Therapeutic effect of rupatadine against l-arginine-induced acute pancreatitis in rats: role of inflammation.

Acute pancreatitis (AP) is an abrupt inflammatory disorder causing high morbidity and mortality. As AP is an insidious medical emergency, a curative modality is required instead of a preventive measure. Thus, we investigated the possible curative effect of rupatadine on a rat model of AP. Rupatadine is a potent histamine receptor 1 (H1R) and platelet-activating factor (PAF) blocker. We used four groups of six Wistar rats as follows: the control group received vehicle; the rupatadine control group received rupatadine as 6 mg/kg orally; the AP group received l-arginine intraperitoneally, and the treatment group received rupatadine at 1, 6, and 24 h after l-arginine injection. The levels of serum amylase, pancreatic oxidative parameters, and pancreatic cytokines were measured. PAF, histamine, and myeloperoxidase levels were determined in the pancreas. Histopathological and immunohistochemical examinations were performed to determine nuclear factor kappa-B (NF-κB) and caspase 3 expressions. Oxidative damage and severe inflammation were detected in the pancreas of the AP group. Rupatadine reduced the oxidative damage and the levels of proinflammatory cytokines, PAF, histamine, myeloperoxidase, NF-κB, and caspase 3 expressions. It restored the pancreatic acini to almost normal condition. Rupatadine induced important anti-inflammatory and antiapoptotic effects against l-arginine-induced AP.

Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: A hospital-based retrospective study.

Failure to thrive (FTT) impairs the expected normal physical growth of children. This study aimed to evaluate the effects of cyproheptadine hydrochloride on growth parameters in prepubertal children with FTT. The medical records of prepubertal children who were newly diagnosed with FTT at China Medical University Hospital between 2007 and 2016 were retrospectively examined. The patients were divided into two groups depending on whether they had (T-group) or had not (NT-group) received cyproheptadine hydrochloride (0.3 mg/kg daily) for at least 14 days. The mean length of the treatment period was 97.22 days (range: 14-532 days). Weight, height, and body mass index were adjusted for age using the median values in the growth charts for Taiwanese boys and girls as the reference. A total of 788 patients aged 3-11 years were enrolled, 50 in the T-group and 738 in the NT-group. No statistically significant difference in the median age-adjusted weight value was noted between the T-group and NT-group during the follow up period. In the T-group, age-adjusted weight and body mass index were inversely associated with age (P <0.001, P <0.001) and positively associated with medication duration (P = 0.026, P = 0.04). Our findings underscore the positive association between cyproheptadine hydrochloride treatment and weight gain among prepubertal children. Further prospective clinical studies with a. longer and consistent treatment course is warranted.

Comparative study evaluating antihistamine versus leukotriene receptor antagonist as adjuvant therapy for rheumatoid arthritis.

PURPOSE: Investigating the efficacy and safety of rupatadine (RUP) versus montelukast (MON) as adjuvant therapy for patients with rheumatoid arthritis (RA). METHODS: From December 2018 to December 2019, 75 patients with active RA were enrolled in this randomized double-blind placebo-controlled study. The patients were randomized into three groups (n = 25 in each group); methotrexate (MTX) group which received MTX 15-25 mg/week plus placebo tablet once daily; MTX/RUP group which received MTX plus RUP 10 mg once daily; and MTX/MON group which received MTX plus MON 10 mg once daily. The treatment duration was 3 months. At baseline and 3 months after treatment, blood samples were collected for the biochemical analysis of high-sensitivity C-reactive protein (hs-CRP), interleukins 8 and 17 (IL-8, IL-17), E-selectin, and clusterin (CLU) levels. Clinical and functional assessments using Disease Activity Score-CRP (DAS28-CRP) and Multidimensional Health Assessment Questionnaire (MDHAQ) were performed. RESULTS: Both RUP and MON produced clinical and functional improvements which were translated by significant improvements in DAS28-CRP score and MDHAQ. Rupatadine significantly reduced all measured parameters (P < 0.05) except for IL-17 and CLU. Montelukast significantly decreased all measured variables (P < 0.05) except for E-selectin. Interleukin-8 was positively correlated with IL-17 and CLU, while hs-CRP was positively correlated with E-selectin and body mass index (BMI). Both drugs were well tolerated; somnolence was the common side effect for RUP. No neuropsychiatric events were reported with MON. CONCLUSION: Rupatadine or montelukast may serve as a potential adjuvant therapy for patients with rheumatoid arthritis secondary to the preliminary evidence of efficacy and safety. ClinicalTrials.gov identifier NCT03770923, December 10, 2018.

OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs.

BACKGROUND: Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib's growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility. DATA SOURCES: All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.

Human corticospinal-motoneuronal output is reduced with 5-HT2 receptor antagonism.

Animal models indicate that serotonin (5-HT) release onto motoneurons facilitates motor output, particularly during strong motor activities. However, evidence for 5-HT effects during human movement are limited. This study examined how antagonism of the 5-HT2 receptor, which is a 5-HT receptor that promotes motoneuron excitability, affects human movement. Ten healthy participants (24.2 ± 1.9 yr) ingested 8 mg of cyproheptadine (competitive 5-HT2 antagonist) in a double-blinded, placebo-controlled, repeated-measures design. Transcranial magnetic stimulation (TMS) of the motor cortex was used to elicit motor evoked potentials (MEPs) from biceps brachii. First, stimulus-response curves (90%-160% active motor threshold) were obtained during very weak elbow flexions (10% of maximal). Second, to determine if 5-HT effects are scaled to the intensity of muscle contraction, TMS at a fixed intensity was applied during elbow flexions of 20%, 40%, 60%, 80%, and 100% of maximal. Cyproheptadine reduced the size of MEPs across the stimulus-response curves (P = 0.045). Notably, MEP amplitude was 22.3% smaller for the cyproheptadine condition for the strongest TMS intensity. In addition, cyproheptadine reduced maximal torque (P = 0.045), lengthened the biceps silent period during maximal elbow flexions (P = 0.037), and reduced superimposed twitch amplitude during moderate-intensity elbow flexions (P = 0.035). This study presents novel evidence that 5-HT2 receptors influence corticospinal-motoneuronal output, which was particularly evident when a large number of descending inputs to motoneurons were active. Although it is likely that antagonism of 5-HT2 receptors reduces motoneuron gain to ionotropic inputs, supraspinal mechanisms may have also contributed to the study findings.NEW & NOTEWORTHY Voluntary contractions and responses to magnetic stimulation of the motor cortex are dependent on serotonin activity in the central nervous system. 5-HT2 antagonism decreased evoked potential size to high-intensity stimulation, and reduced torque and lengthened inhibitory silent periods during maximal contractions. We provide novel evidence that 5-HT2 receptors are involved in muscle activation, where 5-HT effects are strongest when a large number of descending inputs activate motoneurons.

COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome?

COVID-19 derives from infection with Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2] and is associated with high morbidity and mortality due to release of a storm of pro-inflammatory cytokines and thrombogenic agents resulting in destruction of the lungs. Many reports indicate that a considerable number of patients who are positive for SARS-CoV-2 are asymptomatic or have mild symptoms. However, increasing evidence suggests that many such patients who either recovered from or had mild symptoms after COVID-19 exhibit diffuse, multiorgan, symptoms months after the infection. These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C). Now the US Center for Disease Control (CDC) announced the recognition of a similar condition in adults, named Multisystem Inflammatory Syndrome (MIS-A). The symptoms characterizing these conditions are very similar to those associated with Mast Cell Activation Syndrome (MCAS, US ICD-110 code D89.42-idiopathic mast cell activation syndrome). Hence, the possibility of MCAS should be evaluated in any patient with MIS and/or multisystem inflammatory symptoms. In either case, these syndromes should be addressed with liposomal formulation (in olive pomace oil) of the flavone luteolin (e.g. PureLut® or FibroProtek®) together with the antihistamine rupatadine, which also has anti-platelet activating factor (PAF) activity and inhibits mast cells that have been implicated in the pathogenesis of cytokine storms in COVID-19.

