBJECTIVE: We evaluated the effectiveness of synthetic adrenocorticotropic hormone (ACTH) therapy without tapering in treating patients with West syndrome. METHODS: Forty-four patients with cryptogenic (n = 7) or symptomatic (n = 37) West syndrome were treated with synthetic ACTH therapy between 2003 and 2012. The synthetic ACTH dosage was 0.0125 mg/kg/day administered daily for 2 weeks and then stopped without a tapering period. The initial effectiveness, long-term seizure outcome, and adverse effects were examined. RESULTS: During synthetic ACTH therapy, epileptic spasms disappeared in 37 of 44 patients (84.1%) and hypsarrhythmia on electroencephalography disappeared in 42 of 44 patients (95.5%). The average number of synthetic ACTH injections needed to achieve spasm control in these 37 patients was 5.8. Long-term seizure outcomes were assessed in 31 patients followed up for longer than half a year after synthetic ACTH therapy. Nine (29.0%) of these patients experienced recurrence of epileptic spasms, with a mean interval to recurrence of 2.4 months. Overall, 12 patients (38.7%) experienced various types of seizures other than spasms with a mean interval to recurrence of 8.0 months. Although adverse effects such as hypertension, infection, and mild brain shrinkage were noted in 13 patients (29.5%), no severe adverse effects were observed. CONCLUSIONS: These results are comparable to those of other reports on the initial effectiveness and long-term seizure control following synthetic ACTH therapy, and suggest that administration without tapering is reasonable to treat patients with West syndrome.

CCR4 agonists CCL22 and CCL17 are elevated in pediatric OMS sera: rapid and selective down-regulation of CCL22 by ACTH or corticosteroids.

PURPOSE: To study the role of Th2-attracting chemokines in opsoclonus-myoclonus syndrome (OMS), a serious neurological paraneoplastic disorder in need of better immunological understanding and therapy. METHODS: The CCR4 agonists CCL22 and CCL17 were measured in serum by ELISA in children with OMS (238 and 260, respectively), pediatric controls (115 and 143), and other inflammatory neurological disorders (33 and 24). RESULTS: Both CCL22 (+55 %) and CCL17 (+121 %) were significantly elevated in untreated OMS compared to controls and inter-correlated (p < 0.0001). Their concentrations in untreated OMS also were higher than in OIND (21 %, 41 %). The concentration of CCL22 in ACTH and steroids groups (not IVIg) was 51 % lower than in controls, but only a smaller effect of ACTH on CCL17 was found. Prospective longitudinal studies revealed a precipitous 81 % drop in CCL22 even by the first week of high-dose ACTH therapy, staying below control mean for at least 12 weeks, and a 34 % reduction after 8 months of combined treatment. Response to ACTH was dose-related (r = -0.50, p < 0.0001). Luminex detection confirmed the ELISA results for CCL22, which were about 200 % higher. CONCLUSIONS: These data reveal an elevated serum concentration of Th2-attracting chemokines CCL22 and CCL17 in OMS. Marked and rapid reduction in CCL22, not CCL17, with either ACTH or steroid therapy suggests differential regulation and cellular sources of CCR4 ligands, and CCL22 as a potential candidate biomarker for ACTH or corticosteroid effect.

Knockout of the Na,K-ATPase α2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction.

The α2-isoform of the Na,K-ATPase (α2) is the minor isoform of the Na,K-ATPase expressed in the cardiovascular system and is thought to play a critical role in the regulation of cardiovascular hemodynamics. However, the organ system/cell type expressing α2 that is required for this regulation has not been fully defined. The present study uses a heart-specific knockout of α2 to further define the tissue-specific role of α2 in the regulation of cardiovascular hemodynamics. To accomplish this, we developed a mouse model using the Cre/loxP system to generate a tissue-specific knockout of α2 in the heart using ß-myosin heavy chain Cre. We have achieved a 90% knockout of α2 expression in the heart of the knockout mice. Interestingly, the heart-specific knockout mice exhibit normal basal cardiac function and systolic blood pressure, and in addition, these mice develop ACTH-induced hypertension in response to ACTH treatment similar to control mice. Surprisingly, the heart-specific knockout mice display delayed onset of cardiac dysfunction compared with control mice in response to pressure overload induced by transverse aortic constriction; however, the heart-specific knockout mice deteriorated to control levels by 9 wk post-transverse aortic constriction. These results suggest that heart expression of α2 does not play a role in the regulation of basal cardiovascular function or blood pressure; however, heart expression of α2 plays a role in the hypertrophic response to pressure overload. This study further emphasizes that the tissue localization of α2 determines its unique roles in the regulation of cardiovascular function.

Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis.

The therapeutic benefits of adrenocorticotropic hormone in multiple sclerosis are usually ascribed to its corticotropic actions. Evidence is presented that adrenocorticotropic hormone, approved for multiple sclerosis relapses, acts via corticosteroid-independent melanocortin pathways to engender down-modulating actions on immune-system cells and the cytokines they synthesize. Immune response-dampening effects are also brought about by agent-induced neurotransmitters that inhibit immunocytes. The likelihood that adrenocorticotropic hormone promotes microglial quiescence and counteracts glucocorticoid-mediated bone resorption is discussed.

Adrenocorticotropic hormone for the treatment of West Syndrome in children.

OBJECTIVE: To review the current literature on the efficacy and safety of low- versus high-dose adrenocorticotropic hormone (ACTH) regimens, low-dose ACTH regimens, and comparison of ACTH with oral corticosteroids or vigabatrin for the treatment of West syndrome. DATA SOURCES: A literature search was performed using MEDLINE, PubMed, and Inter national Pharmaceutical Abstracts (1975-November 2012) to identify studies for inclusion. In addition, reference citations from identified publications were reviewed. The following search terms were used: infantile spasms, West syndrome, adrenocorticotropic hormone, corticotropin, symptomatic West syndrome, cryptogenic West syndrome, pediatric, children, infant, adolescent, and neonate. STUDY SELECTION AND DATA EXTRACTION: Studies included in this article evaluated low-dose versus high-dose ACTH, low-dose ACTH, and ACTH compared with vigabatrin and oral corticosteroids. Data reporting the efficacy and adverse effects of ACTH, vigabatrin, and oral corticosteroids were extracted from each publication. Only English-language publications were included. We initially reviewed 20 studies, and 14 were included: 5 prospective randomized clinical trials and 9 chart reviews. DATA SYNTHESIS: West syndrome is an age-specific epileptic disorder that occurs in infancy and early childhood. It is characterized by the triad of infantile spasms, neurodevelopmental regression or delay, and hypsarrhythmia on electroencephalogram (EEG). The efficacy and adverse events of ACTH with different dosage regimens were reviewed and analyzed. ACTH compared with vigabatrin and oral corticosteroids was also evaluated. Based on this review, low-dose ACTH is probably as effective as high-dose ACTH. Compared with other agents, ACTH is suggested to be more effective than oral corticosteroids, and compared with vigabatrin, it has improved outcomes in the cessation of spasms. However, studies evaluating the efficacy of ACTH are limited by small sample size, inconsistent dosage regimens, and the use of synthetic or natural ACTH products. Serious adverse events, including intracranial hemorrhage, brain atrophy, Cushing syndrome, infection, weight gain, and hypertension, may deter the use of ACTH. Short-term therapy is recommended to reduce the risk of adverse effects. CONCLUSIONS: The current literature suggests that short-term, low-dose ACTH should be considered first-line treatment of infantile spasms.