Antiallergic action of betotastine besilate (TAU-284) in animal models: A comparison with ketotifen

The effects of betotastine besilate (betotastine: TAU-284), a novel antiallergic drug, on homologous passive cutaneous anaphylaxis (PCA), mediator-induced cutaneous reaction, antigen-induced asthmatic responses and platelet-activating factor (PAF)-induced airway eosinophilia in several animal models, were compared to ketotifen. Betotastine (0.1 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) inhibited both rat PCA and histamine-induced cutaneous reaction, whereas they showed little effect on serotonin-induced cutaneous reaction. Betotastine (0.3 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o. ) significantly inhibited antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. In actively sensitized guinea pigs, the immediate and late phase increase in airway resistance (Rrs) were observed within 5 min and between 4 and 7 h after the aeroantigen challenge. Betotastine (1 mg/kg, p.o.) inhibited both responses. Ketotifen (1 mg/kg, p.o.) inhibited the immediate phase response, but did not affect the late phase response. Exposure of guinea pigs to aerosolized PAF increased the number of eosinophils in bronchoalveolar lavage fluid 24 h after the stimulation. Betotastine (3-10 mg/kg, p.o.) dose-dependently inhibited PAF-induced accumulation of eosinophils in the bronchoalveolar cavity. In contrast, cetirizine (10 mg/kg, p.o.) showed a tendency to inhibit eosinophil accumulation, and ketotifen (10 mg/kg, p.o.) and terfenadine (10 mg/kg, p.o.) did not have any affect. These results indicate that betotastine could be useful in the treatment of allergic disease such as bronchial asthma.     

Effect of oxatomide on experimental allergic rhinitis in guinea pigs

Most psychologic and social theories of anorexia focus on the developmental pressures that challenge adolescent girls. Pregnancy, which causes profound physical, emotional, and cognitive changes, could represent an amplification of these developmental pressures. In this case study, pregnancy is suggested as a possible contributor to the development of anorexia in a 17-year-old female. Although she has other factors associated with the development of anorexia, the psychological and physical changes of pregnancy appear to be the crucial changes which precipitated anorexia nervosa.     

Influence of the anti-allergic agent, azelastine, on tumor necrosis factor-alpha (TNF-alpha) secretion from cultured mouse mast cells

The survival of infants with trisomy 14 mosaicism has been scarcely reported in the literature, with only 15 cases being documented up to 1992. We present a case of a dichorionic twin pregnancy in which prenatal sonography at 24 weeks' gestation showed that one of the twins had several anomalies including intrauterine growth restriction, alobar holoprosencephaly, a cleft lip and palate, a recessive chin, a small stomach, overlapping fingers, a ventricular septal defect, and polyhydramnios. Twin 2 was structurally normal. In view of the lethal condition and associated polyhydramnios affecting one of the twins, prenatal surveillance for signs of tense polyhydramnios and premature labour was undertaken. The pregnancy proceeded uneventfully until 37 weeks, at which time a Caesarean section was performed. At birth, neonatal blood from the abnormal twin confirmed trisomy 14 mosaicism in 12 per cent of lymphocytes. The infant died on day 36 of life.     

Effect of rebamipide, a novel antiulcer agent, on Helicobacter pylori adhesion to gastric epithelial cells

We examined regional cerebral blood flow (rCBF) during a long-term recognition memory task for words in schizophrenic patients and in healthy subjects using positron emission tomography (PET). The task was designed so that performance scores were similar in the patient and control subjects. This memory retrieval task did not increase rCBF in the patients' prefrontal cortex, precuneus and cerebellum as much as it did in the control group. These results point to a dysfunctional corticocerebellar circuit leading to poorly coordinated mental activity ('cognitive dysmetria'), which could explain the broad range of schizophrenic symptoms. In addition, other brain areas were more activated by the task in the patient group than in the control group and may form a compensatory network performing the memory retrieval task by assisting or replacing the dysfunctional cortico-cerebellar circuit.     

