Effects of two antihistamine drugs on actual driving performance.

A double blind placebo controlled experiment was conducted measuring the effects of the centrally active antihistamine triprolidine and the peripherally acting antihistamine terfenadine on actual driving performance in a group of experienced women drivers. Triprolidine greatly impaired driving behaviour, whereas terfenadine did not. Triprolidine also impaired subjective and objective measures of mood and arousal, and despite an awareness that their driving was impaired while they were taking this agent subjects could not correct their performance. This study suggests that drivers who need antihistamine drugs should avoid those that act centrally.     

Energy requirement for the incorporation of amino acids into protein of isolated mouse-liver mitochondria

Mitochondria isolated from mouse liver can incorporate amino acids into mitochondrial protein. Studies with oligomycin and antihistamine drugs indicate that this incorporation may not be an ATP requiring process.     

Benzodiazepine drugs in general medical patients.

Data from a hospital-based drug surveillance programme were used to determine how often benzodiazepine drugs were used in general medical wards. Benzodiazepines were the drugs most commonly used as hypnotics and were given to 32% of these patients. Concomitant use of more than one benzodiazepine drug or of benzodiazepines with other psychoactive drugs was common and often irrational. A series of double-blind patient-preference studies comparing various benzodiazepines and a benzodiazepine with an antihistamine showed that for short-term hypnotic effect there were no differences between three common benzodiazepines but elderly patients preferred benzodiazepines to the antihistamine, which produced more undesired effects. These results suggest that currently diazepam is the hypnotic of choice for medical ward inpatients.     

A clinical drug library screen identifies astemizole as an antimalarial agent

The high cost and protracted time line of new drug discovery are major roadblocks to creating therapies for neglected diseases. To accelerate drug discovery we created a library of 2,687 existing drugs and screened for inhibitors of the human malaria parasite Plasmodium falciparum. The antihistamine astemizole and its principal human metabolite are promising new inhibitors of chloroquine-sensitive and multidrug-resistant parasites, and they show efficacy in two mouse models of malaria.     

Solution-phase combinatorial synthesis of nonpeptide bradykinin antagonists

We describe the solution-phase combinatorial synthesis and pharmacological effect of fifty N,N(')-substituted-N"-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide derivatives as nonpeptide B2 antagonists. The synthesized compounds were tested for their antibradykinin activity by utilizing guinea-pig ileum smooth muscle. Most of the compounds showed antagonistic effects on bradykinin induced contraction. N-acetyl-N(')-(4-methylbenzyl)-N"-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide (A3B1C1) showed the 46% inhibition at 100nM.     

Diseases of the Skin: Drug Therapy of Urticaria

Most patients with urticaria can be assessed by taking a relatively simple history with few or no investigations and controlled by a suitable antihistamine given at appropriate times until spontaneous resolution occurs without a complete diagnosis ever being made. Those that do not respond in this way require sometimes quite elaborate investigations, the institution of which would be an imposition in a mild case. Even after full investigation and ringing the changes of all available drugs, too many cases persist to the frustration of all concerned.     

Synthesis and bradykinin inhibitory activity of novel non-peptide compounds,and evaluation of in vivo analgesic activity

A series of novel non-peptide diamide compounds was synthesized and evaluated as antibradykinin agents by utilizing guinea-pig ileum smooth muscle. Among the final compounds, (Z)-4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-4-oxo-N-(4-phenylbutan-2-yl)but-2-enamide showed most favorable bradykinin inhibitory activity and demonstrated analgesic efficacies in the rat models of inflammatory and neuropathic pain.     

A novel acoustic evaluation system of scratching in mouse dermatitis: rapid and specific detection of invisibly rapid scratch in an atopic dermatitis model mouse

Scratching is an essential and a skin specific behavior induced by itching, which is a common symptom of atopic dermatitis (AD) and other types of dermatitis. Itching sensation and scratching are closely associated and thus scratching times are currently used for evaluating itching in animal models. However, objective measuring systems of scratching to assess the grade of dermatitis and the effectiveness of anti-pruritic drugs in animal dermatitis models are lacking. To investigate a quantitative evaluation system for itching, we have developed a novel acoustic scratching counting system and compared its accuracy with time-consuming slow-motion video recording system. We have also objectively evaluated the efficacy of an antihistamine using this novel system. Scratching behavior of an AD model mouse (K14 driven IL-18 transgenic mouse) was recorded visually and acoustically. Specific scratching sound produced by mice was recorded and counted using a software we have developed, and the results obtained using our acoustic system were not statistically different from data obtained using slow motion video system. Surprisingly, mice scratched more than 10 times/second, which was invisibly rapid motion and revealed inaccuracy of conventional hand counting system. Results were identical to that of measured by 10 times time costing slow-motion video analysis. The antihistamine is clearly effective for suppression of scratching as demonstrated using this objective and accurate method. This novel motion analysis system will open a window for physiological and pathological analysis for animal models and development of anti-pruritic drugs.     