Prediction of Human Disproportionate and Biliary Excreted Metabolites Using Chimeric Mice with Humanized Liver.

The PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [14C]desloratadine, [3H]mianserin, cyproheptadine, and [3H]carbazeran, all reported with disproportionate human metabolites, were orally administered to PXB- or control SCID mice to elucidate the biotransformation of each of them. For [14C]desloratadine in PXB-mice, O-glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine. Both 3-hydroxydesloratadine and its O-glucuronide were detected as major drug-related materials in the bile, whereas only 3-hydroxydesloratadine was detected in the feces, suggesting that a fraction of 3-hydroxydesloratadine in feces was derived from deconjugation of its O-glucuronide by gut microflora. This information can help understand the biliary clearance mechanism of a drug and may fill the gap in a human absorption, distribution, metabolism, and excretion study, in which the bile samples are typically not available. The metabolic profiles in PXB-mice were qualitatively similar to those reported in humans in a clinical study in which 3-hydroxydesloratadine and its O-glucuronide were major and disproportionate metabolites compared with rat, mouse, and monkey. In the control SCID mice, neither of the metabolites was detected in any matrix. Similarly, for the other three compounds, all human specific or disproportionate metabolites were detected at a high level in PXB-mice, but they were either minimally observed or not observed in the control mice. Data from these four compounds indicate that studies in PXB-mice can help predict the potential for the presence of human disproportionate metabolites (relative to preclinical species) prior to conducting clinical studies and understand the biliary clearance mechanism of a drug. SIGNIFICANCE STATEMENT: Studies in PXB-mice have successfully predicted the human major and disproportionate metabolites compared with preclinical safety species for desloratadine, mianserin, cyproheptadine, and carbazeran. In addition, biliary excretion data from PXB-mice can help illustrate the human biliary clearance mechanism of a drug.

Premedication with montelukast and rupatadine decreased rituximab infusion time, rate, severity of reactions and use of rescue medications.

Rituximab-associated infusion reactions (IRs) are significant burdens on oncology patients, caregivers and healthcare providers. We evaluated whether montelukast and rupatadine improve rituximab delivery, decrease frequency/severity of IRs and the number of medications used to control IRs. Using a nonrandomized clinical study design, we assessed adult rituximab naïve patients with B-cell lymphoid malignancies from January 2017 to July 2019. Prior to the first rituximab infusion patients received one of the premedication regimens: (i) standard premedications, diphenhydramine hydrochloride and acetaminophen ("SP" group); (ii) SP + montelukast ("M" group); (iii) SP + rupatadine ("R" group); (iv) SP + rupatadine + montelukast Schedule 1 ("M + R Schedule 1" group); (v) SP + rupatadine + montelukast Schedule 2 ("M + R Schedule 2" group). A total of 223 patients with a median age of 69 years were assessed. Demographics and treatment groups were comparable among all five groups. Mean rituximab infusion time was 290 min in the SP group versus 273, 261, 243 and 236 min in the M, R, M + R Schedule 1 and M + R Schedule 2 groups, respectively. The incidence of rituximab IRs was 75% in the SP group versus 44, 41, 22 and 22% in the M, R, M + R Schedule 1 and M + R Schedule 2 groups, respectively. The median reaction grade was 2 in the SP group and 0 in all other groups. The median number of rescue medications was 3 in the SP group and 0 in all other groups. In conclusion, montelukast and rupatadine significantly improved rituximab delivery, decreased the rate and severity of IRs and reduced the need for rescue medications.

Long-term safety and efficacy of rupatadine in Japanese patients with itching due to chronic spontaneous urticaria, dermatitis, or pruritus: A 12-month, multicenter, open-label clinical trial.

