Diltiazem is a pharmaceutical belonging to a group of calcium channel blockers (CCB) that is widely used in the treatment of angina pectoris and hypertension. The objective of the present study was to assess the effect of diltiazem on rainbow trout (Oncorhynchus mykiss). Juvenile trout were exposed for 21 and 42 days to three nominal concentrations of diltiazem: 0.03 μg L(-1) (environmentally relevant concentration), 3 μg L(-1), and 30 μg L(-1) (sub-lethal concentrations). The number of mature neutrophilic granulocytes was significantly increased by 450 and 400% in fish exposed to 3 μg L(-1) and 30 μg L(-1) diltiazem compared to the control, respectively. Antioxidant enzyme activity was affected in liver and gills of fish exposed to all tested concentrations of diltiazem but the changes were mostly transient and not concentration dependent. Creatine kinase activity was markedly increased (ranging from 520 to 845%) at all tested diltiazem concentrations at the end of the exposure indicating muscle and/or kidney damage. The highest concentration was associated with histological changes in heart, liver, and kidney. These alterations can be attributed to the effects of diltiazem on the cardiovascular system, similar to those observed in the human body, as well as to its metabolism. At the environmentally relevant concentration, diltiazem was found to induce some alterations in the blood, gills, and liver of fish, indicating its potential for adverse effects on non-target organisms in the aquatic environment.

• Klíčová slova
• Calcium channel blocker, Creatine kinase, Haematology, Histopathological changes,
• MeSH
• blokátory kalciových kanálů MeSH
• časové faktory MeSH
• chemické látky znečišťující vodu farmakokinetika   farmakologie   MeSH
• diltiazem farmakologie   MeSH
• játra enzymologie   metabolismus   patologie   MeSH
• kosterní svaly enzymologie   patologie   MeSH
• ledviny metabolismus   patologie   MeSH
• myokard patologie   MeSH
• Oncorhynchus mykiss metabolismus   MeSH
• oxidoreduktasy analýza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• žábry enzymologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• blokátory kalciových kanálů MeSH
• chemické látky znečišťující vodu MeSH
• diltiazem MeSH
• oxidoreduktasy MeSH

RATIONALE: Diltiazem, a calcium channel blocker drug, is widespread in the environment because of its incomplete elimination during water treatment. It can cause negative effects on aquatic organisms; thus, a rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method to detect its presence was developed. Our approach is based on accurate mass measurements using a hybrid quadrupole-orbital trap mass spectrometer that was used to measure diltiazem and its metabolites in fish tissue. METHODS: Blood plasma, muscle, liver, and kidney tissues of rainbow trout (Oncorhynchus mykiss), exposed for 42 days to 30 μg L(-1) diltiazem, were used for the method development. No metabolite standards were required to identify the diltiazem biotransformation products in the fish tissue. RESULTS: Overall, 17 phase I diltiazem metabolites (including isomeric forms) were detected and tentatively identified using the MassFrontier spectral interpretation software. A semi-quantitative approach was used for organ-dependent comparison of the metabolite concentrations. CONCLUSIONS: These data increase our understanding about diltiazem and its metabolites in aquatic organisms, such as fish. These encompass desmethylation, desacetylation and hydroxylation as well as their combinations. This study represents the first report of the complex diltiazem phase I metabolic pathways in fish.

• MeSH
• blokátory kalciových kanálů chemie   metabolismus   MeSH
• chemické látky znečišťující vodu chemie   metabolismus   MeSH
• chromatografie kapalinová metody   MeSH
• diltiazem chemie   metabolismus   MeSH
• hmotnostní spektrometrie metody   MeSH
• játra chemie   metabolismus   MeSH
• ledviny chemie   metabolismus   MeSH
• molekulární struktura MeSH
• ryby metabolismus   MeSH
• svaly chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• blokátory kalciových kanálů MeSH
• chemické látky znečišťující vodu MeSH
• diltiazem MeSH

