In Silico Analysis, Synthesis, and Biological Evaluation of Triazole Derivatives as H1 Receptor Antagonist.

INTRODUCTION: Histamine, a biological amine, is considered as a principal mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. Numerous derivatives have been developed that strive with histamine at the H1 receptor and prevent binding of histamine at the H1 receptor, thereby preventing allergic reactions. Molecules containing a triazole ring fused with six-membered ring systems are found to possess broad applications in the field of medicine and industry. The present study is an attempt to characterize the impact of the nature of the substituent introduced at 5 positions of the-4H-1,2,4-triazole-3-thiol on their capacities to bind with the H1 receptor. METHODS: Molecular docking (PDB ID: 3RZE) revealed that synthesized derivatives and target proteins were actively involved in binding with Tyr-108, Thr-112, Ala-216, and Phe-432 subunits. A pharmacophore model, new 5-(4-substituted phenyl)-4-(phenylamino)-4-H-1,2,4-triazole-3- thiols (5a-5h) were designed and evaluated for H1-blocking activity using isolated segments from the guinea pig ileum. RESULTS: According to in silico analysis, all the compounds have a topological polar surface area (TPSA) less than 140 Å squared, so they tend to easily penetrate cell membranes. The results show that most of the compounds are non-inhibitors of CYP450 substrates that play a fundamental role in drug metabolism. Compounds 5d (50.53±12.03), 5h (50.62±12.33) and 7a (55.07±12.41) are more active than others. CONCLUSION: Finally, these derivatives were screened for H1 receptor antagonist activity using guinea pig ileum, taking chlorpheniramine maleate as a standard. Most of the compounds were found to possess better antihistamine activity.

Histamine H1 Receptor Antagonists Facilitate Electroacupuncture Analgesia.

This study investigated the influence of the histamine H1 receptor antagonists, chlorpheniramine (CHL) and pyrilamine, on the analgesic effects of acupuncture in mice. Nociceptive response was evaluated by the acetic acid-induced abdominal writhe test. Electroacupuncture (EA) at bilateral ST36 reduced the manifestations of acetic acid-induced abdominal writhing, whereas needle insertion without electrostimulation had no such effect. Notably, EA treatment was not associated with any analgesic effects in mice pretreated with naloxone. Low doses of CHL (0.6[Formula: see text]mg/kg; p.o.) or pyrilamine (2.5[Formula: see text]mg/kg; i.p.) as monotherapy did not affect acetic acid-induced abdominal writhing. However, when each agent was combined with EA, acetic acid-induced abdominal writhing was reduced by a greater extent when compared with EA alone. Interestingly, the effects of CHL on acupuncture analgesia were not completely reversed by naloxone treatment. Acetic acid induced increases of phospho-p38 expression in spinal cord, as determined by immunofluorescence staining and Western blot analysis. These effects were attenuated by EA at ST36 and by low doses of histamine H1 receptor antagonists, alone or in combination. Our findings show that relatively low doses of histamine H1 receptor antagonists facilitate EA analgesia via non-opioid receptors. These results suggest a useful strategy for increasing the efficacy of EA analgesia in a clinical situation.

Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology.

The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6-11s) and more than 95% dissolution in 5min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration.

A phase I trial assessing the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of single-dose Auron Misheil therapy in healthy male subjects.

BACKGROUND AND OBJECTIVE: Auron Misheil therapy (AMT) is a combination of widely used pharmaceuticals and herbal components that has been used since the 1980s as a supportive therapy, mainly in end-stage cancer patients on a compassionate basis. This phase I study was conducted to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of AMT in a controlled trial environment. METHODS: The study was conducted in a single rising dose, double-blind, placebo-controlled design. Three groups of eight healthy male volunteers received one of three doses of AMT (0·011, 0·033 or 0·066 mL AMT/kg body weight intramuscularly; n = 6 per group) or placebo (n = 2 per group). RESULTS AND DISCUSSION: Auron Misheil therapy was shown to be well tolerated, revealing no severe or serious adverse events. There were no unexpected PK or PD results for any of the three components of AMT. CONCLUSIONS: These data provide important PK, PD and safety data for AMT, and support further controlled clinical investigation in patients with different types of cancer as an option for supportive care.

[Observation on short and long-term effects of Tuina for treatment of infants eczema].

OBJECTIVE: To access the therapeutic effect of Tuina for treatment of infants eczema. METHODS: Two hundred and forty children with eczema were randomly divided into a Tuina group and a medication group, 120 cases in each group. The Tuina group was treated with Tuina on ten points using the thumb and middle finger, and the medication group was treated with oral administration of Chlorpheniramine and topical application of zinc oxide ointment or Youzhuoer ointment, etc. The therapeutic effects were evaluated after 3 weeks. RESULTS: The cured-markedly effective rate and total effective rate were 94.2% and 99.2% in the Tuina group and 98.0% and 100.0% in the medication group, respectively, the therapeutic effects were similar in the two groups (both P>0.05); 6 months after treatment, the recurrence rate of 3.8% in the Tuina group was significantly lower than 42.9% in the medication group (P<0.01), and there were no adverse reactions in the whole research process. CONCLUSION: Tuina on ten points for treatment of infants eczema has unequivocal short-term effect, a stable long-term effect, and low recurrence rate.