BACKGROUND: Rupatadine is a novel H1 antihistamine with platelet-activating factor antagonist activity. Its efficacy and safety on pruritic skin diseases have been demonstrated by 10mg/day rupatadine in a two weeks clinical trial. OBJECTIVE: To investigate the long-term efficacy and safety of rupatadine in the management of pruritus, and the clinical effect of updosing to 20mg in Japanese adult and adolescent patients. METHODS: In this 52-week, multicenter, open-label clinical trial (JapicCTI-152787), 206 patients (132, eczema or dermatitis; 58, pruritus; and 16, chronic spontaneous urticaria) received the study medication. The primary efficacy endpoint was change from baseline in the total pruritus score to Week 2 by treatment with rupatadine 10mg once daily. From Week 3 to Week 52, rupatadine updosing to 20mg was allowed. RESULTS: The mean [95% CI] change from baseline to Week 2 in the total pruritus score was -1.241 [-1.450, -1.033] (paired t test, P< 0.001). The therapeutic effect persisted up to Week 52 (paired t test, P< 0.001). Adverse drug reactions (ADRs) were reported at an overall incidence of 18.0% (45 events in 37 patients). No serious or clinically significant ADRs were reported. Somnolence was the most common ADR (14.1%). CONCLUSIONS: This clinical trial demonstrated the short- and long-term benefits of rupatadine in the management of patients with chronic spontaneous urticaria, dermatitis, and pruritus. Rupatadine 10 and 20mg doses are effective for the treatment of itch in adults and adolescents, and can be used safely on a long-term basis.

Preventive effect of cyproheptadine on sleep and appetite disorders induced by methylphenidate: an exploratory randomised, double-blinded, placebo-controlled clinical trial.

OBJECTIVES: Insomnia and loss of appetite are the most common side effects of methylphenidate in patients with attention deficit/hyperactivity disorder (ADHD). The adverse effects may limit optimal dosing and patients' compliance with treatment leading to the discontinuation of treatment. This research evaluates the preventive effects of cyproheptadine on sleeping and appetite disorders induced by methylphenidate in ADHD children. METHODS: During this exploratory, randomised, double-blinded, placebo-controlled clinical trial, forty patients with ADHD diagnosis who had received methylphenidate randomly were assigned to participate in the cyproheptadine or the placebo group. Patients' weight and Pittsburgh Sleep Quality Index (PSQI) score were recorded at baseline, after four, six and eight weeks of treatment. The ADHD Parent Rating Scale-V score was also defined at the beginning and the end of study for each patient. RESULTS: There was no significant difference between the cyproheptadine and the placebo groups regarding their weight, rate of growth and PSQI score in the monthly assessment. In addition, there was no significant difference in response to the therapy between the two groups. CONCLUSIONS: Based on our findings, cyproheptadine does not have any considerable preventive effect on sleeping and appetite disorders induced by methylphenidate in ADHD children.

CB1 receptors in the paraventricular nucleus of the hypothalamus modulate the release of 5-HT and GABA to stimulate food intake in rats.

Endocannabinoids and their receptors not only contribute to the control of natural processes of appetite regulation and energy balance but also have an important role in the pathogenesis of obesity. CB1 receptors (CB1R) are expressed in several hypothalamic nuclei, including the paraventricular nucleus (PVN), where induce potent orexigenic responses. Activation of CB1R in the PVN induces hyperphagia by modulating directly or indirectly orexigenic and anorexigenic signals; however, interaction among these mediators has not been clearly defined. CB1R mRNA is expressed in serotonergic neurons that innervate the PVN, and activation of 5-HT receptors in the PVN constitutes an important satiety signal. Some GABAergic terminals are negatively influenced by 5-HT, suggesting that the hyperphagic effect of CB1R activation could involve changes in serotonergic and GABAergic signaling in the PVN. Accordingly, the present study was aimed to characterize the neurochemical mechanisms related to the hyperphagic effects induced by activation of CB1R in the PVN, studying in vitro and in vivo changes induced by direct activation these receptors. Here, we have found that the neurochemical mechanisms activated by stimulation of CB1 receptors in the PVN involve inhibition of 5-HT release, resulting in a decrease of serotonergic activity mediated by 5-HT1A and 5-HT1B receptors and inducing disinhibition of GABA release to stimulate food intake. In conclusion, these neurochemical changes in the PVN are determinant to the cannabinoid-induced stimulation of food intake. Our findings provide evidence of a functional connection among CB1R and serotonergic and GABAergic systems on the control of appetite regulation mediated by endocannabinoids.