Diltiazem is a human therapeutic drug and a member of the group of calcium channel blockers having widespread use in the treatment of angina pectoris and hypertension. The objective of the present study was to assess the bioconcentration, metabolism, and half-life time of diltiazem in rainbow trout Oncorhynchus mykiss. Juvenile trout were exposed for 21 and 42 days to three nominal concentrations of diltiazem: 0.03 µg L(-1) (environmentally relevant concentration), 3 µg L(-1), and 30 µg L(-1) (sub-lethal concentrations). The bioconcentration factor (BCF) of diltiazem was relatively low (0.5-194) in analysed tissues, following the order kidney > liver > muscle > blood plasma. The half-life of diltiazem in liver, kidney, and muscle was 1.5 h, 6.2 h, and 49 h, respectively. The rate of metabolism for diltiazem in liver, kidney, muscle, and blood plasma was estimated to be 85 ± 9%, 64 ± 14%, 46 ± 6%, and 41 ± 8%, respectively. Eight diltiazem metabolites were detected. The presence of desmethyl diltiazem (M1), desacetyl diltiazem (M2), and desacetyl desmethyl diltiazem (M3) suggests that rainbow trout metabolize diltiazem mainly via desmethylation and desacetylation, similar to mammals. In addition, diltiazem undergoes hydroxylation in fish. At environmentally relevant concentrations, diltiazem and its metabolites were identified in liver and kidney, indicating the potential for uptake and metabolism in non-target organisms in the aquatic environment.

• Klíčová slova
• Bioconcentration factor, Calcium channel blocker, Half-life, Metabolites,
• MeSH
• chemické látky znečišťující vodu krev   farmakokinetika   MeSH
• diltiazem krev   farmakokinetika   MeSH
• játra metabolismus   MeSH
• ledviny metabolismus   MeSH
• Oncorhynchus mykiss metabolismus   MeSH
• poločas MeSH
• svaly metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chemické látky znečišťující vodu MeSH
• diltiazem MeSH

UNLABELLED: Diltiazem hydrochloride is an antihypertensive agent which undergoes extensive first pass metabolism making it a possible candidate for buccal delivery. Diltiazem mucoadhesive buccal patches were prepared using HPMC, chitosan, PVP, PVA and carbopol. The physicochemical interactions between diltiazem and the polymers were investigated by FTIR and DSC, results revealed no interaction between drug and polymers. The patches were evaluated for various physicochemical parameters, in vitro release studies and ex vivo permeation through porcine buccal mucosa. Residual solvent content in patches was determined by gas chromatography and are largely below the tolerated limits. The formulations showed an extended release of the drug upto a period of 12 hours during ex vivo permeation and showed non Fickian drug release. Stability of the optimized formulation was investigated as per ICH guidelines and was found to be stable with respect to drug content and ex vivo permeation. KEYWORDS: diltiazem hydrochloride buccal patches residual solvents mucoadhesion in vitro drug release ex vivo permeation.

• MeSH
• adhezivita MeSH
• diltiazem * MeSH
• farmaceutická chemie MeSH
• lékové transportní systémy MeSH
• stabilita léku * MeSH
• techniky in vitro MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• diltiazem * MeSH

Pellets containing drugs of different properties were prepared in a Rotoprocessor in order to study changes in the formulation process and resulting pellet characteristics. Diltiazem hydrochloride, diclofenac sodium, and theophylline were chosen as model drugs. Pellet size distribution, sphericity, density, hardness, friability, and repose angle were determined using standard methods. The amount of water as a wetting agent necessary for successful pellet formulation was observed for each sample and changed depending on drug solubility, concentration, and particle size. The pelletization of freely soluble diltiazem hydrochloride required 24.8-23.1% of the wetting agent and its amount decreased as the drug concentration increased. The demand for water in the formulation of theophylline pellets was 31.0-34.4% and it increased with increasing drug concentration. The pellet samples containing both drugs were easy to prepare. However, the cohesion of micronized diclofenac sodium particles negatively influenced both the pellet size distribution and the formulation process itself. When the drug concentration exceeded 40%, it was not possible to produce pellets of an appropriate size and the process was not reproducible.

• MeSH
• algoritmy MeSH
• antiflogistika nesteroidní aplikace a dávkování   chemie   MeSH
• blokátory kalciových kanálů aplikace a dávkování   chemie   MeSH
• bronchodilatancia aplikace a dávkování   chemie   MeSH
• celulosa MeSH
• diklofenak aplikace a dávkování   chemie   MeSH
• diltiazem aplikace a dávkování   chemie   MeSH
• farmaceutická chemie * MeSH
• laktasa chemie   MeSH
• pomocné látky MeSH
• příprava léků přístrojové vybavení   MeSH
• rozpustnost MeSH
• theofylin aplikace a dávkování   chemie   MeSH
• velikost částic MeSH
• voda MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• blokátory kalciových kanálů MeSH
• bronchodilatancia MeSH
• celulosa MeSH
• diklofenak MeSH
• diltiazem MeSH
• laktasa MeSH
• microcrystalline cellulose MeSH Prohlížeč
• pomocné látky MeSH
• theofylin MeSH
• voda MeSH

