Concentrations Of Amlodipine Research Articles

Teratoma induced by amlodipine drug in fetus rats

The current study, performed during the period from February 2021 to June 2022 at the University of Thi- Qar/ College of Education for Pure Sciences, and aimed to follow the changes in external morphological features at different Embryonic developmental stages in pregnant rats treated with different doses of amlodipine. Usage In this study, 18 pregnant rats were randomly divided into three groups, each with six pregnant rats. Each group received different concentrations of amlodipine (0.3, 0.5) in oral doses until the 20th day of gestation, while the control group was injected with 0.9% normal saline. Teratomas are bizarre tumors derived from embryonic tissue that are normally found only in the gonadal and sacral regions of adults. Primary retroperitoneal teratomas are rare and present challenging management options. In one outcome, a teratoma was found in one of the amlodipine-treated groups. Complete excision of the teratoma mass was performed.

Therapeutic Drug Monitoring in Uncontrolled Arterial Hypertension: Result of the Pilot Part of Study

INTRODUCTION: Despite the recently established evidence-based and systemic approach to treatment for arterial hypertension (AH), not in all cases its control can be achieved.
 AIM: To conduct a comparative analysis of the concentration of antihypertensive drugs (AHTDs) in blood serum of patients with controlled and uncontrolled AH.
 MATERIALS AND METHODS: Fifty six patients were included. Inclusion criteria: age 18 years, signing of informed consent, established diagnosis of AH, regular intake of any two of study antihypertensive drugs (lisinopril, amlodipine, valsartan) and also of indapamide at stable doses, for women adequate contraception. According to the results of daily monitoring of the arterial pressure (AP), patients were divided into two groups: the first group controlled hypertension (AP 140/90 mmHg; n = 39), the second uncontrolled hypertension (AP 140/90 mmHg; n = 17). The mean age of patients in the first group was 65.03 10.80 years, in the second 63.50 8.31 (p = 0.576). In the first group, women prevailed (64.1% vs. 35.3%, p = 0.047) and the mean body mass index was lower (26.30 1.38 kg/m2 vs. 32.20 4.15 kg/m2, p = 0.02). In patients of both groups, venous blood was taken in fasting condition in the morning and 2 hours after intake of AHTDs to assess their concentration by high-performance liquid chromatography. The analytical range for lisinopril, indapamide, amlodipine was 5500 ng/ml, for valsartan 1010,000 ng/ml.
 RESULTS: In the first group, equilibrium concentration of lisinopril was 2.67 times higher (p = 0.053), and concentration of indapamide in 2 hours after intake was 1.83 times higher (р = 0,084); when normalized to the dose, the differences were leveled out (p 0.05). Concentrations of amlodipine and valsartan did not differ between the groups both before and 2 hours after intake (p 0.05). In 3 of 39 (7.7%) patients with controlled hypertension and in one of 17 patients (5.9%, p = 1.0) with uncontrolled hypertension, AHTDs were detected in blood serum, which were not administered to them.
 CONCLUSIONS: Results of the pilot part of the study (n = 56) demonstrated the absence of difference between the mean concentrations of the study AHTDs in the blood serum of patients with controlled and uncontrolled AH, and in some cases the presence of traces of AHTDs not administered by the doctor.

Therapeutic Drug Monitoring in Arterial Hypertension.

(1) Background: This study was planned to assess the concentration of antihypertensive drugs (AHD) in the blood serum in patients with controlled and uncontrolled arterial hypertension (AH). (2) Methods: We assessed 46 patients with AH. Based on the results of 24 h blood pressure monitoring (ABPM), the patients were randomized into two groups. The first group consisted of the patients with controlled AH; the second group consisted of the patients with uncontrolled AH. Venous blood was taken in both groups of patients in the morning before and 2 h after taking drugs to assess the concentration of lisinopril, amlodipine, valsartan, and indapamide. (3) Results. The first group included 27 patients, and the second group 19 patients. In patients with uncontrolled AH, the median concentrations of lisinopril, indapamide, amlodipine, and valsartan before and after taking the drugs did not differ from patients who reached the target BP values. (p > 0.05). In some patients with uncontrolled and controlled (shown for the first time) AH the concentration of AHD was below the limit of quantitative determination. (4) Conclusions. The obtained results indicate that the pharmacokinetics of AHD, apparently, does not play a significant role in the development of ineffectiveness of the ongoing therapy for AH. Therapeutic drug monitoring can be used to test adherence to the treatment.

