A pilot study to examine the feasibility of insulin glargine in subjects with impaired fasting glucose, impaired glucose tolerance or new-onset type 2 diabetes.

OBJECTIVE: People with early type 2 diabetes and pre-diabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) are at risk of hyperglycaemia-related complications, including cardiovascular disease. Insulin, traditionally reserved as late treatment in type 2 diabetes, may also be a useful therapy in this population. We examined the short-term efficacy and tolerability of insulin glargine (glargine) in individuals with early or pre-type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicentre, double-blind, placebo-controlled, randomized, parallel group, 12-day study, subjects with IGT/IFG (n=9), newly diagnosed type 2 diabetes (n=9) or normal glucose tolerance (n=3) (confined to a clinical research unit taking a prescribed diet) were randomized to once-daily glargine (n=16) or placebo (saline; n=5) at bedtime. Dose was titrated to achieve target fasting blood glucose (FBG) 80-95 mg/dL. RESULTS: Over the treatment period, mean FBG decreased in glargine-treated subjects (from 100.0+/-18.8 to 85.6+/-18.4 mg/dL), but was unchanged in placebo-treated subjects (from 112.5+/-10.6 to 111.3+/-17.5 mg/dL). Mean eight-point blood glucose value decreased by 9.7 mg/dL in the glargine group, but increased by 8.1 mg/dL in the placebo group. Mean post-exercise blood glucose was similar before and after glargine treatment, but increased after placebo treatment. Five subjects receiving glargine experienced 16 mild symptomatic hypoglycaemia episodes; however, no hypoglycaemia occurred during exercise. Mean body weight decreased in both the glargine (-0.44 kg) and placebo (-0.25 kg) groups, in line with dietary restrictions. CONCLUSIONS: The results of this pilot study suggest that glargine can be used by people with IFG, IGT or new-onset type 2 diabetes for management of hyperglycaemia with low risk of hypoglycaemia. However titration of insulin in people on dietary restrictions should be more cautious as they may be more prone to hypoglycaemia. Further studies are warranted to determine the clinical benefits of this approach.

RHC 3288 [1-methyl-2(1,3,4-oxadiazol-2(3H)-one-5-yl) benzimidazole] and related compounds. Novel inhibitors of histamine release from rat mast cells and human basophils.

RHC 3288 [1-methyl-2(1,3,4-oxadiazol-2(3H)-one-5-yl) benzimidazole] and twenty-five related 5-substituted oxadiazolones have been investigated for their antiallergic activities in three in vitro models of anaphylaxis. Sixteen compounds were potent (I50 less than or equal to 50 microM) inhibitors of antigen-induced release of histamine (AIR) from rat mast cells (RMC), and seven compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 100 microM). The antiallergic activity profiles of RHC 3288 and three other compounds in these models have been compared with that of disodium cromoglycate (DSCG). As inhibitors of AIR from RMC, RHC 3288, 3334, 3354 and 3380 were 3 to 10 times more potent than DSCG. In the same model (AIR from RMC), activity profiles of all four RHC compounds were identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylaxis and cross-tachyphylaxis to each other, and inability to inhibit histamine release stimulated by Ca2+ ionophore, dextran + phosphatidyl serine and compound 48/80. RHC 3288, 3334, 3354 and DSCG had no effect in the other two models, histamine release from guinea pig lung mediated predominantly by IgG1 class of antibodies and anti-IgE-induced histamine release from human basophils. We conclude that RHC 3288 is a potent inhibitor of mediator release with a mechanism of action similar to that of DSCG.

Ototoxic effects of irradiation.

In this study ototoxic effect of ionizing radiation was studied in 70 ears with minimum follow up of 6 months post radiotherapy. Patients of nasopharyngeal carcinoma and with conductive deafness pre radiotherapy were excluded from the study to eliminate mechanical obstruction that may play role in Eustachian tube dysfunction. We found that Eustachian tube dysfunction and conductive deafness were reversible where as Sensorineural hearing loss was an irreversible effect of radiotherapy. Dose of radiation was directly proportional to ototoxicity, minimum 60 Gys of total radiation dose was required to produce significant ototoxicity.