Mechanism of action of antipruritic drugs.

Astemizole and terfenadine, two potent non-sedative H1 antihistamines, had no effect on itch measured objectively as nocturnal scratching and subjectively on a 10 cm line. Trimeprazine, however, a more sedative but less potent H1 antihistamine, was antipruritic, as was nitrazepam, a sedative benzodiazepine. We concluded (a) that antipruritic drugs act centrally by a property related to sedation; (b) H1 receptor antagonists have a peripheral antipruritic action only when itch is due to histamine release, as in the wealing disorders. Thus the new nonsedative H1 antihistamines have no place in the treatment of itch from other causes.     

Antimuscarinic actions of antihistamines on the heart

Summary Antimuscarinic side-effects, which include dry mouth, tachycardia, thickening of mucus possibly sedation, of the antihistamines limited the usefulness of these drugs. The advent of newer agents has reduced the sedative effect of the antihistamine. The data presented here show that one of the newest antihistamines, desloratadine, and a first generation drug, diphenhydramine, are both competitive inhibitors of muscarinic receptor mediated slowing of the heart as measured using a Langendorff preparation. Both agents have apparent sub-micromolar affinities for the muscarinic receptor. Two other agents, cetirizine and fexofenadine, do not interact with muscarinic receptors in the heart at the concentrations used in this study. Structural similarities of the drugs suggest that substitution of a group with a high dipole moment or charge on the side chain nitrogen decreases the binding with muscarinic receptors. We conclude that of the compounds tested fexofenadine and cetirizine have little or no interaction with muscarinic receptors.     

Study of the natural antihistamine-like substance in bile in mammals.

A natural antihistamine substance (NAS) present in bile has been investigated. It was found that the antihistamine activity was not due to proteins, lipids, pigments, or amino acids. On ion exchange chromatography and thin-layer chromatography, this activity was associated with bile acids. Many bile acids could, in varying degrees, inhibit this histamine induced guinea pig ileum contraction, desoxycholic acid being the most potent. However NAS activity could be separated from bile acids and their conjugates using a different solvent system. Furthermore, NAS showed a higher antihistamine activity than bile acids. This substance seems to be responsible for 15-20% of the activity of whole bile. The substance has not yet been identified.     

Effects of antihistamines on the cardiopulmonary changes due to canine anaphylaxis

Histamine has long been considered to be an important chemical mediator in the pathogenesis of immediate hypersensitivity reactions. We evaluated the efficacy of antihistamines to determine the physiological role of histamine in canine anaphylaxis. Either a saline vehicle (control group), an H1 antihistamine (chlorpheniramine, 10 mg/kg), or this H1 antihistamine and an H2 antihistamine (cimetidine, 30 mg/kg) was administered to three separate groups of anesthetized dogs (n = 8). Cardiopulmonary responses and plasma histamine levels were measured after the separate intravenous injection of Ascaris suum antigen and histamine. Results were analyzed only from the animals demonstrating physiological responses or histamine release after antigen injection. In the control group, antigen produced a 43 +/- 15% (mean +/- SE) decrease in mean arterial blood pressure, a 34 +/- 13% fall in cardiac output, and a 19 +/- 9% decrease in lung compliance, whereas pulmonary vascular resistance increased 161 +/- 87% and airway resistance rose 114 +/- 66%. Similar physiological abnormalities were observed with histamine shock. However, peak plasma histamine levels were, in most cases, greater after histamine injection than after antigen injection. An H1 antihistamine alone or in combination with an H2 antihistamine did not alter the physiological changes associated with systemic anaphylaxis. In contrast, the combined use of H1 and H2 antihistamines prevented the cardiopulmonary responses associated with the intravenous administration of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Design,synthesis and biological activity evaluation of desloratadine analogues as H1 receptor antagonists

A series of N-substituted desloratadine analogues were designed and synthesized. They were tested for H₁ antihistamine activity by inhibiting histamine-induced contraction of isolated ileum muscles of guinea-pigs in vitro and inhibiting histamine-induced asthmatic reaction in guinea-pigs in vivo. All the evaluated compounds exhibited significant antihistamine activity compared with desloratadine. Five active compounds induced no sedative effects on mouse and four of them exhibited lower anticholinergic side effects than desloratadine. Among these analogues, compound 10, (1S,4S)-4-chlorocyclohexyl desloratadine displayed the highest activity and best safety profile. And it was believed to be a potential candidate as the 3rd generation antihistamine.     

