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.

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.

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.

Pre-treatment of BALB/c mice with a centrally acting serotonin antagonist (cyproheptadine) reduces mortality from Boophone disticha poisoning.

INTRODUCTION: Crude extracts of Boophone disticha are used in Southern African traditional medical practice for the management of various illnesses and conditions and have also been abused for their claimed euphoric and hallucinogenic effects. Unfortunately, ingestion of Boophone disticha has resulted in toxicity and death. The results of a recent acute toxicity study in a rat model insinuated that central nervous system (CNS) serotonin overdrive could be the cause of toxicity in B. disticha poisoning. The present work sought to test that hypothesis by investigating whether pre-treatment of B. disticha poisoned BALB/c mice with the CNS acting serotonin antagonist, cyproheptadine, has a dose-dependent protective effect on toxicity and mortality. METHODS: A hydroethanolic extract of B. disticha was used in all the experiments. Five groups each with 10 animals were constituted as follows; a negative control group (received 10 ml/kg Normal Saline), a positive control group (received 375 mg/kg of the B. disticha extract), and three test groups each receiving 10 mg/kg, 15 mg/kg and 20 mg/kg cyproheptadine intraperitoneally 15 minutes before oral gavage administration of 375 mg/kg B. disticha extract respectively. The Functional Observational Battery was used to evaluate neurobehavioral and physiological changes resulting from toxicity of the plant extract. The mice were then placed in an open field for another five minutes and the number of rearings and border crossings were counted and recorded. Gait abnormalities, involuntary motor movements, mobility, arousal and stereotypical behavior were also scored according to predefined criteria. All open field investigations were recorded electronically using a LABTEC Webcam(®) and results were later analysed and recorded by one of the group members. All results were entered on data collection forms. Time to death (survival time) was considered as the time period from dosage with Boophone disticha to time of death. The study follow up period was 7 days and those mice that were alive at the end of the 7 day follow-up period were considered as having survived the poisoning episode. The Kaplan Meier plot and Log-rank test were used to compare differences in mortality and median time to death for mice in the 5 treatment groups. RESULTS: We found that cyproheptadine pre-treatment led to a dose-dependent decrease in mortality from 80% in the group not pre-treated with cyproheptadine, to 30% in the 15 and 20 mg/kg cyproheptadine pre-treated groups (n = 10 per group, p < 0.05). There was also a dose-dependent increase in median survival times amongst the groups (p < 0.0001). Pre-treatment with cyproheptadine also resulted in a decrease of other toxic symptoms associated with Boophone disticha. CONCLUSIONS: We conclude that cyproheptadine has a dose-dependent protective effect on mortality and toxicity produced by exposure to Boophone disticha in our mouse model of toxicity.

Effect of compound 48/80 on the thalamic mast cells, serotonin level and corticosterone secretion in rats.

The effect of thalamic mast cells (MCs) degranulation and serotonin liberation by compound 48/80 on the hypothalamic-pituitary-adrenocortical (HPA) activity, measured indirectly through corticosterone secretion, was investigated in conscious rats. All drugs were given intracerebroventricularly (icv), the serotonin antagonists 15 min prior to compound 48/80. One hour after administration, compound 48/80 (1 and 5 micrograms) caused a significant increase in degranulated MC number in the thalamus, from control value of 20% up to 58%, and a considerable rise in the serum corticosterone level, but only minor diminution of the thalamic serotonin content. Pretreatment with methysergide, a serotonin receptor antagonist, only slightly dimished the compound 48/80-induced corticosterone response, while pretreatment with cyproheptadine, an antagonist of serotonin-histamine and cholinergic-receptors, significantly decreased the compound 48/80-elicited corticosterone response. These results show for the first time that thalamic mast cells contain a very small amount of serotonin, which may play only a minor role in increasing the HPA activity by compound 48/80. These findings also suggest that other mediators liberated from mast cells by compound 48/80 are responsible for the considerable increase in the HPA activity.

[Pharmacological effects of Gosha-jinki-gan-ryo extract: effects on experimental diabetes].

Pharmacological effects of Gosha-jinki-gan-ryo extract (KJE) on experimental diabetes induced by cyproheptadine (CPH), aldose reductase activity, and experimental peripheral neuropathy were studied. The effects of KJE were compared with those of Hachimi-jio-gan-ryo extract (HJE). KJE at 417 mg/kg/day (5 times the daily dose in humans) and HJE at 367 mg/kg/day (5 times the daily dose in humans) significantly inhibited the decrease in glucose tolerance by CPH. KJE and HJE inhibited aldose reductase activity, when DL-glyceraldehyde was used as substrate, with IC50 values of 2.68 x 10(-5) g/ml and 4.45 x 10(-5) g/ml, respectively and when D-glucose was used as substrate, with IC50 values of 1.04 x 10(-4) g/ml and 1.55 x 10(-4) g/ml, respectively. KJE at 209 mg/kg/day (2.5 times the daily dose in humans) and HJE at 367 mg/kg/day significantly reduced peripheral neuropathy induced by crushing the sciatic nerve in rats. The potency of these effects of KJE was stronger than that of HJE, when a comparison was made on the basis of the daily dose.