Effects of vesnarinone, a novel orally active inotropic agent with an immunosuppressive action, on experimental cardiac transplantation in rats

BACKGROUND: Vesnarinone (VES) has been used for treatment of patients with congestive heart failure. In addition to inotropic effects, it seems to have immunosuppressive action. We tested the hypothesis that VES suppresses graft rejection, inotropic dysfunction caused by early rejection, and chronic coronary obstruction in a heterotopic rat cardiac transplantation model. METHODS: (1) To study acute rejection, hearts from Lewis-Brown Norway (LBN) rats were transplanted into Lewis rats, which were treated with or without VES (50 or 100 mg/kg/day orally). (2) In a functional study, LBN hearts with or without VES (100 mg/kg/ day) were isolated and perfused on day 3 after transplantation to assess inotropic response to isoproterenol (3 x 10(-8) M). (3) To study chronic rejection, Lewis hearts were transplanted into Fisher 344 rats, which were treated with or without VES (50 mg/kg/day) for 90 days. Coronary obstructive disease was assessed by morphometric analysis. There were five to six animals in each group. RESULTS: (1) VES (100 mg/kg/day) prolonged LBN heart survival (11.7 +/- 0.7 vs. 9.6 +/- 0.7 days in control; P < 0.05). (2) Left ventricular developed pressure was depressed in transplanted hearts regardless of VES treatment (84 +/- 12, 90 +/- 8 vs. 144 +/- 16 mmHg in untransplanted hearts; P < 0.01). The developed pressure after administration of isoproterenol in VES-treated hearts (184 +/- 20 mmHg) was higher than transplanted hearts without VES (118 +/- 16 mmHg; P < 0.05), and similar to untransplanted hearts (203 +/- 27 mmHg; P = NS). (3) Transplanted hearts treated with or without VES showed similar grades of rejection (2.0 +/- 0.3 vs. 2.6 +/- 0.2; P = NS), intimal area (6,996 +/- 3,186 vs. 13,441 +/- 5,165 microns2; NS), and coronary luminal obstruction (45 +/- 16% vs. 67 +/- 14%; NS). CONCLUSIONS: VES produces mild prolongation in survival of rat heart grafts, but has no significant effect on chronic graft atherosclerosis. VES preserves the positive inotropic effects of isoproterenol that are otherwise deteriorated by early acute rejection.     

Pre-clinical evaluation of a novel chloroethylating agent, Clomesone

The in vitro activity of the novel chloroethylating agent, Clomesone, was investigated in a panel of established murine and human tumour cell lines. In vivo anti-tumour activity was examined against three transplantable adenocarcinomas of the mouse colon and in vivo bone marrow toxicity was assessed using a spleen colony forming unit assay. The pharmacokinetic behaviour of the drug in vivo and drug stability in vitro was analysed by gas chromatography with electron capture detection. Clomesone exhibited no activity in vitro against the majority of cell lines derived from solid human colorectal carcinomas. Anti-tumour activity against the murine tumours in vivo was not impressive and was accompanied by myelosuppression. Pharmacokinetic data suggested that the lack of in vivo activity was due to the failure to achieve effective anti-neoplastic drug concentrations at the tumour site. It was concluded that this study found no evidence to suggest that Clomesone was toxicologically more selective than the chloroethylnitrosoureas.     

Effect of topical steroids on nasal nitric oxide production in children with perennial allergic rhinitis: a pilot study

It has been hypothesized that concentrations of exhaled nitric oxide (NO) may be related to the extent of cytokine-mediated airway inflammation. Recent findings indicate the nasal airways as an important site of NO production. Our objective was to evaluate whether children with allergic rhinitis show different nasal NO levels when compared with normal healthy subjects and the effect of topical steroids and anti-histamine therapy. We have measured the concentration of NO drawn from the nose of 21 children (5-17 years old) affected by perennial allergic rhinitis (house dust mite) out of therapy for at least 3 weeks. Thirteen children were then treated with nasal beclomethasone dipropionate (BDP) (400 micrograms daily) and eight subjects with nasal anti-histamine levocabastine (200 micrograms daily). Measurements were performed before and after 10 days of treatment. As a control group we evaluated 21 healthy children aged 5-15 years. To measure NO we used a chemiluminescence analyser. Before treatment the whole group of children with allergic rhinitis showed a mean (+/- SEM) nasal NO concentration of 267 +/- 18 ppb, significantly higher (P < 0.01) than the control group (186 +/- 15 ppb). The group of children treated with BDP showed, after 10 days of therapy, a significant (P < 0.05) decrease of nasal NO concentration (271 +/- 21 ppb vs. 212 +/- 20 ppb). Indeed, in the group treated with levocabastine, nasal NO concentrations did not present a significant difference (P not significant) compared with baseline (261 +/- 33 ppb and 252 +/- 31 ppb, respectively). These data suggest that (1) children with allergic rhinitis have higher levels of nasal NO than non-atopic controls and (2) intranasal steroid therapy significantly reduces nasal NO production in children with allergic rhinitis. We speculate that the allergic inflammatory response may influence the nasal NO levels and that NO measurements may be a useful marker of nasal inflammation.     