Delayed Serotonin Syndrome in the Setting of a Mixed Fluoxetine and Serotonin Antagonist Overdose.

BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.

Cardiac Safety of Rupatadine in a Single-Ascending-Dose and Multiple-Ascending-Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments-Comparison With the Previous White Caucasian Thorough QT Study.

A thorough QT/QTc study in healthy white Caucasian subjects demonstrated that rupatadine has no proarrhythmic potential and raised no cardiac safety concerns. The present phase 1 study aimed to confirm the cardiac safety of rupatadine in healthy Japanese subjects. In this randomized, double-blind, placebo-controlled study, 27 healthy Japanese subjects were administered single and multiple escalating rupatadine doses of 10, 20, and 40 mg or placebo. Triplicate electrocardiogram (ECG) recordings were performed on days -1, 1, and 5 at several points, and time-matched pharmacokinetic samples were also collected. Concentration-effect analysis based on the change in the QT interval corrected using Fridericia's formula (QTcF) from average baseline was performed. Data from the formal TQT study in white Caucasian subjects was used for a comparison analysis. The ECG data for rupatadine at doses up to 40 mg did not show an effect on the QTc interval of regulatory concern. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF on days 1 and 5 four hours after a standardized meal. The data from this study exhibited no statistically significant differences in the QTc effect between Japanese and white Caucasian subjects.

Population pharmacokinetic modelling of rupatadine solution in 6-11 year olds and optimisation of the experimental design in younger children.

AIMS: To optimise a pharmacokinetic (PK) study design of rupatadine for 2-5 year olds by using a population PK model developed with data from a study in 6-11 year olds. The design optimisation was driven by the need to avoid children's discomfort in the study. METHODS: PK data from 6-11 year olds with allergic rhinitis available from a previous study were used to construct a population PK model which we used in simulations to assess the dose to administer in a study in 2-5 year olds. In addition, an optimal design approach was used to determine the most appropriate number of sampling groups, sampling days, total samples and sampling times. RESULTS: A two-compartmental model with first-order absorption and elimination, with clearance dependent on weight adequately described the PK of rupatadine for 6-11 year olds. The dose selected for a trial in 2-5 year olds was 2.5 mg, as it provided a Cmax below the 3 ng/ml threshold. The optimal study design consisted of four groups of children (10 children each), a maximum sampling window of 2 hours in two clinic visits for drawing three samples on day 14 and one on day 28 coinciding with the final examination of the study. CONCLUSIONS: A PK study design was optimised in order to prioritise avoidance of discomfort for enrolled 2-5 year olds by taking only four blood samples from each child and minimising the length of hospital stays.

Pharmacokinetics, Safety and Cognitive Function Profile of Rupatadine 10, 20 and 40 mg in Healthy Japanese Subjects: A Randomised Placebo-Controlled Trial.

INTRODUCTION: Rupatadine is a marketed second generation antihistamine, with anti-PAF activity, indicated for symptomatic treatment of allergic rhinitis and urticaria. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of rupatadine in healthy Japanese subjects after single and multiple oral doses. METHODS: In this randomised, double-blind, placebo-controlled study, 27 male and female healthy Japanese subjects were administered single and multiple escalating rupatadine dose of 10, 20 and 40 mg or placebo. Blood samples were collected at different time points for PK measurements and subjects were assessed for safety and tolerability. The effect of rupatadine on cognitive functioning was evaluated by means of computerized cognitive tests: rapid visual information processing (RVP), reaction time (RT), spatial working memory (SWM) and visual analogue scales (VAS). RESULTS: Exposure to rupatadine as measured by Cmax and AUC was found to increase in a dose dependent manner over the dose range of 10-40 mg for both single and multiple dose administration. The safety assessments showed that all treatment related side effects were of mild intensity and there were no serious adverse events (SAEs) or withdrawals due to treatment-emergent adverse events (TEAEs) in this study. The therapeutic dose of rupatadine did not show any CNS impairment in any of the cognitive tests. CONCLUSIONS: This study demonstrated that rupatadine is safe and well tolerated by Japanese healthy subjects. The PK-PD profile confirmed previous experience with rupatadine.