The paper focuses on the study of the effect of pH of dissolution medium on the release of diltiazem hydrochloride from carbomeric matrices. Swelling of carbomers, high-molecular cross-linked anionic polymers, is dependent on the value of pH, which decides whether these polymers exist in an ionized or a non-ionized form. In alkaline medium, carboxylic groups of carbomers ionize and hydrate markedly, which also facilitates their interaction with cationic drugs, in this case with diltiazem hydrochloride. The development of a sparingly soluble complex drug-polymer, the presence of which was demonstrated with the use of Fourier IR spectrophotometry, is one of the factors which causes decelerated release of the drug as well as decreased swelling of matrices in this dissolution medium. In both selected dissolution media, an assumption has been confirmed that with an increasing concentration of the polymer in the system a smaller share of the drug is released. Drug release from matrix tablets is also influenced by the rate of dissolution of the drug in dependence on the pH of the medium. Being a salt of a feeble base and a strong acid, diltiazem hydrochloride is more slowly soluble in an alkaline medium than in the medium with pH 1.2. This factor also contributes to its slower release in the medium of phosphate buffer of pH 7.4.

• MeSH
• akrylové pryskyřice MeSH
• diltiazem chemie   MeSH
• farmaceutická technologie MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem * MeSH
• polyvinyly * MeSH
• pomocné látky * MeSH
• rozpustnost MeSH
• tablety MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• akrylové pryskyřice MeSH
• carboxypolymethylene MeSH Prohlížeč
• diltiazem MeSH
• léky s prodlouženým účinkem * MeSH
• polyvinyly * MeSH
• pomocné látky * MeSH
• tablety MeSH

A persistent, chronic dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors therapy. The mechanism of this respiratory adverse effect is related to the inhibition of ACE and the accumulation of bradykinin, substance P, prostanoids and other inflammatory neuropeptides in the airways. The aim of this study was to follow the relationship between 15-day administration of enalapril and the defense reflexes (cough and bronchoconstriction) of the airways in experimental animals, as well as the possibility of their pharmacological restriction with simultaneous diltiazem administration. Cough reflex was investigated by the method of mechanical irritation of laryngopharyngeal and tracheobronchial area in non-anesthetized cats. The reactivity of tracheal smooth muscles of the airways to bronchoconstrictor mediators (histamine 10 nM - 1 mM, acetylcholine 10 nM - 1 mM and KCl 1 mM - 100 mM) was evaluated by an in vitro method in guinea pigs. Enalapril 5 mg/kg/day and diltiazem 30 mg/kg/day were administered perorally for 15 days. The results showed that long-lasting administration of enalapril resulted in a significant increase of measured cough parameters and increased reactivity of tracheal smooth muscle to histamine and KCl. Simultaneous administration of enalapril together with diltiazem significantly decreased the enalapril induced cough, and decreased enalapril induced hyperreactivity of tracheal smooth muscles to KCl. The results showed a partially protective effect of diltiazem and enalapril co-administration on the respiratory adverse effects induced by enalapril therapy.

• MeSH
• blokátory kalciových kanálů aplikace a dávkování   MeSH
• bronchokonstrikce účinky léků   MeSH
• diltiazem aplikace a dávkování   MeSH
• enalapril aplikace a dávkování   škodlivé účinky   MeSH
• fixní kombinace léků MeSH
• kašel chemicky indukované   diagnóza   prevence a kontrola   MeSH
• kočky MeSH
• morčata MeSH
• stupeň závažnosti nemoci MeSH
• svaly hladké cévní účinky léků   MeSH
• vazodilatancia aplikace a dávkování   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• kočky MeSH
• morčata MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• blokátory kalciových kanálů MeSH
• diltiazem MeSH
• enalapril MeSH
• fixní kombinace léků MeSH
• vazodilatancia MeSH

Hydrophilic matrix tablets based on hydroxypropylmethylcellulose (HPMC) and other cellulose derivatives rank among dosage forms with retarded effect widely used in contemporary pharmacotherapy. The active ingredient is released from them in dependence on its properties either by dissolution and diffusion, or erosion of the compact. The dissolution profile of the active ingredient can be influenced by variables of formulation and manufacture, e.g. by the type of HPMC employed, its concentration, other added auxiliary substances, and compression force which is reflected in the strength of tablets. Two drugs with different solubility were used to study the effect of drug solubility on its release from matrices: well soluble diltiazemium chloride and badly soluble ibuprofen. Higher solubility of the drug and lower solubility of compacts resulted in more rapid release of the active ingredient. Also lower concentration of HPMC accelerates the release of both drugs. The effect of the degree of viscosity of the polymer on drug release was not markedly manifested.

