Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new diltiazem research articles will be listed here shortly after becoming available to us.
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Medical research on diltiazem
Transplant Proc. 2008 Jun; 40(5): 1690-5
Loh PT, Lou HX, Zhao Y, Chin YM, Vathsala A
Calcineurin inhibitors (CNI) are metabolized by cytochrome-P4503A (CYP3A) enzymes and extruded into the intestinal lumen by the drug efflux pump, P-glycoprotein (P-gp). The impact of single nucleotide polymorphisms (SNPs) of genes encoding CYP3A5 and P-gp on CNI dosing was examined among Asian renal transplant recipients. Frequencies of CYP3A5*1 versus *3 and MDR1-C3435T were correlated with tacrolimus (TAC) and cyclosporine (CSA) concentration-to-dose (C/D) ratios. Among 82 recipients (49% male; 88% Chinese), the majority were CYP3A5 expressors (*1*1 and *1*3, 11% and 40%, respectively) and 49% were nonexpressors (*3/*3). The prevalence of MDR-1-C3435T variants was 3435CC (41%), 3435CT (46%), and 3435TT (13%). Among 18 TAC-treated recipients, all receiving Diltiazem (DTZ), the median C/D ratio was lower for CYP3A5 *1/*1 versus *1/*3 versus *3/*3 (1.9, 4.6, and 13.5 ng/mL per 0.1 mg/kg/d, respectively; P = .001). The median C/D ratio was higher for TAC-treated patients with MDR-1-3435CC (14.1, 7.3, and 2.2 ng/mL per 0.1 mg/kg/d for CC, CT, and TT, respectively; P = .023). Neither CYP3A5 nor MDR-1-C3435T variants had an impact on CSA C/D ratios. Thus, CYP3A5 SNP has a significant impact on TAC dosing in Asian renal transplant recipients, which was likely to facilitate TAC metabolism. Although MDR-1-3435CC with higher P-gp expression should experience more TAC efflux and, therefore, lower TAC C/D ratios, all MDR-1-3435CC carriers were CYP3A5 nonexpressors; the latter ultimately contributed to the observed higher TAC C/D ratios in this population. This study advocates starting with a higher TAC dose for CYP3A5 expressors. Coadministration of DTZ may further optimize the TAC level through preferential P-gp binding and CYP3A4 inhibition.
Prevalence of adverse drug combinations in a large post-mortem toxicology database.
Int J Legal Med. 2008 Jun 27;
Launiainen T, Vuori E, Ojanperä I
The prevalence of important adverse drug combinations was studied among the 37,367 cases included in the Finnish post-mortem toxicology database during 2000-2006. The new SFINX interaction database (Swedish, Finnish, INteraction X-referencing) was utilised to identify adverse drug combinations. Consequently, the 24 drugs chosen for the study generated 96 two-compound combinations possessing potentially severe interactions. The total number of hits for the combinations found in the post-mortem database was 267, which accounts for approximately 0.71% of all cases. The potential role of adverse drug interaction (ADI) in these cases was evaluated from the background information and death certificate. The possible ADI cases comprised 23% of all hits and 0.17% of all cases analysed. In cases with a pharmacodynamic mechanism, the most prominent combinations were medicines causing serotonin syndrome or a beta(1)-blocker with verapamil or diltiazem. In cases with a pharmacokinetic mechanism, half of the cases involved digoxin in combination with verapamil. In one third of the possible ADI cases, a forensic pathologist had noted the studied compounds as an underlying or contributing cause of death, although the agents' specific role in ADIs was rarely recognised.
Citric acid monohydrate as a release-modifying agent in melt extruded matrix tablets.