Antiallergic activity profiles in vitro of RHC 3164 and related compounds. II. Comparison of RHC 3164 with disodium cromoglycate.

RHC 3164 has been investigated for its antiallergic activities in 3 in vitro models of anaphylaxis. RHC 3164 was 6 times more potent than DSCG as an inhibitor of antigen-induced release of histamine (AIR) from rat mast cells (RMC) and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties, cross-tachyphylaxis to DSCG, and inability to inhibit nonimmunologic release of histamine. Neither RHC 3164 nor DSCG had any effect on immunologic release of histamine from human basophils or guinea pig lung slices. We conclude that RHC 3164 is a potent inhibitor of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG.

Antigen- and ionophore-induced signal transduction in rat basophilic leukemia cells involves protein tyrosine phosphorylation.

Treatment of rat basophilic leukemia cells (RBL-2H3) with antigen or ionophore leads to an increase in cellular protein tyrosine phosphorylation. Three major proteins of molecular mass of 72, 92, and 110 kDa are targeted by antigen and a 110-kDa species by ionophore, A23187. The antigen- and ionophore-induced tyrosine phosphorylation responses are dose-dependent and correlate with increases in serotonin release from activated cells. The presence of extracellular Ca2+ is required to sustain the antigen- and ionophore-stimulated tyrosine phosphorylation as well as mediator release. A protein tyrosine kinase inhibitor, RG 50864, differentially inhibits the antigen-stimulated tyrosine phosphorylation in the decreasing order of 72, 91, and 110-kDa proteins. The compound inhibition of the 72-kDa protein tyrosine phosphorylation correlates with that of serotonin release. In ionophore-stimulated cells, the inhibition of the 110-kDa protein tyrosine phosphorylation and serotonin release by RG 50864 occurs in parallel. These results suggest that the 72- and 110-kDa phosphoproteins may represent the respective regulators of serotonin release in antigen- and ionophore-activated cells. The 110-kDa tyrosine phosphorylated proteins from antigen- and ionophore-stimulated cells exhibit identical electrophoretic mobility and V8 protease-generated phosphopeptide maps, suggesting that these two proteins may be the same. These results provide new evidence that both the stimulatory actions of antigen and ionophore on mediator release are mediated through enhanced protein tyrosine phosphorylation in RBL-2H3 cells. Significantly, the present study suggests the presence of multiple tyrosine phosphorylation signaling pathways in RBL cells and that their selective utility may be determined by the nature of the stimulus.

Antagonism by some beta-adrenoceptor-blocking agents to cholinergic stimulation of skeletal muscle in vitro.

Antiacetylcholine activity some beta-adrenoceptor-blocking drugs was investigated using isolated guinea pig cremaster muscle and frog fectus abdominis muscle. On the cremaster muscle, the antagonism to acetylcholine was non competitive in K0 1313, (+/-)-INPEA and (--)-INPEA, competitive in (+)-INPEA and functional in practolol; All three INPEA isomers, practolol and propranolol behaved as noncompetitive antagonists of acetylcholine on frog rectus muscle. Caffeine-induced contractions of this muscle were partially inhibited by propranolol but not by the other drugs. It is suggested that the beta-adrenoceptor-blocking drugs produce their antiacetylcholine action by interaction with sites on the muscle which are different from the cholinceptor, and which vary between compounds and species.

Novel cytokine release inhibitors. Part II: Steroids.

Steroidal derivatives as IL-1 beta release inhibitors are discussed.

RHC 3024: antiallergic activity in vitro and comparison with disodium cromoglycate and other antiallergic agents.

RHC 3024 has been investigated for its antiallergic activity in three in vitro models of anaphylaxis. We have also compared its activity profile in these models with that of disodium cromoglycate (DSCG) and other antiallergic agents. As an inhibitor of antigen-induced release of histamine from rat mast cells RHC 3024 was 4 times more potent than DSCG. In the same model the activity profile of RHC 3024 was identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, reversibility of the inhibition, tachyphylaxis and cross-tachyphylaxis to each other and inability to inhibit histamine release stimulated by Ca++ ionophore, dextran/phosphatidyl serine and compound 48/80. Both drugs had no effect in the other two models, IgG1-mediated histamine release from guinea pig lung and anti-IgE-induced histamine release from human basophils. We conclude: (1) RHC 3024 is a potent inhibitor of mediator release with a mechanism of action similar to that of DSCG, M&B 22,948, PRD-92-Ea and AH-7725 and (2) the in vitro activity profiles of proxicromil, doxantrazole, ICI 74,917 and WY-16,922 are different from DSCG and RHC 3024.

