Diltiazem Research Articles

Exploration of a Novel Terpolymer Nanoparticle System for the Prevention of Alcohol-Induced Dose Dumping.

Alcohol-induced dose dumping (AIDD) remains a serious challenge in the controlled delivery of high potency drugs, such as opioids, which requires extensive investigation and innovative solutions. Current technologies rely on ethanol-insoluble excipients, such as guar gum and sodium alginate, to counteract the increased solubility of hydrophobic polymeric excipients in ethanol. However, these excipients pose several shortcomings, such as high viscosity of coating dispersion, high solution temperature, rapid gelation, and heterogeneity of resulted film. In this work, we explored the application of a cross-linked terpolymer nanoparticle (TPN) as an alcohol-resistant excipient in a water-insoluble controlled release film of ethylcellulose (EC) for the prevention of AIDD. Herein, we optimized the composition of TPN using a central composite design (CCD) to minimize swelling and weight loss of TPN-EC film in the presence of 20% ethanol. The optimized TPN showed a negligible effect on the viscosity of the coating dispersion, while guar gum increased the viscosity by 76-fold. Permeability studies in a pH 1.2 media containing 0% or 40% v/v ethanol revealed that cationic drugs (propranolol HCl, diltiazem HCl, and naloxone HCl (an opioid receptor-binding model drug)) exhibited significantly lower permeability ratios (P40%/P0%) than un-ionized drugs (theophylline and salicylic acid). FTIR analysis indicated an increase in ionic hydrogen bonding between TPN and the cationic drug in the presence of ethanol. These results suggest that drug-polymer-solvent interactions play an important role in alcohol-independent drug permeability through the TPN-EC film. By leveraging the drug permeability altering capability of the TPN-EC system, the release of cationic drugs in hydroethanolic media appeared to be suppressed, suggesting a promising new mechanism of alcohol resistance.

Formulation, Optimization, and Evaluation of Solid-lipid Formulation for Bioavailability Enhancement Utilizing Diltiazem Hydrochloride

Background: Cardiac arrhythmia is a health concern, requiring effective medication for proper treatment. Diltiazem hydrochloride (DTZ.HCL), a class IV anti-arrhythmic calcium channel blocker, was used as a model drug due to its ability to block Ca++ channels in the SA and AV nodes, reducing calcium entry into cardiac cells and subsequently decreasing the force of contraction and oxygen consumption by the heart. Despite its good oral absorption, DTZ.HCL bioavailability is reduced to approximately 40% due to extensive first-pass metabolism. A nano-enabled drug delivery system has the advantage of incorporating both lipophilic and hydrophilic drugs with improved physical stability and enhanced bioavailability. Objective: The objective of this study was to develop a solid-lipid formulation utilizing diltiazem hydrochloride and evaluate it for its bioavailability enhancement. Method: In the experimental study, SLNs were prepared using the microemulsion technique. A blend ratio (1:1) of lipid (stearic acid: compritol 888 ATO), span 80, PEG 200, and water was selected based on the microemulsion region obtained from the Triplot (4.1) ternary phase diagram. The hydrophilic drug diltiazem hydrochloride was incorporated into the lipid blend, and a preheated Smix was maintained at 80°C to obtain a transparent microemulsion, which then crystallized to form SLNs upon subsequent dispersion in cold water (1:25). Critical process parameters, including magnetic stirring speed, homogenizer speed, and probe sonication cycle, were optimized using Design Expert 10 software to achieve the desired particle size diameter, PDI, and entrapment efficiency. Results: The results revealed that the particle size and PDI were significantly influenced by the span 80 and PEG 200. An increase in the concentration of the lipid blend resulted in large particle sizes. The optimized formulation showed a particle size of 415.4±0.2 nm, PDI of 0.184±0.01, and zeta potential of -24.19±0.12 mV. These results were corroborated by DSC thermograms, which indicated reduced enthalpy associated with the reduced particle size of SLNs. Given that diltiazem hydrochloride is a hydrophilic drug with high water solubility, the entrapment efficiency was relatively 30.6% ±0.45. In vitro release studies demonstrated an initial burst release, followed by a sustained release of 85% over 24 hours. The optimized SLNs followed the Higuchi matrix model, with a coefficient of correlation (R²) value of 0.9369. Conclusion: Results concluded successful development of SLNs with improved bioavailability when compared by way of in-vitro method with marketed preparations.