Comparative efficacy of terfenadine, loratadine, and astemizole in perennial allergic rhinitis

BACKGROUND: It is not known how many children with epilepsy may not need treatment with antiepileptic drugs (AEDs), how many respond unsatisfactorily to subsequent treatment regimens, and how many achieve "acceptable control" despite lack of remission. METHODS: In a prospective multicenter hospital-based study, 494 children with a broad range of seizure types and types of epilepsy were followed up for at least 2 years. There was no standard treatment protocol. We describe the treatment strategies applied to these children by the neurologists in charge and outcome with respect to remission from seizures. RESULTS: Treatment was initially withheld in 29% of the children, and after 2 years 17% still had not received any AEDs. There were no serious complications caused by withholding treatment. Of the children treated with AEDs, 60% were still using the first AED after 2 years; 80% received monotherapy and 20%, polytherapy. Children with severe symptomatic epilepsies, such as the West or Lennox-Gastaut syndrome, received polytherapy early on in the course of treatment. When 3 regimens had failed, the chance of achieving a remission of more than 1 year with subsequent regimens was 10%. Nevertheless, 15 of 50 children receiving AEDs in whom the "longest remission ever" was less than 6 months did achieve acceptable seizure control according to the neurologist in charge of treatment. Hence, of 494 children, only 35 (7%) developed an intractable form of epilepsy, defined as failure to bring seizures under acceptable control. CONCLUSIONS: A substantial percentage of children with new-onset epilepsy did not need treatment with AEDs. Chances of achieving a good outcome declined with subsequent treatment regimens. Not all children with recurrent seizures were suffering from intractable epilepsy; some had achieved acceptable control of seizures.     

Studies on the mechanism of action of a novel anorectic agent, (--)-threo-chlorocitric acid

(--)-threo-Chlorocitric acid, a novel and potent anorectic agent in rats and dogs, decreased food intake to a comparable extent in rats fed chow, low fat, or high fat diets. This inhibition of food intake was not the result of conditioned aversion. Unlike (--)-threo-hydroxycitric acid, a structurally related compound which inhibits fatty acid synthesis, (--)-threo-chlorocitric acid did not suppress fatty acid synthesis in an isolated hepatocyte system or in vivo. (--)-threo-Chlorocitric acid significantly delayed the rate of gastric emptying. Of the four stereoisomers of chlorocitric acid, (--)-threo-chlorocitric acid was the most active both in delaying gastric emptying and producing anorexia in rats. It is suggested that the mechanism by which (--)-threo-chlorocitric acid may suppress food intake is through a reduction of gastric emptying.     

Baseline consideration of liposomal contrast agent. CNS transport by macrophages in experimental allergic encephalomyelitis

The purpose of this study was to investigate a specialized liposomal contrast agent for magnetic resonance imaging (MRI), as part of a program to examine infiltrating immune cells in lesions of experimental allergic encephalomyelitis (EAE). A potent investigational liposomal contrast agent, phosphatidylethanolamine-DTPA-gadolinium, was chosen which has been shown to remain tightly liposomal-associated, with long persistence in vivo. Europium (Eu3+), a fluorescent paramagnetic metal, was also utilized in these experiments in place of gadolinium. This material is avidly taken up by monocytes in vivo. Thirty-four animals received some form of liposomal material either before or during the opening of the blood-brain barrier (BBB). Twenty-seven Hartley guinea pigs were inoculated for EAE with homogenized brain and Complete Freunds Adjuvant (CFA) and seven control animals received CFA alone. Eighty-two percent of the experimental animals exhibited degeneration of the BBB with inflammation and edema in the brain, while all control animals had normal brain scans. T1-weighted MRI, performed to detect the presence of liposomal contrast material in experimental animals, was not different from untreated animals. Fluorescent microscopy revealed no characteristic changes associated with Eu3+ presence in the brains of treated or control animals. Therefore, it would seem that insufficient material crosses the disrupted BBB, either in free form or subsequent to macrophage ingestion, to be detected by MRI or fluorescent microscopic examination.     

Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL-4943A), a novel drug for treating ocular allergic diseases

Olopatadine (AL-4943A; KW-4679) [(Z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2-acetic acid hydrochloride] is an antiallergic/antihistaminic drug under development for topical ocular use. The effects of the compound on release of proinflammatory mediators (histamine, tryptase and prostaglandin D2) from monodispersed human conjunctival mast cells were assessed. Histamine receptor subtype binding affinities and functional potencies were determined with ligand binding and phosphoinositide turnover assays, respectively. Olopatadine inhibited the release of histamine, tryptase and prostaglandin D2, in a concentration-dependent manner (IC50 = 559 microM). Evaluation of the interaction of olopatadine with histamine receptors revealed a relatively high affinity for the H1 receptor (Ki = 31.6 nM, pKi = 7.5 +/- 0.1, n = 7) but lower affinities for H2 receptors (Ki = 100 microM, pKi = 4.0 +/- 0.19, n = 7) and H3 receptors (Ki = 79.4 microM, pKi = 4.1 +/- 0.16, n = 7). The H1 selectivity of olopatadine was superior to that of other ocularly used antihistamines studied, such as ketotifen, levocabastine, antazoline and pheniramine. The profiling of olopatadine in 42 nonhistamine receptor binding assays revealed that olopatadine interacts with only two nonhistamine receptor/uptake sites to any significant degree (pIC50 < or = 5-6). Olopatadine inhibited histamine-induced phosphoinositide turnover in human conjunctival epithelial cells (IC50 = 10 nM, pIC50 = 8.0, n = 4) and in other human ocular cells (IC50 = 15.8-31.6 nM, pIC50 = 7.5-7.8) and exhibited apparent noncompetitive antagonist properties in these cells, with an estimated dissociation constant (Kb) of 19.9 nM (pKb = 7.7, n = 6). This combination of mast cell mediator release inhibition and selective H1 receptor antagonism suggests that olopatadine may be particularly useful in the treatment of ocular allergic diseases. Indeed, olopatadine has recently shown clinical efficacy in an allergic conjunctivitis model in human subjects.     

Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties

OBJECTIVES: This study was designed to evaluate how the atrial electrophysiological and antiarrhythmic effects of azimilide compare with those of the specific rapid delayed rectifier (IKr) blocker dofetilide. BACKGROUND: Azimilide, a new class III drug, was initially believed to be a highly selective blocker of the slow delayed rectifier (IKs), but recent studies suggest that azimilide potently blocks IKr. Thus, it has been suggested that azimilide's in vivo effects may simply be due to IKr blockade. METHODS: Dose regimens producing stable effects over time were developed, and two dose levels of azimilide (10 and then 20 mg/kg) or dofetilide (0.08 and then 0.16 mg/kg) were administered to morphine/chloralose-anesthetized dogs during sustained vagal atrial fibrillation (AF). Epicardial mapping was used to measure conduction velocity and AF cycle length. RESULTS: Azimilide terminated AF in 13/14 dogs (93%), while dofetilide terminated AF in 6/12 (50%, P < 0.05). While dofetilide had strong reverse use-dependent effects on atrial ERP (e.g. at lower doses, dofetilide increased ERP by 51 +/- 3% at a basic cycle length, BCL, of 400 ms and by 17 +/- 3% at a BCL of 200 ms), azimilide's effects on ERP were rate-independent (ERP increased at lower dose by 38 +/- 6%, BCL 400 ms; 35 +/- 10%, BCL 200 ms). Neither drug affected conduction. CONCLUSIONS: Azimilide is effective against experimental AF, and increases ERP with a frequency dependence different from the IKr blocker dofetilide, suggesting that azimilide's actions on atrial tissue cannot be attributed exclusively to IKr block, and that effects on other currents (such as IKs) are likely to be important.     

Induction, localization, and purification of a novel sialidase, deaminoneuraminidase (KDNase), from Sphingobacterium multivorum

Recently, we reported the discovery of a new type of sialidase, KDNase, which specifically hydrolyzes the ketosidic linkages of 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN), but not N-acylneuraminyl linkages. We now report that this enzyme, designated KDNase SM, is an inducible enzyme that is localized in the periplasm of Sphingobacterium multivorum. Growth of S. multivorum in the presence of KDN-containing oligosaccharide alditols, KDNalpha2-->3Galbeta1-->3GalNAc alpha1-->3[KDNalpha2--> (8KDN alpha2-->)n-->6]GalNAcol, as a sole carbon source induced KDNase SM activity 15 40-fold, compared with growth in the absence of inducer. KDN, Neu5Ac, or Neu5Ac oligomers were ineffective as inducers. The enzyme was released from the periplasm of induced cells by cold osmotic shock and purified 700-fold to homogeneity. The specific activity of the pure enzyme was 82,100 units/mg of protein. KDNase SM activity resided in a single polypeptide chain with an estimated molecular weight of approximately 47,500. Enzyme activity was maximal at near neutral pH. The availability of pure KDNase will now make it possible to study the structure and functional role of KDN-glycoconjugates and to determine the molecular mechanism whereby the enzyme can discriminate between KDN and N-acylneuraminic acid.     