Int J Pharm. 2008 Jun 5;
Schilling SU, Bruce CD, Shah NH, Malick AW, McGinity JW
Incomplete drug release and particle size-dependent dissolution performance can compromise the quality of controlled release matrix systems. The objective of the current study was to investigate the ability of citric acid monohydrate (CA MH) to enhance the release of diltiazem hydrochloride from melt extruded Eudragit((R)) RS PO tablets and to eliminate drug particle size effects. Preformulation studies demonstrated the thermal stability of all components, drug insolubility in the polymer but miscibility with the CA MH. Tablets with either constant polymer levels or constant drug-to-polymer ratios and containing different drug particle size fractions and increasing amounts of CA MH were manufactured by melt extrusion and characterized by dissolution testing, powder X-ray diffraction and scanning electron microscopy. The addition of CA MH to the formulation promoted the thermal processibility and matrix integrity by plasticization of the polymer. The drug release from systems with constant drug-to-polymer ratio was significantly increased when CA MH was added as a result of enhanced pore formation. Particle size effects were eliminated when large amounts of CA MH were used due to the loss of drug crystallinity. Matrix tablets with CA MH furthermore showed a faster and more complete drug release compared to systems with drug only or alternative pore formers (sucrose, NaCl, or PEG 3350). The enhanced drug release was attributed to the amorphous character of the soluble components, improved drug dispersion in the plasticized polymer along with increased polymer permeability. In summary, CA MH promoted the miscibility between the drug and Eudragit((R)) RS PO during hot-melt extrusion, resulting in the extrusion of an amorphous system with improved dissolution characteristics.
Anaesthesia. 2008 Jul; 63(7): 714-8
Roberts DM, Roberts JA, Boots RJ, Mason R, Lipman J
The effect of charcoal haemoperfusion on the pharmacokinetics of diltiazem is described in a patient with severe clinical toxicity following acute overdose. The patient presented within 3 h following acute ingestion of multiple medications including sustained-release diltiazem. Routine resuscitation and supportive care were administered, but hypotension did not resolve despite intravenous fluids and infusions of calcium, adrenaline, noradrenaline and vasopressin. Multiple-doses of activated charcoal, haemodialysis and charcoal haemoperfusion were prescribed to expedite the elimination of diltiazem. The maximum diltiazem concentration (577 microg.l(-1)) was recorded 7 h post ingestion which was followed by an erratic and prolonged elimination phase. The maximum clearance of diltiazem due to haemoperfusion was calculated to be 19.4 and 15.1 ml.min(-1) at different times, equating to removal of approximately 1.5 mg diltiazem during 4 h of haemoperfusion. Haemoperfusion did not appear to remove sufficient diltiazem to recommend its routine use in the treatment of patients with acute diltiazem overdose.
Doppler-Guided Haemorrhoidal Artery Ligation: Long-Term Outcome And Patient Satisfaction.
Colorectal Dis. 2008 Jun 20;
Wilkerson P, Strbac M, Reece-Smith H, Middleton S
Objective Conventional Milligan-Morgan haemorrhoidectomy is associated with significant pain and potentially hazardous complications. Doppler-Guided Haemorrhoidal Artery Ligation (DGHAL) may offer a lower risk, pain-free alternative. We present our early and long-term outcome experience with DGHAL, combined with patient views and satisfaction with the procedure. Patients and Methods 113 DGHALs were performed over a 13 month period by 2 surgeons in a single centre. Patients graded the severity of post-operative pain on visual-analogue scales. Clinical follow-up was at 6 weeks (n=103), with long-term follow-up (n=90) by postal questionnaire at median of 30 months. Results 7/103 (6%) patients reported post-operative discomfort requiring analgesia. 93/103 (90%) patients reported complete relief or significant improvement in their symptoms at 6 weeks, dropping to 77/90 (86%) at 30 months. Anal fissures developed in 2/103 (2%) patients, both treated with Diltiazem ointment. Further surgery was required in 8/90 (9%) patients. 82/90 (91%) patients said they would undergo DGHAL again. Conclusions DGHAL is a relatively painless, safe, and effective procedure for symptomatic stage I-III haemorrhoids, for which we have demonstrated long-term durability and acceptability. Its role lies between office based procedures and more invasive operative interventions.