Potential pharmacokinetic interactions in fixed-dose combinations of perindopril/indapamide/amlodipine compared with perindopril/indapamide and amlodipine in healthy Chinese volunteers

S05590 is a fixed-dose combination of perindopril tert-butylamine 4 mg/indapamide 1.25 mg, and S06593 is a fixed-dose combination of perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg. The purpose of this study was to determine whether pharmacokinetic interactions exist among the components of S06593, compared with S05590 and amlodipine as reference drugs, in healthy Chinese male volunteers after a single oral administration under fasting conditions. A single-center, open-label, randomized, three-period, six-way crossover study was conducted. A total of 42 participants were enrolled and randomized to receive S05590 plus amlodipine, or S06593. The doses of perindopril were 3.34 mg in both S05590 and S06593, calculated as free acid. Blood samples were collected in each treatment period to determine the plasma concentrations of perindopril, indapamide and amlodipine, as well as perindoprilat, the main metabolite of perindopril. A total of 39 participants completed this study. The 90% confidence intervals of the geometric mean ratios of Cmax, AUC0-tand AUC0-∞for perindopril, perindoprilat, indapamide and amlodipine were all within 80.00–125.00%, thus indicating that S05590 plus amlodipine and S06593 were pharmacokinetically equivalent. During the study, only one serious emergent adverse event was reported, which was deemed not to be associated with the study drug. No serious treatment-associated adverse events were observed.

Bioequivalence study of fixed-dose combination Losartan + amlodipine + rosuvastatin Sanofi in comparison with coadministered fixed- dose combination Lozap® AM and monocomponent drug Crestor® in healthy subjects

Introduction. The advantages of fixed-dose combination losartan + amlodipine + rosuvastatin compared to mono-drugs and two-component combinations are to increase the therapeutic efficacy, to reduce the cost of the product and to make the drug easier to take which helps to improve patient adherence to therapy. A bioequivalence study of the three-component fixed-dose combinations Losartan + amlodipine + rosuvastatin Sanofi with coadministered Lozap® AM (Losartan+Amlodipine) and Crestor® (Rosuvastatin) was conducted. Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of two strengths of fixed-dose combination: 1) Losartan + amlodipine + rosuvastatin Sanofi (tablets, 50 mg + 5 mg + 10 mg) in comparison with coadministrated drugs Lozap® AM (losartan + amlodipine, tablets, 50 mg + 5 mg,) and Crestor® (rosuvastatin, tablets, 10 mg) in fasting healthy volunteers after a single administration; 2) Losartan + amlodipine + rosuvastatin Sanofi (tablets, 100 mg + 5 mg + 20 mg) in comparison with coadministrated drugs Lozap® AM (losartan + amlodipine, tablets, 100 mg + 5 mg) and Crestor® (rosuvastatin, tablets, 20 mg) in fasting healthy volunteers 18–45 years old after a single dose. Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period clinical trial was conducted for each strengths of fixed-dose combination. The concentrations of losartan, amlodipine and rosuvastatin in blood plasma samples obtained from volunteers were determined by a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals (CI) for the pharmacokinetic parameters Сmax, AUC0-72 (for amlodipine) and AUC0-t (for losartan and rosuvastatin) were calculated. Results and discussion. Based on the results of statistical and pharmacokinetic analysis, it was shown that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of losartan, amlodipine and rosuvastatin. 90 % CI were in the acceptable range for Сmax (of amlodipine), AUC0-72 (of amlodipine) and AUC0-t (of losartan and rosuvastatin). 90 % CI for Сmax of losartan and rosuvastatin were in the acceptable extended calculated range according to the protocol. Conclusion. Thus, according to the criteria used in the studies, the three-component fixed-dose combinations Losartan + amlodipine + rosuvastatin Sanofi are proved to be bioequivalent in comparison with coadministered Lozap® AM and Crestor®.

Evaluation of cytogenetic damage induced by antihypertensive drug Amlodipine: in vitro

Background: Amlodipine is a calcium channel blocker medication used to treat high blood pressure and coronary artery diseases for long term of use. Sufficient studies reporting the cytogenetic effects of this drug have not reporting yet. Aim of study: This study aimed to assess the frequency of chromosomal aberrations of amlodipine on human blood lymphocytes in vitro. Material and Methods: In this study, the in vitro genotoxic effects of amlodipine have been determined in human peripheral blood lymphocytes by using chromosomal aberrations: 0; 5; 10; 15; 25 and 50mg/mL concentrations of amlodipine was used. All samples cultured in 37°C incubation for 72 hours. Then treated with Colcemid. Results: Amlodipine did not appear to have cytogenetic effects in vitro, as no significant increases in the frequency of chromosomal aberrations were found in cultures treated with different concentrations compared to cultures treated with the recommended concentration (10 mg/mL). The highest concentrations (50 mg/mL) of amlodipine increased chromosomal aberrations compared to negative control, but these increases were not statistically significant Conclusion: Amlodipine is not seemed to be genotoxic active ingredients in human lymphocytes in vitro.