Comparison of the local anesthetic effects of chlorpheniramine, midazolam, lidocaine, and normal saline after intradermal injection.

BACKGROUND: Local anesthetic effects of antihistamines are well known, but have been tested more for diphenhydramine than for chlorpheniramine. Midazolam, a benzodiazepine gamma-aminobutyric acid type A receptor agonist, induces spinally mediated analgesia. However, the local anesthetic effects of chlorpheniramine and midazolain have not been adequately studied. The purpose of this study was to assess the infiltration pain and the local anesthetic effects of intradermial chlorpheniramine and midazolam. MATERIAL/METHODS: This prospective, double-blind study compared the effects of intradermal chlorpheniramine, midazolam, lidocaine, and saline for pain on injection and degree of local anesthesia in adult volunteers. Each received 0.5 ml of the four solutions as intradermal injections in a standardized manner on the volar side of the forearm. Pain on injection and the degree of local anesthesia (tested by pinprick, light touch, and cold) at each site was evaluated on a 0-3 scale at designated time intervals. RESULTS: Pain on injection of chlorpheniramine was more intense than saline (p=0.047) and lidocaine (p<0.001). Midazolam was significantly more painful than lidocaine (p<0.001), but not different from saline (p=0.170). Lidocaine caused a significant reduction in sensation to pinprick, touch, and cold during the study period compared with saline and midazolam. Chlorpheniramine also produced a significant reduction in sensation to pinprick and cold until the 120th minute and in sensation to touch until the 90th minute compared with saline. CONCLUSIONS: Intradermal chlorpheniraline, but not midazolam, produced a local anesthetic effect; however, the duration of this effect of chlorpheniramine was shorter than that of lidocaine.

Apoptosis in rat jejunal mucosa is regulated partly through the central nervous system, which controls feeding behavior.

AIM: The aim of this study was to investigate whether central nervous system-related feeding behavior regulates mucosal apoptosis in rat small intestines. METHODS: The test solutions used in this study were an H(1) receptor antagonist (chlorpheniramine maleate), 2-deoxy-D-glucose, leptin, and 1-deoxy-D-glucosamine (2-amino-1,5-anhydro-2-deoxy-D-glucitol). Test solutions were injected into the third cerebroventricles of rats. Feeding behavior and jejunal apoptosis were evaluated both with and without truncal vagotomy. Intestinal apoptosis was evaluated by percentage fragmented DNA, electrophoresis, and TUNEL staining. RESULTS: Chlorpheniramine and 2-deoxy-D-glucose elicited feeding, whereas leptin and 1-deoxy-D-glucosamine suppressed feeding. The test solutions, which elicited feeding (0.24 and 24 micromol/rat of chlorpheniramine and 2-deoxy-D-glucose, respectively), suppressed mucosal apoptosis in the rat jejunum 1 h after cerebroventricular infusion. In contrast, the test solutions, which suppressed feeding (8 and 24 micromol/rat of leptin and 1-deoxy-D-glucosamine, respectively), induced jejunal mucosal apoptosis 3 h after infusion. The effects of the test solutions on feeding behavior and changes in apoptosis were not affected by truncal vagotomy. CONCLUSION: The central nervous system, which regulates feeding behavior, might control intestinal function through the regulation of intestinal apoptosis.

Hypersensitivity reactions to oxaliplatin in two asian patients.

OBJECTIVE: To report 2 cases of hypersensitivity reactions associated with oxaliplatin treatment in Asian patients. CASE SUMMARIES: A 33-year-old Chinese woman received adjuvant oxaliplatin in combination with fluorouracil and leucovorin. Shortly during her sixth infusion, she developed a severe hypersensitivity reaction. Despite prophylactic measures, she developed another reaction of similar severity during her subsequent infusion and was not further rechallenged with oxaliplatin. The second case involved a 45-year-old Malay woman who received oxaliplatin, fluorouracil, and leucovorin for metastatic colorectal cancer. Shortly during her ninth infusion, she developed a mild hypersensitivity reaction. With prophylactic measures, she developed less marked reactions with her subsequent 3 infusions. DISCUSSION: Hypersensitivity reactions to oxaliplatin have been reported to be between 12% and 16% in the Western population. As of April 20, 2005, there are only 2 previously published reports of hypersensitivity reactions to oxaliplatin in 6 Asian patients. The incidence rates of such reactions in different Asian ethnic groups could vary. The cumulative dose, time of exposure to oxaliplatin, and clinical features were variable and unpredictable in all of the reported Asian patients who developed hypersensitivity reactions. An objective causality assessment using the Naranjo probability scale revealed that oxaliplatin was the highly probable cause of hypersensitivity in the 2 Asian patients reported by our center. CONCLUSIONS: Patients who develop mild to moderate reactions can be rechallenged with the drug administered as a slow infusion with prophylactic measures. Desensitization may allow patients who experience severe hypersensitivity reactions to oxaliplatin to further receive effective therapy for their colorectal cancer.