Clin Pharmacokinet. 2008; 47(7): 463-74
Neuvonen PJ, Backman JT, Niemi M
HMG-CoA reductase inhibitors (statins) dose-dependently lower both the level of low-density lipoprotein cholesterol and risk of cardiovascular disease. In 2004, the UK approved a low-dose over-the-counter (OTC) simvastatin, but the US has rejected applications for non-prescription preparations of statins. The pharmacokinetics and interaction potentials of the possible OTC candidate statins simvastatin, lovastatin, fluvastatin and pravastatin are clearly different. Simvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A, fluvastatin is metabolized by CYP2C9, and pravastatin is excreted largely unchanged. Several cell membrane transporters can influence the disposition of statins, e.g. the organic anion transporting polypeptide (OATP) 1B1 enhances their hepatic uptake. The c.521T>C (p.Val174Ala) genetic polymorphism of SLCO1B1 (encoding OATP1B1) considerably increases the plasma concentrations of simvastatin acid and moderately increases those of pravastatin but seems to have no significant effect on fluvastatin. Strong inhibitors of CYP3A (itraconazole, ritonavir) greatly (up to 20-fold) increase plasma concentrations of simvastatin, lovastatin and their active acid forms, thus enhancing the risk of myotoxicity. Weak or moderately potent CYP3A inhibitors such as verapamil, diltiazem and grapefruit juice can be used cautiously with low doses of simvastatin or lovastatin, but their concomitant use needs medical supervision. Potent inducers of CYP3A can greatly decrease plasma concentrations of simvastatin and simvastatin acid, and probably those of lovastatin and lovastatin acid. Although fluvastatin is metabolized by CYP2C9, its concentrations are changed less than 2-fold by inhibitors or inducers of CYP2C9. Pravastatin plasma concentrations are not significantly affected by any CYP inhibition and only slightly affected by inducers. Ciclosporin inhibits CYP3A, P-glycoprotein and OATP1B1. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. Ciclosporin and gemfibrozil increase plasma concentrations of statins and the risk of their myotoxicity, but fluvastatin seems to carry a smaller risk than other statins. Inhibitors of OATP1B1 may decrease the benefit-risk ratio of simvastatin, lovastatin and pravastatin by interfering with their (active acid forms) entry into hepatocytes. Understanding the differences in the pharmacokinetics and interaction potential of various statins helps in their selection for possible non-prescription status. On the pharmacokinetic basis, fluvastatin and pravastatin can be better choices than simvastatin or lovastatin for an OTC statin.
Etiology, pathophysiology, and treatment of atrial fibrillation: part 1.
Cardiol Rev. 2008 Jul-Aug; 16(4): 181-8
Aronow WS
Atrial fibrillation (AF) is associated with a higher incidence of mortality, stroke, and coronary events than is sinus rhythm. AF with a rapid ventricular rate may cause a tachycardia-related cardiomyopathy. Immediate direct-current cardioversion should be performed in patients with AF and acute myocardial infarction, chest pain due to myocardial ischemia, hypotension, severe heart failure, or syncope. Intravenous beta blockers, verapamil, or diltiazem may be given to immediately slow a very rapid ventricular rate in AF. An oral beta blocker, verapamil, or diltiazem should be used in persons with AF if a fast ventricular rate occurs at rest or during exercise despite digoxin. Amiodarone may be used in selected patients with symptomatic life-threatening AF refractory to other drugs. Digoxin should not be used to treat patients with paroxysmal AF. Nonpharmacologic therapies should be used in patients with symptomatic AF in whom a rapid ventricular rate cannot be slowed by drugs. This is part 1 of a 2-part review of the etiology, pathophysiology, and treatment of atrial fibrillation. The second part will be published in the subsequent issue of Cardiology in Review.
Risk Management of Simvastatin or Atorvastatin Interactions with CYP3A4 Inhibitors.