Pharmacokinetic comparison between a fixed-dose combination of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a corresponding loose combination of fimasartan/amlodipine 60/25 mg and hydrochlorothiazide 25 mg in healthy subjects.

For the treatment of hypertension, fixed-dose combinations (FDCs) of antihypertensive drugs can provide complementary benefits from improved compliance and cost-effectiveness compared with loose combinations of corresponding drugs. A new FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg is undergoing clinical development. A randomized, open-label, single-dose, 3-period, 3-sequence, partially replicated crossover phase 1 study was conducted to compare the pharmacokinetics (PKs) between the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a loose combination of a dual-combination FDC (fimasartan/amlodipine 60/10 mg) and hydrochlorothiazide 25 mg. Sixty healthy subjects were randomized, and 55 subjects completed the study. Serial blood samples were collected, and plasma concentrations of fimasartan, amlodipine and hydrochlorothiazide were measured to analyze PK parameters. The PK profiles of the FDC were similar to those of the loose combinations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to loose combinations for the maximum plasma concentration (Cmax) and area under the curve until the last measurable time point (AUClast) were within the conventional bioequivalent range of 0.80 to 1.25. The GMRs and 90% CIs of fimasartan, amlodipine and hydrochlorothiazide were 1.0163 (0.8681–1.1898), 0.9595 (0.9256–0.9946), and 1.1294 (1.0791–1.1821) for Cmax and 1.0167 (0.9347–1.1059), 0.9575 (0.9317–0.9841), and 1.0561 (1.0170–1.0967) for AUClast, respectively. Both the FDC and loose combinations were well tolerated. In conclusion, the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg showed similar PK profiles to those of the corresponding loose combination, and both treatments were well tolerated.

Plasma Trough Concentrations of Antihypertensive Drugs for the Assessment of Treatment Adherence: A Meta-Analysis.

Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5-10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4-64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5-462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (β1=0.9; P<0.05), mean age, and mean body weight for the mean trough concentration of hydrochlorothiazide (β1=2.2, P<0.05, respectively, β1=-4.0, P<0.05) and no significant moderators for valsartan. Plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan, measured with liquid chromatography-tandem mass spectrometry, are highly heterogeneous over the different studies. Use of the pooled trough concentration as a cutoff in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence, which may seriously harm the patient-physician relationship, and is therefore not recommended.

Pharmacokinetic and Bioequivalence Study of Telzap AM® (Telmisartan/amlodipine Fixed-dose Combination) and Coadministered Mikardis® (Telmisartan) and Norvask® (Amlodipine) in Healthy Subjects

Introduction. A fixed dose combination of telmisartan and amlodipine is widely used in clinical practice during hypertension treatment. Combination of telmisartan and amlodipine demonstrates potentiating synergistic effect on blood pressure decrease. A bioequivalence study of Telzap® AM with coadministered Mikardis® and Norvask® was conducted with 60 volunteers.Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of the fixed dose combination drug product Telzap® AM (telmisartan + amlodipine, tablets, 80 + 10 mg, Zentiva ks company, Czech Republic) and coadministrated monocomponent drug products Mikardis® (telmisartan, tablets 80 mg, Beringer Ingelheim International GmbH, Germany) and Norvask® [amlodipine, tablets 10 mg, Pfizer HCP Corporation (USA), Russia] in healthy volunteers after a single administration under fasting.Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period replicate clinical trial was conducted. The concentrations of amlodipine and telmisartan in plasma samples were determined by a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals for the pharmacokinetic parameters Cmax and AUC0-72 were calculated.Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of amlodipine and telmisartan. All 90 % confidence intervals for the estimated pharmacokinetic parameters of amlodipine were in the range of 80–125 %, 90 % confidence intervals for telmisartan were within the bioequivalence range of 80–125 % for AUC0-72, and 76.73–130.32 % for Cmax.Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent.