Ecabapide, a novel gastroprokinetic agent, ameliorates gastric emptying of stroke-prone spontaneously hypertensive rats (SHRSP)

The effect of ecabapide, a novel gastroprokinetic agent, on gastric emptying was examined in stroke-prone spontaneously hypertensive rats (SHRSP), which are known to exhibit gastric malfunctions as a result of autonomic nervous system disorder. Ecabapide was administered orally to SHRSP in various dose-regimens. Gastric emptying was evaluated by the acetaminophen (APAP) method using semi-solid meal under the conscious conditions. Ecabapide significantly enhanced gastric emptying of SHRSP at 1 mg/kg in single administration, 0.3 and 1 mg/kg in 2-week treatment and 7.7 mg/kg in 4-week (diet) exposure. These results suggest that the effect of ecabapide is exerted without showing tachyphylaxis.     

Intestinal transport of gentamicin with a novel, glycosteroid drug transport agent

PURPOSE: The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. METHODS: Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. 3H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. RESULTS: The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal orjejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. CONCLUSIONS: TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.     

Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus

Repaglinide is a new, short-acting, insulin-releasing agent recently approved for the monotherapy of type 2 diabetes mellitus, and in combination with metformin in patients failing repaglinide or metformin monotherapy. Repaglinide appears to trigger insulin release by regulating adenosine triphosphate-sensitive potassium channels on the surface of pancreatic beta cells, which in turn affect calcium influx, the principal mediator of insulin release. Repaglinide mainly affects postprandial plasma glucose concentrations. It reduces glycosylated hemoglobin concentrations by 1-2% U. The agent's short duration of action may lessen the risk of long-lasting hypoglycemia and of down-regulation of beta cell sensitivity (the latter promoting secondary drug failure), although data are sparse in this regard. Its major adverse effect is hypoglycemia. Its role in the therapy of type 2 diabetes is unclear at present, vis-à-vis its use instead of or in combination with other antidiabetic agents other than metformin. The need for multiple daily doses, based on its brief duration of action, may be a barrier to compliance.     

Solid-state characterization of AG337 (Thymitaq), a novel antitumor drug

AG337 (Thymitaq) is an antitumor compound synthesized by Agouron Pharmaceuticals, Inc., using protein structure-based drug design. AG337 is a hydrochloride salt with a molecular formula of C14H12N4OS.2HCl. This compound was subjected to thermal analyses, Karl Fischer titrimetry, powder X-ray diffractometry, scanning electron microscopy, and FTIR. On the basis of the Karl Fischer and thermogravimetric analysis, it was conclude to be a dihydrate. The differential scanning calorimetric studies revealed, that on heating, AG337 dehydrates and form a metastable form with a melting point of 213 degrees C followed by crystallization into a stable form at 261 degrees C. This stable form was finally melted at 312 degrees C with decomposition. On the basis of the FTIR and HPLC studies, it was concluded that the final exothermic peak at 320 degrees C was due to sample decomposition. The powder X-ray diffraction studies confirmed the existence of these two polymorphs of AG337. Scanning electron microscopic studies revealed that the crystal habits of both the polymorphs were quite different. FTIR spectra of both the polymorphs showed pronounced difference in the range of 600-1800 cm-1.     

Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis

Uric acid, the naturally occurring product of purine metabolism, is a strong peroxynitrite scavenger, as demonstrated by the capacity to bind peroxynitrite but not nitric oxide (NO) produced by lipopolysaccharide-stimulated cells of a mouse monocyte line. In this study, we used uric acid to treat experimental allergic encephalomyelitis (EAE) in the PLSJL strain of mice, which develop a chronic form of the disease with remissions and exacerbations. Uric acid administration was found to have strong therapeutic effects in a dose-dependent fashion. A regimen of four daily doses of 500 mg/kg uric acid was required to promote long-term survival regardless of whether treatment was initiated before or after the clinical symptoms of EAE had appeared. The requirement for multiple doses is likely to be caused by the rapid clearance of uric acid in mice which, unlike humans, metabolize uric acid a step further to allantoin. Uric acid treatment also was found to diminish clinical signs of a disease resembling EAE in interferon-gamma receptor knockout mice. A possible association between multiple sclerosis (MS), the disease on which EAE is modeled, and uric acid is supported by the finding that patients with MS have significantly lower levels of serum uric acid than controls. In addition, statistical evaluation of more than 20 million patient records for the incidence of MS and gout (hyperuricemic) revealed that the two diseases are almost mutually exclusive, raising the possibility that hyperuricemia may protect against MS.