Diltiazem activity

Patients having high plasma renin activity (PRA) (>8 ng/(mLh)) respond best to an ACE inhibitor or a -adrenoceptor blocker those having low PRA (<1 ng/(mLh)) usually elderly and black, respond best to a calcium channel blocker or a diuretic (184). -Adrenoceptor blockers should not be used in patients who have diabetes, asthma, bradycardia, or peripheral vascular diseases. The thiazide-type diuretics (qv) should be used with caution in patients having diabetes. Likewise, -adrenoceptor blockers should not be combined with verapamil or diltiazem because these dmgs slow the atrioventricular nodal conduction in the heart. Calcium channel blockers are preferred in patients having coronary insufficiency diseases because of the cardioprotective effects of these dmgs. 

Diltiazem inhibits calcium influx via voltage-operated channels and therefore decreases intracellular calcium ion. This decreases smooth muscle tone. Diltiazem dilates both large and small arteries and also inhibits a-adrenoceptor activated calcium influx. It differs from verapamil and nifedipine by its use dependence. In order for the blockade to occur, the channels must be in the activated state. Diltiazem has no significant affinity for calmodulin. The side effects are headache, edema, and dizziness. 

The pharmacological activity of the 1,5-benzothiazepine derivative diltiazem has given further impetus for synthetic routes to this ring system. A traditional preparation of the intermediate 62 by the reaction sequence shown in Scheme 12 has been subject to microwave studies, when the final product was obtained as a mixture of isomers <96TL6413>. Under optimised conditions irradiation in toluene at 390 watts for 20 minutes gave mainly the cis-isomer as the main product (cis/trans 9 1) in 75% yield. However, reaction at 490 watts in the presence of acetic acid resulted in a reversal of this ratio and a yield of 84%. The... 

Key findings that demonstrated that the 0 subunit is the essential component of L-type channels have come from studies of the channel activity of the expressed protein. Expression studies performed in mammalian liver fibroblasts have demonstrated that the oti subunit alone can form a channel [77] and contains the receptors for the DHPs, PAAs and diltiazem [64]. In very elegant studies using a mouse model of muscular dysgenesis it has been demonstrated that the ] subunit DNA can restore Ca currents and the charge movement that arises from the voltagesensing function of the channels to the mutant cells that normally lack these activities [21,78,79]. The restoration of these activities restores excitation-contraction coupling. Thus it is clear that the aj subunit is the major functional unit of L-type Ca channels. 

Biochemical studies with purified preparations incorporated into liposomes have also been performed [32,33,96-98]. Reconstituted receptors from skeletal muscle bound DHPs, PAAs and diltiazem with high affinity and in a 1 1 1 stoichiometry [97], In general, the reconstituted proteins exhibit the characteristic pharmacological properties expected for these channels. In recent studies, our laboratory has reconstituted partially purified channels into liposomes containing the Ca -sensitive fluorescent dye, fluo-3 [33,96]. These channels exhibit Ca influx that is sensitive to activation by Ca channel activators and inhibitors with affinities similar to those observed in intact cells, and the Ca influx is dependent on the establishment of a gradient in the presence of valinomycin [132]. This assay provides a convenient and rapid approach to obtaining a macroscopic picture of the activity of the channels under different conditions, while the more complex studies in lipid bilayers provide a more complete analysis of the single channel behavior. 

L-type calcium channels (voltage-gated calcium channels L-subtype) Similarity to Diltiazem and a second ligand. ZINC db ( 50 K commercially available subset screened but most filtered to achieve desired PK profile using VolSurf). SHOP similarity, and feature-presence filtering down to 36 compounds 7 hits 18 tested, active in a vasorelaxant assay and some had novel structures. [67]... 

Fig. 20.8. P -gp-ATPase activation profiles obtained by measurements of extracellular acidification rates in living cells by means of a cytosensor physiometer. (A) Cyclosporin A ( ), progesterone (0)> trifluoperazine (A) and verapamil ( ) in LLC-MDR1 cells (B) amitriptyline ( ), calcein-AM (A), diltiazem ( ) and vinblastine (T) in LLC-MDR1 cells.

