Diltiazem is an orally and intravenously active calcium channel blocking agent shown to be an effective and well-tolerated treatment for stable angina and angina due to coronary artery spasm Its efficacy in these diseases has generally been similar to that of nifedipine or verapamil - alternative calcium channel blockers with which diltiazem has many electrophysiological, haemodynamic, and antiarrhythmic similarities The antianginal mechanism of diltiazem cannot be precisely described; however, it appears to increase myocardial oxygen supply and decrease myocardial oxygen demand, mainly by coronary artery dilatation and/or via both direct and indirect haemodynamic alterations Diltiazem has also shown substantial efficacy in the treatment of unstable angina, hypertension, and supraventricular tachyarrhythmias, but further study is necessary before its place in the treatment of these diseases may be clearly established Although headache due to peripheral vasodilatation and depression of atrioventricular nodal conduction may be troublesome, side effects occur in only 2 to 10% of patients receiving diltiazem and are generally minor in nature Thus, diltiazem offers a worthwhile alternative to other agents currently available for the treatment of angina pectoris Although the infrequency of serious side effects may offer an advantage, its relative place in therapy compared with that of other calcium channel blockers remains to be clarified

Diltiazem. A review of its pharmacological properties and therapeutic efficacy.

To determine the role in chemosensation of intestinal solitary cells that express taste receptors and Trpm5, we carried out a microarray study of the transcriptome of FACS-sorted transgenic mouse intestinal cells expressing enhanced green fluorescent protein (eGFP) under the control of the Trpm5 promoter and compared it with that of intestinal cells that do not express eGFP. The findings of the study are: 1) Morphology and expression of markers show that most eGFP+ cells are brush cells. 2) The majority of proteins known to be involved in taste signal transduction are expressed in the eGFP+ cells, although the isoforms are not always the same. 3) eGFP+ cells express pre- and postsynaptic markers and nerves are often found in close proximity. 4) Several genes that play a role in inflammation are expressed specifically in eGFP+ cells. Furthermore, these cells express the entire biosynthesis pathway of leucotriene C4, an eicosanoid involved in modulation of intestinal smooth muscle contraction. 5) Angiotensinogen, renin, and succinate receptor genes are expressed in the eGFP+ cells, suggesting a role in the regulation of water and sodium transport, vasomotricity, and blood pressure. These data suggest that the Trpm5-expressing cells integrate many signals, including chemical signals from ingested food, and that they may regulate several physiological functions of the gastrointestinal tract. J. Comp. Neurol. 509:514–525, 2008. © 2008 Wiley-Liss, Inc.

Murine intestinal cells expressing Trpm5 are mostly brush cells and express markers of neuronal and inflammatory cells

The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family.

Ibudilast is a relatively nonselective phosphodiesterase inhibitor which has been marketed for almost 20 years in Japan for treating asthma. More recently it has been found to have anti-inflammatory activity in both the peripheral immune system and in the CNS via glial cell attenuation. This CNS-directed anti-inflammatory activity is of potential use in the treatment of multiple sclerosis, neuropathic pain, and in the improved efficacy and safety of opioids by decreasing opioid tolerance, withdrawal and reinforcement. Its suitable pharmacokinetics and generally good tolerability make it a promising potential treatment for these conditions.

https://rsds.org/wp-content/uploads/2015/02/Rolan_Ibudilast_Review.pdf

Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease

Heterocyclic Compounds The invention relates to cyclic imino derivatives of formula I (I) (wherein A, B, C, D, E, F, G, R1, Z1, Z2, Z3, Z4, Z5, Z6, X and Yare as defined in any one of claims 1 to 5) and the tautomers, stereoisomers, mixtures and salts thereof, particularly the physiologically acceptable salts thereof. The new compounds have valuable pharmacological properties, in particular aggregation-inhibiting properties.