Optimization, Formulation, and Ex vivo Evaluation of Solid Lipid Nanoparticles for Transdermal Delivery of Diltiazem Hydrochloride.

Cardiac arrhythmia, is a medical condition that reduces the heart's efficiency in pumping blood, and can be fatal, requires long-term management with conventional drugs, despite their limited efficacy. Diltiazem hydrochloride, chosen as a model drug, has a short biological half-life and extensive metabolism. Administering drug through skin is challenging, particularly due to the penetration via stratum corneum. However, solid lipid nanoparticles as a particulate carrier system can enhance its permeation and bioavailability. The study aimed to develop a matrix type transdermal patch with diltiazem hydrochloride encapsulated in solid lipid nanoparticles Methods: The study used the solvent diffusion technique to prepare SLNs by mixing the drug and solid lipid in an organic phase at 80°C, then slowly adding it to an aqueous phase with continuous stirring for 45 minutes. The resulting nanodispersion was freeze-dried and analyzed for morphological studies, encapsulation efficiency & drug content. A patch was formulated using solvent evaporation technique, incorporating HPMC E50 (2% w/v), propylene glycol, and ethanolic oleic acid (1.5% v/v). SLNs loaded with diltiazem hydrochloride taken equivalent to diltiazem hydrochloride dose in the transdermal patch. The patch was then evaluated for In vitro and skin permeation studies. The result showed a positive correlation between lipid concentration and particle size. Probe sonication and homogenization increased particle size, while stirring speed reduced it. SEM and TEM images confirmed spherical particles with a size of 488.1±4.01nm and an entrapment efficiency of 55.03±1.99%. Drug release studies demonstrated 70.7% drug release from lipid matrix over 24 hrs. The formulated patch with uniform SLN distribution, had a drug content 89.37 ± 0.04% with a surface pH of 6.1 ± 0.53, close to skin pH. The uniformity of content in 3x3 patch estimated to be 14.587 ± 1.404 mg, close to the theoretical content 16.318 ± 1.08 mg, confirmed homogenous distribution of diltiazem hydrochloride SLNs throughout the patch diameter. Cumulative amount released from patch formulation at pH 5.6 and pH 7.4 was 518.1414μg/cm2 and 404.4466 μg/cm2. Synergistic flux enhancement was observed with oleic acid propylene glycol blend. Ex vivo study of the patch showed steady-state flux of 6.9 μg/cm2/hr, permeability coefficient 0.00362 cm/hr, diffusion coefficient 0.000103 cm/hr, cumulative drug permeation (Dmax) 814.885 μg after 24 hrs, and followed a Higuchi-matrix release model. The developed patch possessed improved bioavailability with reduced dosing and enhanced patient compliance.

Analytical Quality by Design (AQbD) Principles in Development and Validation of Stability‐Indicating RP‐HPLC Method for Simultaneous Estimation of Diltiazem HCl and Eugenol in Nanoethosomes

ABSTRACTThe study developed and validated a robust reverse‐phase high‐performance liquid chromatography (RP‐HPLC) method for a simultaneous estimation of Diltiazem HCl and Eugenol in nanoethosomes using analytical quality by design (AQbD) principles. The optimized method utilized a mobile phase of methanol and 0.1% Orthophosphoric acid (OPA) in a 50:50 % v/v ratio, with a flow rate of 1.0 mL/min and isocratic elution on a Phenomenex Luna C‐18 column (5 µm, 150 mm × 4.6 mm) at 30°C. This setup resulted in retention times of 6.838 min for Diltiazem HCl and 23.135 min for Eugenol. Validation followed International Council for Harmonization (ICH) Q2 (R1) guidelines, demonstrating excellent linearity with correlation coefficients of 0.9982 for Diltiazem HCl and 0.9991 for Eugenol across the 5–25 µg/mL range. The limits of detection (LOD) were 1.341 µg/mL for Diltiazem HCl and 0.960 µg/mL for Eugenol, with limits of quantification (LOQ) at 4.065 and 2.912 µg/mL, respectively. Stability testing under acidic, alkaline, oxidative, thermal, and photolytic conditions adhered to ICH Q1A (R2) and Q1B guidelines. This AQbD‐based method is effective for routine analysis of Diltiazem HCl and Eugenol in bulk and pharmaceutical dosage forms, fully complying with ICH standards.