Efficacy of an oral antihistamine, loratadine, as compared with a nasal steroid spray, beclomethasone dipropionate, in seasonal allergic rhinitis.

The aim of the study was to compare the efficacy and side-effects of oral antihistamine and nasal glucocorticoid therapy in seasonal allergic rhinitis. In a double-blind, double-dummy, group-comparative study, 60 birch and grass pollen allergic patients were treated with either loratadine (10 mg daily) or beclomethasone dipropionate (BDP) (100 micrograms in each nostril twice daily) during a 3 weeks' study period. Grading of 4 nasal and 3 non-nasal symptoms was performed at 4 weekly visits, and patients recorded daily symptoms and possible adverse experiences in a diary. Patients treated with BDP showed significantly less nasal blockage than those receiving loratadine (P less than 0.05), but there was no difference (P greater than 0.05) in other nasal symptoms (sneezing, itching and discharge). Patients treated with loratadine showed a statistically significantly greater relief in eye symptoms as compared with BDP (P less than 0.05). The side-effects caused by the 2 treatments were few and insignificant. We conclude that loratadine and intranasal BDP were effective in the treatment of seasonal allergic rhinitis, but the spectrum of individual symptoms controlled was different for the 2 drugs.

Efficacy and safety of loratadine suspension in the treatment of children with allergic rhinitis.

The safety and efficacy of loratadine was compared with that of dexchlorpheniramine in children with allergic rhinitis. Twenty-one children received loratadine 0.11-0.24 mg/kg ideal body weight once daily and 19 dexchlorpheniramine 0.10-0.23 mg/kg every 8 h (0.30-0.69 mg/24 h) for 14 consecutive days. Both loratadine and dexchlorpheniramine were effective in reducing nasal and ocular symptoms in allergic children. Substantial improvement in allergy symptoms was observed at the first evaluation (day 3 of treatment) and was maintained for the study duration. No significant trend of abnormality in laboratory parameters was observed. Drowsiness was present only in the dexchlorpheniramine-treated group. Loratadine appears to be a simple, effective and safe therapy for seasonal allergic rhinitis.

Antiallergic activity of H1-receptor antagonists assessed by nasal challenge.

Most oral drugs used for the treatment of allergic rhinitis are classified as H1-receptor antagonists, and although they represent major sales throughout the world, their mechanism of action is still poorly known. In an attempt to understand better the in vivo therapeutic effects of these drugs, a double-blind, crossover study was carried out. The study compared the effects of terfenadine and loratadine, nonsedative H1-receptor antagonists, on the immediate allergic response of the upper airways to challenge with orchard-grass pollens in 14 highly allergic subjects. Increasing numbers of pollen grains were insufflated into the nostrils, and the response of the subjects was assessed by examining symptoms and measuring the release of histamine and prostaglandin D2 in nasal secretions. Each drug was administered for a week before challenge. This study demonstrated the clinical efficacy of both drugs by comparison to that of a control day, since symptoms were observed for a significantly (p = 0.014) greater number of pollen grains. Only one patient had a significant release of histamine when they were treated with loratadine versus 10 during control day (p less than 0.0023) and six when they were treated with terfenadine (p less than 0.01). Prostaglandin D2 release occurred with a higher allergen dose when patients were treated with both drugs. This study indicates that some H1 antagonists also possess antiallergic activities.

[Potential use of the antiserotonin preparation cyproheptadine (peritol) in Itsenko-Cushing disease]. / Vozmozhnosti ispol'zovaniia antiserotoninovogo preparata tsiprogeptadina (peritola) pri bolezni Itsenko-Kushinga.

Experiments on male rats have shown that the inhibitory effect of peritol on the hypothalamohypophyseal-adrenal system (HHAS) is determined both by its influence on the regulatory mechanisms of the CNS and direct action on secretion and, possibly, synthesis of steroids. The degree of the antiserotonin and the HHAS-inhibiting effects depends on the frequency of drug administrations rather than on its dose. The experimental studies made it possible to successfully apply peritol to the treatment of inpatients suffering from Icenko-Cushing's disease. Almost 60% of the inpatients manifested a remission, which was confirmed by the reduced blood content of ACTH, hydrocortisone and aldosterone.