Halloysite was found to be a viable and inexpensive nanoscale container for the encapsulation of biologically active molecules and drugs as was first demonstrated by Price et al. [5-8]. Its physicochemical characterization as a novel drug delivery system was also reported by Levis and Deasy et al. [9,10], who further demonstrated the controlled release of diltiazem hydrochloride and propanol hydrochloride... 

BK currents consisted of transient and steady-state components. The transient currents were abolished by ryanodine (10 fiM), indicating that they are activated by Ca2+ sparks. The lag from the onset of depolarization (activation of VDCCs) to the first transient BK current was around 50 ms. This delay is much too long to be attributed to local signalling from VDCCs to RyRs such as occurs in heart, and instead is consistent with the idea of loose coupling between VDCCs and RyRs (Fig. 1 A) (Collier et al 2000). Spark-activated transient BK currents remained in the presence of the VDCC antagonist diltiazem (50 //M). However, the frequency of... 

For example, in the case of compound XX, which among other activities has an IC50 of 60 nM on the calcium channel diltiazem site binding assay, a search for BioPrint compounds with an activity in the similar range yields a series of compounds nearly all of which are known calcium channel blockers (see Table 2.1). 

Figure 2.19 Tinnitus ADR association with Ca2+ channel (L-diltiazem site) activity.

Sutton, D., Butler, A.M., Nadin, L. and Murray, M. (1997) Role of CYP3A4 in human hepatic diltiazem N-demethylation inhibition of CYP3A4 activity by oxidized diltiazem metabolites. Journal of Pharmacology and Experimental Therapeutics, 282 (1), 294-300. 

A pharmacist asked a clinical pharmacist for information about Cartia . Because an electronic drug reference listed the active ingredient as aspirin, the pharmacist was prepared to substitute an aspirin product for Cartia . The clinical pharmacist recognized the new product as Cartia XT (Diltiazem, a calcium channel blocker) and prevented the error. 

Diltiazem is a catamphiphilic ben-zothiazepine derivative with an activity profile resembUng that of verapamil. 

Chemically, calcium channel blockers are synthesized up of a fairly diverse group of compounds, which testifies of the diverse receptive regions both on the cell membrane surface as well as within the cell. Verapamil, which can be viewed as a benzylcyanide derivative, is one of the oldest and most actively used compounds of this class up to the present day. Diltiazem is a thiodiazepine, while nifedipin and nicardipine are derivatives of dihydropyridine. 

Lovastatin (Mevacor/ Altocor) [Antilipemic/HMG-CoA Reductase Inhibitor] Uses Hypercholesterolemia Action HMG-CoA reductase inhibitor Dose 20 mg/d PO w/ PM meal may T at 4-wk intervals to 80 mg/d max or 60 mg ER tab take w/ meals Caution [X, -] Avoid w/ grapefruit juice, gemfibrozil. Contra Active liver Dz Disp Tabs SE HA GI intolerance common promptly report any unexplained muscle pain, tenderness, or weakness (myopathy) Interactions T Effects W/ grapefruit juice T risk of severe myopathy W/ azole antifungals, cyclosporine, erythromycin, gemfibrozil, HMG-CoA inhibitors, niacin T effects OF warfarin >1 effects W/ isradipine, pectin EMS t Risk of photosensitivity Rxns T effects of warfarin concurrent EtOH use t risk of liver tox diltiazem and verapamil can T risk of lovastatin tox OD Unlikely to cause life-threatening Sxs... 

Diltiazem, a benzothiazepine, has a pharmacodynamic and side-effect profile that is intermediary between those of nifedipine and verapamil. Diltiazem is mostly used in the treatment of stable angina. It also displays antihypertensive activity, although it is not widely used in antihypertensive treatment. In certain countries diltiazem is used as an antiarrhyth-mic agent with the same type of applications as verapamil. 

Antiarrhythmic activity (verapamil, possibly also diltiazem) impairment of AV conduction and to a lesser degree also that of sinus node activity. 

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