Antimicrobial activities of Diltiazem Hydrochloride: drug repurposing approach

Background The growing concern of antibiotic-resistant microbial strains worldwide has prompted the need for alternative methods to combat microbial resistance. Biofilm formation poses a significant challenge to antibiotic efficiency due to the difficulty of penetrating antibiotics through the sticky microbial aggregates. Drug repurposing is an innovative technique that aims to expand the use of non-antibiotic medications to address this issue. The primary objective of this study was to evaluate the antimicrobial properties of Diltiazem HCl, a 1,5-benzothiazepine Ca2+ channel blocker commonly used as an antihypertensive agent, against four pathogenic bacteria and three pathogenic yeasts, as well as its antiviral activity against the Coxsackie B4 virus (CoxB4). Methods To assess the antifungal and antibacterial activities of Diltiazem HCl, the well diffusion method was employed, while crystal violet staining was used to determine the anti-biofilm activity. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay was utilized to evaluate the antiviral activity of Diltiazem HCl against the CoxB4 virus. Results This study revealed that Diltiazem HCl exhibited noticeable antimicrobial properties against Gram-positive bacteria, demonstrating the highest inhibition of Staphylococcus epidermidis, followed by Staphylococcus aureus. It effectively reduced the formation of biofilms by 95.1% and 90.7% for S. epidermidis, and S. aureus, respectively. Additionally, the antiviral activity of Diltiazem HCl was found to be potent against the CoxB4 virus, with an IC50 of 35.8 ± 0.54 μg mL−1 compared to the reference antiviral Acyclovir (IC50 42.71 ± 0.43 μg mL−1). Conclusion This study suggests that Diltiazem HCl, in addition to its antihypertensive effect, may also be a potential treatment option for infections caused by Gram-positive bacteria and the CoxB4 viruses, providing an additional off-target effect for Diltiazem HCl.

Synthesis, recognition properties and drug release behavior of diltiazem‐imprinted chitosan‐based biomaterials

AbstractIn this study, we prepared diltiazem (DTZ)‐imprinted biomaterials for TDDS using chitosan, PVA, plasticizers, and sulfosuccinic acid. DTZ and the prepared biomaterials were characterized using field emission scanning electron microscopy, Fourier transform infrared, and 1H nuclear magnetic resonance. DTZ recognition properties were confirmed by the binding isotherm, Scatchard plot analysis, the adsorption of materials with structures similar to DTZ, selectivity factor (α), and the imprinting‐induced promotion of binding (IPB). Results revealed that adsorbed amount (Q) of DTZ‐imprinted biomaterials was 1.63–2.53 times higher than that of non‐imprinted biomaterials. In addition, it could be verified that DTZ‐imprinted biomaterials have a binding site for DTZ according to Scatchard plot analysis. Furthermore, the results of α and IPB indicated that the recognition capacity of the prepared DTZ‐imprinted biomaterials is superior to that non‐imprinted biomaterials. DTZ release properties were evaluated under various pH buffers and artificial skin. Results indicated that the DTZ release in buffers at low pH was faster than that in buffers at high pH. The DTZ release using artificial skin was continuous over 20 days. Furthermore, the DTZ release profile in the buffer followed the pseudo‐Fickian diffusion mechanism, whereas the profile in the artificial skin test followed a non‐Fickian diffusion mechanism.

An Efficient and Cost-effective Modified Carbon Paste Electrodes for Diltiazem Hydrochloride Determination in Tablets