Plasma trough concentrations of antihypertensive drugs for the assessment of treatment adherence: a meta-analysis

Abstract Background Non-adherence to antihypertensive drugs is an important behavioral contributor to poor blood pressure control and is associated with increased risk of cardiovascular disease, hospitalization and increased healthcare costs. Biochemical drug screening in plasma is an accurate method for the detection of non-adherence. When performed qualitatively (present/not present) this method may lead to overestimation of adherence to drugs with long half-lives. Detection of non-adherence may be improved by performing it quantitatively (measurement of exact concentrations) making use of reliable, drug-specific cut-off values based on exposure parameters in plasma. Purpose To perform a literature review and meta-analysis of pharmacokinetic studies to determine plasma population trough concentrations of three frequently prescribed antihypertensive drugs with different pharmacological properties; amlodipine, hydrochlorothiazide and valsartan. These population trough concentrations could possibly be used as drug-specific cut-off values for the diagnosis of (non-)adherence. Methods PubMed was searched for pharmacokinetic studies regarding amlodipine, hydrochlorothiazide and valsartan up to December 2019. Eligible studies reported steady-state mean trough concentration estimates and their variance measured in healthy subjects or in patients with hypertension without hepatic or renal failure. Pooled trough concentrations were estimated using a DerSimonian and Laird random-effect approach. To take dependency between mean trough concentrations into account a multilevel meta-analysis was performed. Meta-regression was used to explore sources of heterogeneity identified by the I2 statistic. Results The literature search identified 1154 potentially relevant articles of which 44 were eligible for inclusion; 23 for amlodipine, 10 for hydrochlorothiazide and 11 for valsartan. The overall pooled mean trough concentration estimate was 9.3 ng/ml (95% confidence interval: 8.4–10.2) for amlodipine, 29.4 ng/ml (24.4–43.3) for hydrochlorothiazide and 355.4 ng/ml (294.1–416.6) for valsartan (figure 1A-C). Substantial heterogeneity was present for all three pooled estimates (I2 &amp;gt;90%). Based on meta-regression 33.3%, 20.3% and 8.2% of the heterogeneity between the studies can be explained by differences in dose for amlodipine, hydrochlorothiazide and valsartan, respectively. Conclusions Plasma trough concentrations of amlodipine, hydrochlorothiazide and valsartan are highly heterogeneous over the different study populations. This heterogeneity is caused, at least in part, by differences in drug dose. Use of the pooled trough concentration mean estimate as a cut-off in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence and should therefore be implemented with caution. Future research might focus on combining drug specific pharmacokinetics with individual patient characteristics to predict personalized trough concentrations. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): UMC Utrecht

Postmortem fatal and non-fatal concentrations of amlodipine

Amlodipine is a dihydropyridine calcium channel blocker widely used in the treatment of high blood pressure and coronary heart disease. Intoxication can lead to reflex tachycardia following massive hypotension and death. The objective of this work was to study the post-mortem concentrations of amlodipine in 62 patients in order to determine whether the use of the reference concentrations from the living patients was applicable in postmortem setting, and to define more precisely the fatal and non-fatal postmortem concentrations of amlodipine. The amlodipine concentrations were measured in femoral whole blood by LC–MS/MS validated method. When sufficient information was available, the data were classified into 2 different groups, based on the conclusions of the autopsy and toxicological results: G1: non-toxic death and G2: fatal poisoning involving amlodipine alone or as part of a multidrug poisoning. The median concentration of amlodipine [1st quartile - 3rd quartile] of the whole population (n = 62) was 81 [42–134] ng/mL. Twenty-two cases were classified as G1 and thirteen as G2. The observed median [1st quartile - 3rd quartile] concentration of amlodipine was 66 [40.5–79.5] ng/mL in G1 and 240 [170–404] ng/mL in G2. The median concentrations observed in “non-toxic” deaths (66 ng/mL) were three times higher than those usually observed in living patients. Amlodipine distribution ratio between plasma and whole blood concentrations seems insufficient to explain this difference and postmortem redistribution from organs should be considered, and could suggest the same redistribution pattern for other drugs belonging to the same family.