5-membered heterocyclic compounds, processes for preparing them and pharmaceutical compositions containing these compounds

Phenoxyalkylcarboxylic acid derivative represented by the following formula, 
wherein R 1 indicates hydrogen atom, methyl group or ethyl group, m is an integer from 2 to 5, and n is an integer from 3 to 8, X 1 and X 2 each independently represent sulfur atom, oxygen atom, sulfinyl group or sulfonyl group, proviso X 1 and X 2 are not simultaneously oxygen atom; their alkali salts and hydrates thereof are useful as antiallergic agents.

Phenoxyalkylcarboxylic acid derivatives and process for their preparation

Effects of drugs on behavior, heart rate and catecholamine levels in thiamine-deficient rats.

1. The effects of a novel anti-asthmatic drug, 3-isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (ibudilast, KC-404) on leukotriene D4 (LTD4)-induced formation of inositol phosphates were studied in slices of guinea-pig lung and hippocampus. 2. In guinea-pig lung, ibudilast inhibited LTD4 (0.01-1 microM)-induced formation of inositol monophosphate (IP1) in a concentration-dependent manner (IC50 = 10 microM) without affecting LTD4 receptor binding. 3. Ibudilast (10 microM) inhibited histamine (0.1-1 mM)-induced formation of IP1 in guinea-pig lung slices but not in hippocampal slices. 4. Inhibition of agonist-induced formation of IP1 by ibudilast was non-competitive. 5. Ibudilast had no effect on either GTP- or calcium-stimulated phosphatidylinositol specific-phospholipase C activity of lung membranes. 6. These results suggest that ibudilast has no direct effect on LTD4 receptors, GTP binding proteins (G proteins) or phospholipase C, but inhibits inositol phosphate formation, possibly by interfering with the coupling between receptors and G proteins.

Inhibition by ibudilast of leukotriene D4-induced formation of inositol phosphates in guinea-pig lung.

1. 1. KC-404 prevented mice from death and rats from A-V block, both induced by rapid i.v. injection of adenosine diphosphate (ADP), at high doses (5–100 mg/kg, i.v.). 2. 2. KC-404, at relatively lower doses (0.5–2 mg/kg, i.v.), inhibited the electroencephalographic (EEG) change in rat rapidly administered with arachidonic acid (AA) into the internal carotid artery. 3. 3. KC-404 (0.3–3 mg/kg, p.o.) inhibited the necrotic change of lower leg, paw or finger of rat when injected with sodium laurate into the femoral artery. 4. 4. KC-404 at doses up to 100 mg/kg, p.o. did not alter bleeding time in rat. 5. 5. Thus, KC-404 is expected to be of therapeutic value in cerebrovascular disorders accompanying thrombus in cerebral vasculature.

Anti-thrombotic effect of KC-404, a novel cerebral vasodilator.

The present invention provides novel thiazolidine-2,4-dione derivatives possessing blood sugar-lowering action and aldose reductase-inhibitory action, their salts, their preparative processes and drugs containing them, and relates to thiazolidine-2,4-dione derivatives represented by a general formula (1) ##STR1## [wherein R 1 and R 2 denote identically or differently hydrogen atoms or lower alkyl groups, R 3 denotes a phenyl group, naphthyl group, benzoyl group or 5-membered or 6-membered heteroring and its benzene-condensed ring, which may have one or more substituents, A denotes a carbonyl group, sulfonyl group or bonding hand, and B denotes a lower alkylene, lower alkenylene or bonding hand], or their salts, or thiazolidine-2,4-dione derivatives represented by a general formula (2) ##STR2## [wherein R 4 denotes a hydrogen atom or lower alkyl group, and R 1 and R 3 are same as above ], or their salts.

Mitsuo Ohashi

Papers

Phenoxyalkylcarboxylic acid derivatives and process for their preparation

Effects of drugs on behavior, heart rate and catecholamine levels in thiamine-deficient rats.

Inhibition by ibudilast of leukotriene D4-induced formation of inositol phosphates in guinea-pig lung.

Anti-thrombotic effect of KC-404, a novel cerebral vasodilator.

Thiazolidine-2,4-dione derivatives, their salts and their preparation processes