Stereoselective synthesis of desloratadine derivatives as antagonist of histamine

A series of desloratadine derivatives were stereoselectively synthesized and evaluated for H₁ antihistamine activity. For the evaluation of H₁ antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) was used. The synthesized desloratadine derivatives 7, 8 and 9 are structurally related to rupatadine and were generated by replacement of the 5-methyl-3-pyridine group of rupatadine with γ-alkylidene butenolide. Their H₁ antihistamine activities have shown a high dependence on the exact nature of the substituent in the lactone ring. Optimum structures 7, 8a and 8g display potent activity inhibiting histamine-induced effects.     

In situ preparation of peptidylated polymers as ready-to-use adsorbents for rapid immunoaffinity chromatography

Summary The preparation method of peptide ligands employing polymer-supported solid-phase synthesis and leading to biospecific sorbents has been designed and optimized. This approach directly affords porous polymer sorbents for biospecific chromatography and avoids the cleavage of the synthesized peptide moieties from the carrier and their isolation. The specifics of both peptide synthesis and biospecific chromatography using hydrophilic macroporous polymer supports based on porous poly(glycidyl methacrylate-co-ethylene dimethacrylate) beads and discs were also investigated. The protecting groups can be removed from the target peptide (bradykinin) attached to the polymer support by trifluoromethylsulfonic acid without any significant loss of the attached peptide from the polymer carrier. Introduction of styrene as a comonomer into the copolymer structure improves the reactivity of the support. However, no nonspecific adsorption of proteins in the course of the biospecific isolation of antibradykinin antibodies was observed with these media. In contrast, the nonspecific sorption of proteins increases as a result of increasing peptide loading.     

Anti-inflammatory, analgesic and antipyretic activities of Linum usitatissimum L. (flaxseed/linseed) fixed oil

The fixed oil of L. usitatissimum (flaxseed/linseed) inhibited PGE2-, leukotriene-, histamine- and bradykinin-induced inflammation. The oil also inhibited arachidonic acid-induced inflammation, suggesting its capacity to inhibit both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism. In tail immersion model, the oil raised the pain threshold to a lesser extent than morphine but showed excellent peripherally acting, analgesic activity comparable to aspirin, against acetic acid-induced writhing in mouse. In typhoid paratyphoid A/B vaccine-induced pyrexia, the oil showed antipyretic activity comparable to aspirin. The oil contains 57.38% alpha-linolenic acid. Dual inhibition of arachidonic acid metabolism, antihistaminic and antibradykinin activities of the oil could account for the biological activity and the active principle could be alpha-linolenic acid an omega-3 (18:3, n-3) fatty acid.     

Antihistamine use and immunoglobulin E levels in glioma risk and prognosis

Objective: An inverse association between personal history of allergies/asthma and glioma risk has been fairly consistently reported in the epidemiologic literature. However, the role of regular antihistamine use remains controversial due to a small number of studies reporting contradictory findings. We evaluated the association between regular use of oral antihistamines and glioma risk, adjusting for a number of relevant factors (e.g., immunoglobulin E levels and history of chickenpox). Methods: We used a subset of the Harris County Case-Control Study, which included 362 pathologically confirmed glioma cases and 462 cancer-free controls, to evaluate this association using unconditional multivariable logistic regression. These models were run among the overall study population and stratified by allergy status. Cox regression was utilized to examine whether antihistamine use was associated with mortality among all cases and separately among high-grade cases. Results: Antihistamine use was strongly associated with glioma risk among those with a positive allergy/asthma history (OR: 4.19, 95% CI: 2.06–8.51), but not among those with a negative history (OR: 1.59, 95% CI: 0.95–2.67). There were no significant associations between antihistamine use and survival among cases. Conclusion: The current study implies that regular antihistamine use may increase glioma risk. However, several larger studies are necessary before definitive conclusions can be drawn.