The anti-allergic effects of a cromolyn sodium-chlorpheniramine combination compared to ketotifen in the conjunctival allergen challenge model.

PURPOSE: To compare the inhibitory effects of a topical combination product, cromolyn sodium (DSCG) 4% with the antihistamine, chlorpheniramine, with those of topical ketotifen 0.05% on the clinical allergic reaction induced by the conjunctival allergen challenge (CAC). METHODS: Ten allergic but non-active patients were challenged in both eyes with increasing doses of specific allergen to obtain a positive bilateral reaction (visit 1). They were then rechallenged after 1 week to confirm the allergic threshold dose response (visit 2). After 2 weeks, a third CAC was performed bilaterally 30 minutes after topical application of DSCG-chlorpheniramine in one eye and ketotifen in the contralateral eye in a double-masked fashion (visit 3). Clinical signs and symptoms were registered 5, 10, 15, and 20 minutes after challenge using the standard scoring system. Tear cytology was performed 30 minutes after challenge. RESULTS: Comparing the two drug effects at visit 3, DSCG-chlorpheniramine was shown to be superior to ketotifen at all time points for itching (p < 0.01) and at 5 minutes for redness (p < 0.01). For the total signs score, DSCG-chlorpheniramine was shown to be superior to ketotifen at all time points (p < 0.01), and at 10 and 15 minutes for the total symptoms score (p < 0.05). Compared to visit 2, DSCG-chlorpheniramine significantly lowered itching (p < 0.001) and redness (p < 0.05) at 5, 10, 15, and 20 minutes after challenge. Ketotifen significantly lowered itching at 5 and 10 minutes (p < 0.001) and redness at 5, 10, and 15 minutes (p < 0.05). Both drugs reduced the total number of cells evaluated by tear cytology during the early-phase reaction (p < 0.05). CONCLUSIONS: DSCG-chlorpheniramine was found to be more effective than ketotifen at preventing itching and redness in the CAC model.

An in vitro method to investigate food effects on drug release from film-coated beads.

The influence of simulated high-fat meals on drug release from beads coated with modified-release ethylcellulose coating formulations was investigated as a function of plasticizer type and concentration, and coating level. Ethylcellulose-coated beads were soaked in peanut oil prior to testing to simulate the influence of concomitant administration of the dosage form with ingestion of fatty meals. The USP apparatus 3 dissolution procedure was employed to study the drug release properties of the beads. It was found that the ethylcellulose-coated beads plasticized with either triethyl citrate (TEC) or dibutyl sebacate (DBS) had faster drug release rates after the peanut oil treatment. Scanning electron microscopy (SEM) revealed that the peanut oil soak caused the polymeric films to detach from the surface of the bead, producing a series of uneven ridges and cracks in the coating. Modulated differential scanning calorimetry (DSC) demonstrated that the glass transition temperature was increased for DBS-plasticized films soaked in peanut oil, and that it was not influenced for TEC plasticized films. Similar results were found for the puncture strength, percent elongation, and modulus of elasticity for the DBS- and TEC-plasticized films soaked in peanut oil. The results verified that the DBS was solubilized and extracted from the plasticized film during the peanut oil soak, and that the film plasticized with the TEC was not significantly affected by the peanut oil soak. Drug release was influenced by the plasticizer type and concentration, and coating level applied to the beads.

Pharmacological studies of allergic cough in the guinea pig.