Rupatadine 20 mg and 40 mg are Effective in Reducing the Symptoms of Chronic Cold Urticaria.

Chronic cold urticaria (ColdU) is a rare disease characterized by mast cell-mediated wheals and angioedema following cold exposure. Second-generation H1-antihistamines, such as rupatadine, are the recommended first-line therapy. As of yet, the effects of rupatadine up-dosing on development of ColdU symptom have only been partially characterized. Two-centre, randomized, double-blind, 3-way crossover, placebo-controlled study in patients with a confirmed ColdU was designed to assess the effects of up-dosing of rupatadine. A total of 23 patients were randomized to receive placebo, rupatadine 20 mg/day, and rupatadine 40 mg/day for 1 week. The primary outcome was change in critical temperature thresholds and critical stimulation time thresholds after treatment. Secondary endpoints included assessment of safety and tolerability of rupatadine. Both 20 and 40 mg rupatadine were highly effective in reducing critical temperature thresholds (p < 0.001) and critical stimulation time thresholds (p < 0.001). In conclusion, rupatadine 20 and 40 mg significantly reduced the development of chronic cold urticaria symptom without an increase in adverse effects.

Serotonin syndrome overlapping with neuroleptic malignant syndrome: A case report and approaches for differentially diagnosing the two syndromes.

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are life-threatening adverse reactions caused by serotonergic antidepressants and neuroleptics, respectively. SS and NMS have overlapping clinical features, and thus differentially diagnosing the syndromes can be difficult in patients who are taking both types of drugs. Here, the author reports a unique case of a patient who developed SS that overlapped with NMS after taking imipramine and lithium carbonate with the subsequent addition of metoclopramide. This is the first case report of SS that overlapped with NMS. The author also briefly summarizes the clinical symptoms of each syndrome and describes the approaches that were used to differentially diagnose the two syndromes.

Cyproheptadine significantly improves the overall and progression-free survival of sorafenib-treated advanced HCC patients.

OBJECTIVE: Sorafenib is a recommended treatment for advanced hepatocellular carcinoma. The study is to evaluate the efficacy of sorafenib plus cyproheptadine compared with sorafenib alone in patients with advanced hepatocellular carcinoma. METHODS: A retrospective cohort study reviewed all consecutive advanced hepatocellular carcinoma cases with Child-Pugh Class A disease starting sorafenib treatment at our hospital from August 2012 to March 2013. They were followed up until 31 December 2013. A total of 52 patients were enrolled: 32 patients in the combination (sorafenib-cyproheptadine) group and 20 patients in the control (sorafenib alone) group. The response to treatment, overall survival and progression-free survival were compared. RESULTS: The median overall survival was 11.0 months (95% confidence interval: 6.8-15.1 months) in the combination group compared with 4.8 months (95% confidence interval: 3.1-6.6 months) in the control group (crude hazard ratio = 0.45, 95% confidence interval: 0.22-0.82). The median progression-free survival time was 7.5 months (95% confidence interval: 5.1-10.0 months) in the combination group compared with 1.7 months (95% confidence interval: 1.4-2.1 months) in the control group (crude hazard ratio = 0.43, 95% confidence interval: 0.22-0.86). Kaplan-Meier survival analysis revealed that both overall survival and progression-free survival in the combination group were significantly longer than that in the control group. The multivariate model found patients in the combination group were 76% less likely to die (adjusted hazard ratio = 0.24, 95% confidence interval: 0.10-0.58) and 82% less likely to have progression (adjusted hazard ratio = 0.18, 95% confidence interval: 0.08-0.44) during the 17 months of follow-up. CONCLUSION: Cyproheptadine may significantly improve survival outcomes of sorafenib-treated advanced hepatocellular carcinoma patients.