Background and Objective: This study presented new sensitive and selective modified carbon paste (MCPE) potentiometric sensors modified with different ion pairs for the determination of the antihypertensive drug diltiazem hydrochloride (DTM-HCl) in biological fluids, pharmaceutical preparations, and in its pure form. Methods: Plasticizers, ion pair type, ion pair content, response time, temperature, and pH were just a few of the experimental factors evaluated that were found to affect electrode efficiency. The two electrodes that show the best sensitivity were prepared by mixing diltiazem-tetraphenyl borate (DTM-TPB) ion pair, graphite, and TCP or o-NPOE as a plasticizer. Result: Over the concentration ranges of 1.0x10-5–1.0x10-2, the produced electrodes I and II demonstrated monovalent Nernstian responses of 55.7±0.902 and 57.6±0.451 mV decade-1. The selectivity property of the suggested electrodes was used to study the interference ions. The concentration of DTM-HCl in pharmaceutical formulations and biological fluids was measured using these modified electrodes. During the validation procedure, metrics like linearity, accuracy, precision, limit of detection, limit of quantification, and specificity were used. Conclusion: The obtained results showed good agreement with the HPLC technique as indicated by the F and t-test values and can conclude the possibility of using this potentiometric method in the routine analysis of DTM-HCl.

A validated HPTLC method for quantification of a new combination containing Lidocaine HCl and Diltiazem HCl

Regulators approve newer medications and medication combinations for the treatment of various disorders. For the treatment of anal fissures, a novel combination of currently available medications, such as lidocaine HCl and diltiazem HCl, has been approved. The current work represents high-performance thin layer chromatographic method to estimate the amounts of lidocaine hydrochloride and diltiazem hydrochloride in a combined gel dosage form called Crema-L gel (2% W/W of lidocaine and 2% W/W of diltiazem hydrochloride). This method has been validated. The mobile phase in this method consisted of a mixture of toluene, methanol, ethyl acetate (7:2: 1% v/v/v) and two drops of ammonia. The stationary phase was pre-coated aluminium sheet with silica gel G60 F254 (10 × 10 cm, 0.2 mm layer thickness). The drugs’ resolved peaks were found at the Rf values of 0.59 for Lidocaine HCl and 0.48 for Diltiazem HCl. The overlay UV spectra of the two medications were used to determine the analytical wavelength and at 220 nm, both drugs showed appreciable absorbance. The concentration range of 400–1200 ng/band was determined to be the linear approach for both lidocaine HCl and diltiazem HCl, as indicated by their respective correlation coefficients (r2) of 0.9987 and 0.9980. The technique for simultaneously estimating lidocaine hydrochloride and diltiazem hydrochloride in bulk and pharmaceutical dosage form was shown to be robust, accurate, precise, and repeatable.Graphical

Biofabrication of aminated nanocellulose reinforced polyvinyl alcohol/chitosan nanofibrous scaffold for sustained release of diltiazem hydrochloride

In the modern environment conscious era, there has been a huge demand for the effective green method to fabricate biomaterials for sustained transdermal release of diltiazem hydrochloride to treat hypertension and cardiac failure. In this vein, the present study explores the amination of waste jute sourced nanocellulose (ANC) and its effect as a reinforcing filler to design electrospun polyvinyl alcohol (PVA)/chitosan based polymeric nanofibrous scaffold for drug delivery. The characterization results of FTIR (Fourier Transform Infrared Spectroscopy) confirm the successful chemical modification of nanocellulose (NCC). SEM (Scanning Electron Microscopy) results indicate the morphological modifications in ANC due to grafting. ANC enhances the mechanical properties of scaffold and sustains the release of the loaded drug to 67.89±3.39% as compared to the pure PVA/chitosan scaffold of 92.63±4.63% over a period of 72 h as shown by the results of in-vitro drug release study. Moreover, the incorporation of 0.5 % ANC improves the anti-bacterial activity against both gram-positive (97.4±4.87%, reduction in viable cells count) and gram-negative bacteria (98.5±4.93%, reduction in viable cells count). Further, the skin irritation and MTT assay authenticate the biocompatibility of the developed scaffold. The overall findings hence prove the efficacy of the engineered scaffold as a potential transdermal patch for sustained drug delivery applications.

A validated liquid chromatographic method for simultaneous quantification of Lidocaine hydrochloride and Diltiazem hydrochloride

A validated liquid chromatographic method for simultaneous quantification of Lidocaine hydrochloride and Diltiazem hydrochloride

Diltiazem Hydrochloride Floating Matrix Tablet: Formulation and in vitro-in vivo Evaluation.