The pharmacological mechanisms of allergic cough in the guinea pig were studied. Actively sensitized guinea pigs were exposed to aerosols of antigen to elicit coughing. In separate experiments, naive guinea pigs were exposed to aerosols of capsaicin to elicit coughing. Both allergic and capsaicin-induced cough were inhibited by loratadine (0.3-10 mg kg-1 p.o.) and chlorpheniramine (0.1-3.0 mg kg-1 p.o.). Neither cimetidine (10 mg kg-1 s.c.), nor thioperamide (3-10 mg kg-1 s.c.), inhibited allergic or capsaicin-induced cough. Codeine (3-30 mg kg-1 p.o.), salbutamol (0.003-3.0 mg kg-1 s.c.) and ipratropium (0.03-1.0 mg kg-1 s.c.) inhibited both allergic and capsaicin-induced cough. Hexamethonium (10 and 30 mg kg-1 s.c.) inhibited allergic, but not capsaicin-induced cough. Allergic and capsaicin-induced cough were unaffected by phenidone (5.0 and 10.0 mg kg-1 s.c.). Indomethacin (5.0 and 10.0 mg kg-1 s.c.) had no effect on allergic cough but slightly inhibited capsaicin-induced cough. We conclude that allergic and capsaicin-induced cough are modulated by histamine H1 receptor and cholinergic mechanisms. Histamine H2 or histamine H3 receptor mechanisms, and lipoxygenase and cyclooxygenase products of arachidonic acid metabolism do not influence allergic and capsaicin-induced cough. Ganglionic mechanisms play a minor role in the production of allergic cough and no role in capsaicin-induced cough.

Adverse reactions to intravenous N-acetylcysteine in Chinese patients with paracetamol (acetaminophen) poisoning.

The incidence of adverse reactions to intravenous N-acetylcysteine (NAC) was studied in 56 Chinese patients with paracetamol (acetaminophen) poisoning. Eight (14%) patients developed a skin rash (n = 7) or fever (n = 1) mostly during the initial high dose infusion of the antidote. In four subjects (three with toxic plasma paracetamol levels), the infusion was continued without a worsening of the adverse reaction. NAC was discontinued in the remaining four subjects in whom the paracetamol levels were subsequently found to be non-toxic. Intravenous chlorpheniramine was given to six subjects. All eight subjects completely recovered. In the dose that is recommended for the treatment of acute paracetamol poisoning, intravenous NAC is generally safe in Chinese but mild side effects are common. We recommend that the initial loading dose is given over 60 rather than 15 min.

Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats.

To clarify involvement of hypothalamic neuronal histamine in feeding circadian rhythm, we analyzed rat behavioral patterns using chemical probes which affect endogenous histaminergic activity. Sustained infusion of alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine-synthesizing enzyme, into the rat third cerebral ventricle disrupted light-dark cycles of feeding, drinking, and ambulatory behavior. Food and water intake and ambulatory activity during the 12-h light period increased, and those during the 12-h dark period decreased after the infusion. The ratio of the light period to the 24-h total period (L/T ratio) increased in all behavioral parameters. Assessed by 3-h cumulative analysis, amplitudes of circadian rhythmicity decreased in all behavioral parameters, whereas only the acrophase of ambulatory activity shifted forward after FMH infusion. Chlorpheniramine, an H1-antagonist, selectively increased food intake during the light and decreased it during the dark period. Consequently, the antagonist increased the L/T ratio in food intake, but did not affect the ratio in water intake or ambulatory activity. Famotidine, an H2-antagonist, did not affect the ratio in any parameter. Thioperamide, an antagonist of auto-inhibitory effects on histamine synthesis and release at presynaptic H3-receptor sites, decreased food intake during the dark, but did not affect the L/T ratio in any parameter. These findings indicate that neuronal histamine may regulate feeding circadian rhythm through the hypothalamic histamine H1-receptor in rats.

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.

Neuronal histamine modulates feeding behavior through H1-receptor in rat hypothalamus.

To clarify the physiological role of hypothalamic neuronal histamine in control of food intake, ingestive behavior and neuronal activity were investigated under blockade or diurnal fluctuation of hypothalamic neuronal histamine. Histamine H1- but not H2-receptor antagonist potently induced feeding in a dose-related manner after infusion into rat third cerebroventricle at 1100 h. Elicitation was attenuated after infusion at 1940 h when histamine content in the hypothalamus was low and was abolished after intraperitoneal pretreatment with 0.11 mmol alpha-fluoromethylhistidine (alpha-FMH), a specific suicide inhibitor of histidine decarboxylase. Electrophoretic application of a histamine H1-receptor antagonist to ventromedial hypothalamic neurons specifically suppressed activities of glucose-responding neurons that are related to food intake. The suppressive effect was also attenuated by intraperitoneal pretreatment with alpha-FMH. These results suggest that feeding induced by histamine H1-receptor antagonists is due to blockade of neuronal histamine at the site of histamine H1-receptors, at least in part, in the ventromedial hypothalamus and that diurnal fluctuation of feeding behavior may reflect circadian variation of neuronal histamine level.

Clinical investigation of terfenadine, a non-sedating antihistamine.

Terfenadine was evaluated for the relief of symptoms in patients with allergic pollinosis on a double-blind basis. Terfenadine 20 mg tid was as effective as Chlorpheniramine maleate 4 mg tid. Chlorpheniramine consistently showed a higher incidence of sedation than placebo. None of the terfenadein dosage schedules up to 200 mg tid caused sedation significantly different from that of placebo. Terfenadine appears to be the first antihistamine to lack significant central nervous system effects.