An integrated separation process for recovery and enantioseparation of amlodipine from wastewater: Supported liquid membrane-aqueous/organic phase crystallization

An integrated separation process is proposed for recovery and enantioseparation of a chiral antihypertensive drug amlodipine from wastewater. Utilizing this integrated technology, both high recovery (Y) and high enantiomeric excess (ee) were obtained due to the strong enrichment ability of supported liquid membrane with strip dispersion (SLM-SD) and the good enantioseparation ability of organic phase crystallization. These two steps were coupled by an intermediate step: aqueous phase crystallization. In the SLM-SD, an extractant P204 (bi(2-ethylhexyl)phosphoric acid) was dissolved in n-heptane to form a liquid membrane phase, and hydrochloric acid was used as stripping agent. One-stage SLM-SD recycled the amlodipine from wastewater into a stripping phase with a removal (EAD) of 99.67% and a Y1,AD of 87.91% after optimizing the parameters: pH and the concentrations of P204, hydrochloric acid, and amlodipine. Sodium hydroxide and (L)-tartaric acid were added into the stripping aqueous phase to obtain amlodipine-1/2(L)-tartrate acid crystals, which were directly used in the subsequent organic phase crystallization without tedious additional steps. The Y2, AD of aqueous phase crystal reached 99% at a pH of over 6.68 and a molar ratio of over 0.5 for (L)-tartrate acid to amlodipine. Using (L)-tartaric acid or (D)-tartaric acid as resolving agent and dimethylsulfoxide as solvent, high-value-added products (R)-amlodipine and (S)-amlodipine were obtained by two steps of organic phase crystallization. The ee of products was over 99% after optimizing the dosages of dimethylsulfoxide and resolving agent. To increase the total yield, the generated mother liquors were re-treated by SLM-SD with the recovery of over 99% for residual amlodipine.

Evaluation of pharmacokinetics and safety with bioequivalence of Amlodipine in healthy Chinese volunteers: Bioequivalence Study Findings.

Background and ObjectiveAmlodipine, a main series of L‐type calcium channel blockers (CCBs), exerts potent antihypertensive effects. The aim of this trial was to explore the pharmacokinetics (PK) and safety with bioequivalence of orally administered Amlodipine provided by two sponsors in healthy volunteers (HVs).MethodsTwo separate randomized, open‐label, single‐dose, crossover‐design studies were conducted: a fasting study (n = 24) and a fed study (n = 24). In each study, HVs were randomized to Fangming Pharmaceutical Group (Test, T) followed by NORVASC® (Reference, R), or vice versa. Each study subject received a 5‐mg Amlodipine tablet with a 15‐day washout. The plasma concentrations of Amlodipine were measured using a LC‐MS/MS method, and PK parameters were determined by noncompartmental model.ResultsForty‐eight healthy volunteers were enrolled. And overall demographics were as follows: the fasting study: female (n = 16/24), age (18‐54 years), weight (47‐76 kg), and BMI (19.5‐26.0). The fed study: female (n = 16/24), age (20‐49 years), weight (45.5‐69 kg), and BMI (19.1‐25.0). All PK endpoints met the pre‐specific criteria for PK equivalence. In fasting subjects, the maximum plasma concentration (C max) was 3.881 ± 0.982 ng/mL at 6 hours (median) of sponsor T, and 4.042 ± 1.147 ng/mL at 6 hours (median) of sponsor R. In fed subjects, C max was 3.312 ± 0.789 ng/mL at 6 hours (median) of sponsor T, and 3.392 ± 0.902 ng/mL at 5 hours (median) of sponsor R. Both fasting and fed studies achieved a plausible bioequivalence.ConclusionsAmlodipine is well tolerated and have a favorable safety profile. The observed adverse events were mild (the severity was assessed according to the Common Terminology Criteria for Adverse Events [version CTCAE4.03]) and all of them were recovered without severe sequences. And the bioequivalence is achieved under fasting and fed conditions, supporting the demonstration of biosimilarity.

Pharmacokinetics and bioequivalence of fixed-dose combination of candesartan cilexetil/amlodipine besylate (16/10 mg) versus coadministration of individual formulations in healthy subjects.