Drug Saf. 2008; 31(7): 587-96
Molden E, Skovlund E, Braathen P
BACKGROUND: Co-administration of cytochrome P450 (CYP) 3A4 inhibitors with simvastatin or atorvastatin is associated with increased risk of developing myopathy or rhabdomyolysis. OBJECTIVE: To detect co-prescriptions of CYP3A4 inhibitors with simvastatin or atorvastatin in community pharmacies and assess the risk-preventive actions taken by the prescribing physicians who were alerted about the co-prescription by the pharmacist. METHODS: This naturalistic study was performed during four separate 6-week periods in 2004 and 2005, and involved 110 Norwegian community pharmacists (25-30 in each period). Co-prescription of the selected CYP3A4 inhibitors diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, itraconazole and ketoconazole with either simvastatin or atorvastatin was detected with the aid of a simple computer programme. In instances where the pharmacist alerted the prescribing physician about the co-prescription, information on possible strategies to minimize the risk associated with the interaction was also provided. Odds ratios (ORs) were estimated to describe the associations between prescription variables and frequencies of physician information and prescription change, respectively. RESULTS: In total, 245 co-prescriptions of CYP3A4 inhibitors with simvastatin (134 events) or atorvastatin (111) were detected. Diltiazem (86 events), verapamil (72), erythromycin (48) and clarithromycin (29) were the most commonly co-prescribed CYP3A4 inhibitors. Physicians were informed in 168 out of 245 cases (68.6%). The prescription was subsequently changed in 100 out of 168 cases (59.5%). Another 50 physicians (29.8%) responded that they would consult the patient and monitor potential adverse effects, while only 18 physicians (10.7%) replied that they had already managed the interactions or considered the issue as irrelevant. The adjusted OR for the informing of the physician was 1.89 (95% CI 0.98, 3.63) in patients receiving a daily HMG-CoA reductase inhibitor ('statin') dose of >/=40 mg compared with patients receiving a statin dose of
PDA J Pharm Sci Technol. 2008 Mar-Apr; 62(2): 97-110
Sudhakar Y, Bandyopadhyay AK
In the current investigation, white mustard mucilage from whole seeds of Sinapis alba was evaluated for its physical properties and compared with the other mucoadhesive polymers such as hydroxy propyl methylcellulose 5Cps and Carbopol 934P. Further, methanol precipitable solids from whole leaves of Aloe Vera L were used as permeation enhancer. To achieve improved bioavailability of diltiazem, novel buccal adhesive tablets (NBATs) in cup and core fashion designed to achieve unidirectional release towards mucosa were prepared in a three-stage process using specially fabricated punches. The adhesive cups were studied for its shear, tensile, and peel strengths by specially designed apparatus using excised ruminant and porcine buccal mucosa as model substrates. Ex vivo permeation studies in a Franz diffusion cell were conducted through porcine buccal mucosa. Fourier transform infrared spectroscopy studies and differential scanning calorimetry thermographs showed no remarkable interactions. Histopathological studies showed no remarkable damage of buccal mucosa by the NBATs. In vivo studies were conducted on anaesthetized male New Zealand albino rabbits, estimated by reversed-phase high-performance liquid chromatography, and the pharmacokinetics were compared with the oral and intravenous bolus injection. NBATs exhibited a Cmax 74.6 ng/mL, Tmax 3.5 h, t(1/2) 4.36 h. The NBATs prevented salivary scavenging effect and exhibited 82.1% bioavailability.
Alteration in prehospital drug concentration after thermal exposure.
Am J Emerg Med. 2008 Jun; 26(5): 566-73
Gammon DL, Su S, Jordan J, Patterson R, Finley PJ, Lowe C, Huckfeldt R
OBJECTIVE: The aim of the study was to determine the remaining concentration of 23 commonly carried emergency medical services medications used in the United States after they have experienced thermal extremes that have been documented in the prehospital environment for a period of 1 month. METHODS: Pharmaceuticals were thermally cycled (-6 degrees C and 54 degrees C) every 12 hours and then assayed by high-performance liquid chromatography. RESULTS: Eight (35%) of 23 prehospital pharmaceuticals revealed ending concentrations of less than 90% with strong correlation to thermal exposure time. These included lidocaine, diltiazem, dopamine, nitroglycerin, ipratropium, succinylcholine, haloperidol, and naloxone. CONCLUSION: A decrease in concentration was found to be statistically significant in 8 (35%) of 23 commonly carried emergency medical services pharmaceuticals. These results provide new information and perspective regarding stability of emergency drugs in the prehospital environment by evaluating a broad range of pharmaceuticals as well as by using thermal exposure points that have been documented in the United States.