Diltiazem hydrochloride is a calcium channel-blocker with a plasma elimination half-life of 4.4 ± 1.3 h and has a narrow absorption window. So, this work aimed to prepare a gastro-retentive floating matrix tablet. The direct compression method was used to manufacture tablets. 32 factorial design was applied for optimization, taking Hydroxypropyl Methylcellulose K100M (HPMC K 100M) and the amount of sodium bicarbonate as independent factors and cumulative percentage release at 1 h, at 6 h, and at 12 h and floating lag time as dependent variables. The high amount of HPMC K100M and sodium bicarbonate shows good results. The optimized preparation was evaluated for differential scanning calorimetry, in-vivo gastric retention in male albino rabbits, kinetic modeling, and stability study. An in vivo study revealed gastric retention of tablets up to 6 h in healthy male Albino rabbits. The stability study indicated no significant change in the buoyancy and release profiles of the drug. From this study, it can be concluded that the gastro-retentive diltiazem hydrochloride floating matrix tablet was successfully prepared and retained inside the rabbit stomach for up to 6 h and was stable under accelerated stability study.

Research on Formulation and Evaluation of Floating Microspheres

The purpose of this study is to design and evaluate a floating multipart oral delivery system for diltiazem hydrochloride that can provide sustained release. The aim of the work is also to study various parameters that influence the behaviour of floating multiparticles in an oral dosage form. Floating microspheres were prepared by a non-aqueous emulsifying solvent evaporation technique using ethyl cellulose and Eudragit RS-100 asthe rate-controlling polymer. In vitro activity was evaluated using standard pharmacopoeia and other tests such as drug-polymer compatibility, (%)yield, particle size analysis, drug entrapment efficiency, surface topography, in vitro buoyancy and release studies. The results show that the mixing ratio of the components in the organic phase affected the size, size distribution (199-320 µm), drug concentration(59-84%), percent yield (57-77%) and drug. Liberation microsphere (45-99aftern12 hours) and swimming time > 12 hours. The best results were obtained in the ratio drug: polymer Eudragit RS-100 (1:3). Good in vitro floating behaviour was observed in most cases, and various drug release patterns could be achieved by varying the polymer ratio, which was optimized to match the target release profile. Stability studies showed no significant change in the drug content of the formulation even after 3months. The data obtained in this study therefore suggest a floating dose of micro particles

Exploring the Effectiveness of Carboxymethylated and Crosslinked Albizia procera Gum in Diltiazem Hydrochloride Matrix Tablets: A Comparative Analysis.

This study investigates the efficacy of modified Albizia procera gum as a release-retardant polymer in Diltiazem hydrochloride (DIL) matrix tablets. Carboxymethylated Albizia procera gum (CAP) and ionically crosslinked carboxymethylated Albizia procera gum (Ca-CAP) were utilized, with Ca-CAP synthesized via crosslinking CAP with calcium ions (Ca2+) using calcium chloride (CaCl2). Fourier Transform (FT) IR analysis affirmed polymer compatibility, while differential scanning calorimetry (DSC) and X-ray diffraction (XRD) assessed thermal behavior and crystallinity, respectively. Zeta potential analysis explored surface charge and electrostatic interactions, while rheology examined flow and viscoelastic properties. Swelling and erosion kinetics provided insights into water penetration and stability. CAP's carboxymethyl groups (-CH2-COO-) heightened divalent cation reactivity, and crosslinking with CaCl2 produced Ca-CAP through -CH2-COO- and Ca2+ interactions. Structural similarities between the polymers were revealed by FTIR, with slight differences. DSC indicated modified thermal behavior in Ca-CAP, while Zeta potential analysis showcased negative charges, with Ca-CAP exhibiting lower negativity. XRD highlighted increased crystallinity in Ca-CAP due to calcium crosslinking. Minimal impact on RBC properties was observed with both polymers compared to the positive control as water for injection (WFI). Ca-CAP exhibited improved viscosity, strength, controlled swelling, and erosion, allowing prolonged drug release compared to CAP. Stability studies confirmed consistent six-month drug release, emphasizing Ca-CAP's potential as a stable, sustained drug delivery system over CAP. Robustness and accelerated stability tests supported these findings, underscoring the promise of Ca-CAP in controlled drug release applications.

Utility of native emission quenching of erythrosine B for the determination of diltiazem in different dosage forms.