• MeSH
• diltiazem chemie   MeSH
• farmaceutická chemie MeSH
• ibuprofen chemie   MeSH
• kardiovaskulární látky chemie   MeSH
• laktosa analogy a deriváty   MeSH
• léky s prodlouženým účinkem MeSH
• methylcelulosa analogy a deriváty   MeSH
• oxaziny MeSH
• rozpustnost MeSH
• tablety MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• diltiazem MeSH
• ibuprofen MeSH
• kardiovaskulární látky MeSH
• laktosa MeSH
• léky s prodlouženým účinkem MeSH
• methylcelulosa MeSH
• MK 458 MeSH Prohlížeč
• oxaziny MeSH
• tablety MeSH

The aim of this study was to investigate the effects of calcium channel blockers on tertbutyl hydroperoxide (TBH) induced liver injury using isolated perfused rat hepatocytes. Rat hepatocytes were immobilized in agarose threads and perfused with Williams E medium. Hepatocyte injury was induced by the addition of tertbutyl hydroperoxide (1 mM) to the perfusion medium 30 min after the addition of either verapamil or diltiazim. Hepatocyte injury was observed by monitoring the functional and metabolic competence of hepatocytes or by ultrastructural morphological examination of hepatocytes. Verapamil (0.5 mM) reduced lactate dehydrogenase leakage in TBH-injured hepatocytes as compared to the controls (154+/-11% vs. 247+/-30%). Lipid peroxides production was reduced after verapamil pretreatment as compared to the controls and oxygen consumption was increased by pretreatment of hepatocytes with verapamil. Verapamil pretreatment increased the protein synthesis activity at both levels of granular endoplasmic reticulum and free polysomes in cytoplasm and decreased ATPase activity. Diltiazem was qualitatively effective as verapamil. It is concluded that in hepatocyte oxidative injury, calcium channel blockers exhibited hepatoprotective properties. The hepatoprotective effect of calcium channel blockers was accompanied by a decrease in ATPase activity, which may implicate a normalization of Ca2+i after TBH intoxication.

• MeSH
• adenosintrifosfatasy metabolismus   MeSH
• blokátory kalciových kanálů farmakologie   MeSH
• diltiazem farmakologie   MeSH
• hepatocyty účinky léků   ultrastruktura   MeSH
• krysa rodu Rattus MeSH
• L-laktátdehydrogenasa metabolismus   MeSH
• lékové postižení jater MeSH
• lipidové peroxidy antagonisté a inhibitory   MeSH
• nemoci jater prevence a kontrola   MeSH
• oxidační stres * MeSH
• perfuze MeSH
• potkani Wistar MeSH
• spotřeba kyslíku účinky léků   MeSH
• terc-butylhydroperoxid MeSH
• verapamil farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• blokátory kalciových kanálů MeSH
• diltiazem MeSH
• L-laktátdehydrogenasa MeSH
• lipidové peroxidy MeSH
• terc-butylhydroperoxid MeSH
• verapamil MeSH

Calcium antagonists have been shown to influence some endocrinological processes in mammals. The use of calcium channel blockers in clinical practice is well documented. The current study monitored nocturnal melatonin, prolactin, and cortisol levels in 19 healthy volunteers before and after administration of calcium channel blockers. The effect of nifedipine was tested in 9 subjects, while diltiazem was administered in 10 men. The nocturnal profile of the given parameters was studied between 23:00 and 05:00 h. At midnight (zero time), the participants were given placebo, nifedipine (in a sublingual dose of 20 mg) or diltiazem (in a single dose of 90 mg). The hypothesis that calcium channel blockers decrease nocturnal melatonin secretion has not been confirmed. The mean nocturnal levels of melatonin between 01:00 and 05:00 h were: 78.1+/-8.8 (control study) vs. 82.4+/-10.2 ng/l (nifedipine study) and 73.0+/-5.3 ng/l (control study) vs. 75.1+/-5.1 ng/l (diltiazem study). In conclusion, the calcium channel blockers used in this study do not alter the nocturnal melatonin secretory process in healthy men.

• MeSH
• blokátory kalciových kanálů aplikace a dávkování   farmakologie   MeSH
• časové faktory MeSH
• cirkadiánní rytmus účinky léků   MeSH
• diltiazem aplikace a dávkování   farmakologie   MeSH
• dospělí MeSH
• hydrokortison krev   MeSH
• krevní tlak účinky léků   MeSH
• lidé MeSH
• melatonin krev   MeSH
• nifedipin aplikace a dávkování   farmakologie   MeSH
• prolaktin krev   MeSH
• tma MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• blokátory kalciových kanálů MeSH
• diltiazem MeSH
• hydrokortison MeSH
• melatonin MeSH
• nifedipin MeSH
• prolaktin MeSH