Inhibition of IL-1 release from human monocytes and suppression of streptococcal cell wall and adjuvant-induced arthritis in rats by an extract of Tripterygium wilfordii Hook.

1. It was investigated whether an extract of Tripterygium wilfordii Hook f (TW) inhibits IL-1 production by monocytes and suppresses the development of IL-1-dependent arthritis induced in rats with streptococcal cell wall and adjuvant. 2. TW preferentially inhibited IL-1 alpha and IL-1 beta production by bacterial lipopolysaccharide (LPS)-stimulated human monocytes with IC50 of approximately 1 microgram/ml. 3. Oral administration of TW dose-dependently suppressed joint swelling and structural damage in streptococcal cell wall-induced arthritis (ED50 = 20 mg/kg/day) and in adjuvant-induced arthritis (ED50 = 46 mg/kg/day for developing and 8 mg/kg/day for established arthritis).

Antiallergic activity profiles in vitro of RHC 3164 and related compounds. I. A lack of correlation between inhibition of cyclic nucleotide phosphodiesterases and antigen-induced release of histamine from rat mast cells.

A series of 26 compounds belonging to the chemical class of (1,2,4)triazolo(4,3-a)-quinoxaline-1,4-diones have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis. Effects of these and other known antiallergic agents on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells have also been investigated. 18 compounds were potent (I50 less than or equal to 45 microM) inhibitors of antigen-induced release of histamine (AIR) from rat mast cells (RMC), 3 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 25 microM) and none of the compounds significantly affected AIR from guinea pig lung slices. 13 of the compounds were more potent than theophylline as inhibitors of cyclic AMP-PDE and/or cyclic GMP-PDE from RMC. Parallel concentration-response curves for the inhibition of cyclic AMP-PDE and cyclic GMP-PDE indicated that these compounds probably interact with enzyme in the same manner. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC by these compounds revealed no statistically significant correlation between the inhibition of AIR and inhibition of cyclic AMP-PDE or cyclic GMP-PDE. We conclude: (1) some of these compounds are potent inhibitors of immunologic release of histamine from RMC with an in vitro activity profile similar to that of DSCG, and (2) inhibition of cyclic AMP or cyclic GMP hydrolysis by cNUD-PDE by these compounds, DSCG, and 6 known antiallergic agents is not the biochemical mechanism by which they inhibit AIR from RMC.

The inhibition of 5-lipoxygenase by RG 6866.

The generation of leukotrienes C4, D4 and E4 from arachidonic acid is dependent upon the activity of 5-lipoxygenase (5-LOX). The effects of RG 6866 (N-methyl-4-benzyloxyphenylacetohydroxamic acid) on the activity of guinea pig 5-LOX in vitro and in vivo were determined in the present study. The generation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) from arachidonic acid by isolated guinea pig peritoneal polymorphonuclear (PMN) cells was inhibited by incubation with RG 6866 (IC50 = 0.20 microM). A similar effect (IC50 = 0.23 microM) was observed when 5-HETE production was measured in a supernatant fraction from PMNs. Additionally, the compound did not inhibit 3H-LTD4 binding to guinea pig membranes. In actively sensitized guinea pigs pretreated with indomethacin, propranolol and pyrilamine, RG 6866 inhibited antigen-induced systemic anaphylaxis and LTD4-dependent bronchoconstriction in a dose-dependent manner following oral administration. In the pulmonary anaphylaxis model, significant (p less than 0.05) inhibition of the mortality was observed within 30 min and maintained through four hours after treatment with RG 6866 (50 mg/kg i.g.). Finally, orally administered RG 6866 inhibited the formation of LTC4 in these animals with an ED50 = 24.0 mg/kg. These findings indicate that RG 6866 is an inhibitor of 5-LOX both in vitro and in vivo.