This study introduces a practical and cost-effective method for tracking diltiazem (DLZ) analytically. It utilizes a fluorimetric approach that relies on the modulation of fluorescence intensity of a dye called erythrosine B. Through a one-pot experiment performed in an acidic environment, a complex is rapidly formed between DLZ and erythrosine B. By observing the decrease in erythrosine B emission, a linear calibration plot is established, enabling the detection and quantification of DLZ concentrations ranging from 40 to 850 ng/ml. The estimated limits of detection and quantitation were 10.5 and 32.1ng/ml, respectively. The variables affecting the DLZ-dye complex system were carefully adjusted. The validity of the approach was confirmed through a thorough evaluation based on the criteria set by ICH guidelines. The accuracy and precision of the methodology were evaluated, and the standard deviation and relative standard deviation were below 2. The strategy was successfully employed to analyze DLZ in tablets and capsules, and no significant variation between the proposed and reported methods as the values of the estimated t-test and F-test at five determinations were below 2.306 and 6.338, respectively. Notably, the method adheres to the principle of green chemistry by utilizing distilled water as the dispersing medium.

A floating 3D printed polypill formulation for the coadministration and sustained release of antihypertensive drugs

Polypharmacy is a common issue, especially among elderly patients resulting in administration errors and patient inconvenience. Hypertension is a prevalent health condition that frequently leads to polypharmacy, as its treatment typically requires the co-administration of more than one different Active Pharmaceutical Ingredients (API’s). To address these issues, floating hollow torus-shaped dosage forms were developed, aiming at providing prolonged gastric retention and sustained drug release. The dosage forms (polypills) containing three anti-hypertensive API’s (diltiazem (DIL), propranolol (PRP) and hydrochlorothiazide (HCTZ)) were created via Fused Deposition Modelling 3D printing. A multitude of the dosage forms were loaded into a capsule and the resulting formulation achieved prolonged retention times over a 12-hour period in vitro, by leveraging both the buoyancy of the dosage forms, and the “cheerios effect” that facilitates the aggregation and retention of the dosage forms via a combination of surface tension and shape of the objects. Physicochemical characterization methods and imaging techniques were employed to investigate the properties and the internal and external structure of the dosage forms. Furthermore, an ex vivo porcine stomach model revealed substantial aggregation, adhesion and retention of the 3D printed dosage forms in porcine stomach. In vitro dissolution testing demonstrated almost complete first-order release of PRP and DIL (93.52 % and 99.9 %, respectively) and partial release of HCTZ (65.22 %) in the 12 h timeframe. Finally, a convolution-based single-stage approach was employed in order to predict the pharmacokinetic (PK) parameters of the API’s of the formulation and the resemblance of their PK behavior with previously reported data.

High-performance thin-layer chromatography‒spectrodensitometric determination of diltiazem hydrochloride and its commonly occurring degradation impurity

High-performance thin-layer chromatography‒spectrodensitometric determination of diltiazem hydrochloride and its commonly occurring degradation impurity

Diltiazem HCl suppresses porcine reproductive and respiratory syndrome virus infection in susceptible cells and in swine

Porcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen for swine, resulting in substantial economic losses to the swine industry. However, there has been little success in developing effective vaccines or drugs for PRRSV control. In the present study, we discovered that Diltiazem HCl, an inhibitor of L-type Ca2+ channel, effectively suppresses PRRSV replication in MARC-145, PK-15CD163 and PAM cells in dose-dependent manner. Furthermore, it demonstrates a broad-spectrum activity against both PRRSV-1 and PRRSV-2 strains. Additionally, we explored the underlying mechanisms and found that Diltiazem HCl -induced inhibition of PRRSV associated with regulation of calcium ion homeostasis in susceptible cells. Moreover, we evaluated the antiviral effects of Diltiazem HCl in PRRSV-challenged piglets, assessing rectal temperature, viremia, and gross and microscopic lung lesions. Our results indicate that Diltiazem HCl treatment alleviates PRRSV-induced rectal temperature spikes, pulmonary pathological changes, and serum viral load. In conclusion, our data suggest that Diltiazem HCl could serve as a novel therapeutic drug against PRRSV infection.

SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function

In skeletal muscle (SM), inward Ca2+-currents have no apparent role in excitation-contraction coupling (e-c coupling), however the Ca2+-channel blocker can affect twitch and tetanic muscle in mammalian SM. Experiments were conducted to study how diltiazem (DLZ) facilitates e-c coupling and inhibits contraction. 1) In complete Extensor Digitorum Longus (EDL) muscle and single intact fibres, 0.03 mM DLZ causes twitch potentiation and decreases force during tetanic activity, with increased fatigue. 2) In split open fibres isolated from EDL fibres, DLZ inhibits sarcoplasmic reticulum (SR) Ca2+-loading in a dose-dependent manner and has a potentiating effect on caffeine-induced SR Ca2+-release. 3) In isolated light SR (LSR) vesicles, SERCA1 hydrolytic activity is not affected by DLZ up to 0.2 mM. However, ATP-dependent Ca2+-uptake was inhibited in a dose-dependent manner at a concentration where e-c coupling is changed. 4) The passive Ca2+-efflux from LSR was reduced by half with 0.03 mM diltiazem, indicating that SR leaking does not account for the decreased Ca2+-uptake. 5) The denaturation profile of the SERCA Ca2+-binding domain has lower thermal stability in the presence of DLZ in a concentration-dependent manner, having no effect on the nucleotide-binding domain. We conclude that the effect of DLZ on SM is exerted by crossing the sarcolemma and interacting directly with the SERCA Ca2+-binding domain, affecting SR Ca2+-loading during relaxation, which has a consequence on SM contractility. Diltiazem effect on SM could be utilized as a tool to understand SM e-c coupling and muscle fatigue.

In vivo Assessment of Diltiazem HCl Immobilized Co-polymeric pH Sensitive Microgels

Novel stimuli responsive coplymeric (2-ethyl hexyl acrylate -co- itaconic acid diltiazem HCl loaded microgels were fabricated and characterized successfully to reduce the degradation of drugs in acidic pH of stomach resulting in reduced bioavailability to minimize dosing frequency and enhance patient compliance. To evaluate the clinical significance, in-vivo studies of recently prepared novel pH sensitive copolymeric microgels are performed and different pharmacokinetic parameters as maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (Tmax), area under the plasma concentration-time curve (AUC 0-?), half-life (t 1/2?) and elimination rate constant (K21) are analyzed. The mean plasma concentration of sustained release DLZ loaded microgels showed higher Tmax for prepared microgels (4.0758±0.22 hrs) than standard drug solution. The half-life t1/2? of test microgels is relatively higher (5.68±5.86 hrs) whereas the Cmax is measured to be 41.06±2.02ng/ml for microgels with AUC0-? calculated as 460.35±39.99 ng.hr/ml. Elimination rate constant K21 for DLZ microgels is 0.18 ± 0.07 hrs-1 for which showed the absorption phase is extended and drug is present for a prolong period of time in the body. This study proved that novel prepared pH sensitive copolymeric p(EHA-co-IA) microgels released model drug in sustained release manner in pH sensitive medium.

Outcomes of non-surgical treatment of chronic anal fissure: A comparative study

Background and objective: Chronic anal fissure is a common health problem related to high morbidity. The chemical option for treating chronic anal fissures is highly preferred. Methods: A clinical prospective comparative study was carried out in the General Surgery Outpatient Department in Rizgary Teaching Hospital, Erbil, KRG, during the period from January 2019 to December 2021,on a sample of 100 patients randomly recruited patients with chronic anal fissures divided into two groups with 50 participants each: the DTZ group, who received 2% diltiazem ointment, and the GTN group, who used 0.2% glyceryl trinitrate ointment twice daily for 6 consecutive weeks. The aim of the study is to compare the efficacy and effects of topical Diltiazem (DTZ) and topical glyceryl trinitrate (GTN) in the management of chronic anal fissures. Results: There was a highly significant association between fissure healing at the 4th week and patients treated with DTZ (P <0.001). A highly significant association was observed at the 6th week between fissure healing and DTZ treatment (P <0.001), while there was later a highly significant association between fissure healing at the 8th week and patients treated with GTN (P <0.001). A significant association was observed between treatment adverse effects and patients treated with GTN (P = 0.05). DTZ was found to be more effective for symptomatic relief than GTN. Conclusion: Both DTZ and GTN are effective in the treatment of chronic anal fissures, but treatment with DTZ is accompanied by faster healing and lower side effects.