This study compared the pharmacokinetics of a fixed-dose combination (FDC) of candesartan (16 mg) and amlodipine (10 mg) versus coadministration of individual formulations to clarify the bioequivalence of the FDC. In this randomized, open-label, single-dose, 2-treatment, 2-way crossover study, healthy Korean volunteers received a single dose of candesartan (16 mg) with amlodipine (10 mg) as either an FDC or single agents concomitantly administered, with a 2-week washout period. Serial blood samples were collected up to 72 hours after dosing for each treatment period, and plasma concentrations of candesartan and amlodipine were measured using a validated liquid chromatography-tandem mass spectrometry method. A total of 39 subjects completed the study. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the peak plasma concentration (Cmax) for candesartan were 1.0182 (0.9562–1.0841) and 0.9492 (0.8726–1.0324), respectively. The GMR and 90% CI for the AUC0-t and Cmax for amlodipine were 1.0552 (1.0255–1.0857) and 1.0668 (1.0259–1.1094), respectively. In conclusion, the new FDC formulation of candesartan (16 mg) and amlodipine (10 mg) was bioequivalent to the concomitant administration of single agents. A single dose of candesartan/amlodipine as the FDC or as single agents was well tolerated.Trial RegistrationClinicalTrials.gov Identifier: NCT02988362

Pharmacokinetic Drug Interactions Between Amlodipine, Valsartan, and Rosuvastatin in Healthy Volunteers

Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug-drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10mg/160mg alone for 10 consecutive days in period I, and the same FDC for 10days with concomitant 7-day administration of 20mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7days in period I, and the FDC for 10days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72h for amlodipine and rosuvastatin, and for up to 48h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography-tandem mass spectrometry. Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029-0.9763) and 0.9316 (0.8970-0.9675) for amlodipine, 0.7698 (0.6503-0.9114) and 0.7888 (0.6943-0.8962) for valsartan, and 0.9737 (0.8312-1.1407) and 0.9596 (0.8826-1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. https://cris.nih.go.kr CRIS KCT0001660. KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.

Impact of non-conventional rescue therapies on quantification of cardiac agents following severe poisoning: Analytical considerations

To assess whether a TurboFlow-LC-MS/MS (TF-LC-MS/MS) method that quantifies calcium channel blockers (CCB) and beta-blockers (BB) in plasma is suitable for monitoring severely-poisoned patients when non-conventional rescue therapies, i.e. lipid emulsions (LE) and Molecular Adsorbent Recirculating System (MARS ® ) are instituted. CCB amlodipine (A), nicardipine (Nic), nifedipine (Nif) and BB nebivolol (Neb) were quantified in plasma with or without lipid emulsion (PLE) and in dialysates (D) by TF-LC-MS/MS using a TLX-1 System interfaced with a TSQ Quantum Ultra ® (ThermoFisher). Impact of intravenous LE was studied with blank plasma spiked with Intralipid 20% (final concentrations between 5 to 30%). The albumin-containing dialysate that circulates through the MARS ® was replicated with an Ydralbum ® solution diluted in physiologic serum to obtain final concentrations of 0, 5, 10 and 15% of human albumin. All samples were analyzed by TF-LC-MS/MS after protein precipitation with acetonitrile containing deuterated internal standards (IS). Calibration curves were established by plotting the area of each analyte with dedicated deuterated IS in plasma samples. Impact of LE and MARS ® was studied with Quality Controls (QCs) spiked with analytes at low and high level concentrations (5 and 150 ng/mL) in PLE and in D, respectively. The method was finally applied to analyze samples obtained from two patients severely poisoned to amlodipine and treated with MARS ® and LE. Calibrations were linear from 2.5 to 200 ng/mL in plasma using 1/X 2 weighted least square regression. When plasma was spiked with LE, intra-day precisions were less than 4, 3, 4, and 8% (expressed as relative standard deviation) for A, Nic, Nif and Neb, respectively, irrespective of the LE final concentration. Intra-day accuracies were not statistically different in PLE compared to blank plasma. QCs prepared artificially with human albumin were confronted to the calibrations established in plasma. Precisions were less than 7% for all analytes, and accuracies did not exceed ±15% as requested by the European Medicine Agency (EMA). Intensities of absolute areas (AA) measured by TF-LC-MS/MS for each analyte and IS were similar in PLE, D and blank plasma. Concentrations of amlodipine were determined in plasma and dialysates sampled from 2 patients treated with MARS ® and ILE. Peak amlodipine concentrations were measured at 664 and 708 ng/mL (therapeutic range: 1–25), respectively. For patient 1, 30% of circulating amlodipine was trapped in LE, and for both patients, 2% of the toxicant was extracted by the MARS ® membrane. Time course levels of amlodipine were followed in plasma until patient's 1 death and patient's 2 full recovery. Massive overdoses with CCB and BB are often responsible for fatal refractory cardiovascular failure. In adjunction with symptomatic pharmacological agents, efficacy of extracorporeal life support like MARS ® and trapping strategy with IL is currently being assessed. Thus, concentrations of toxicants should be monitored in plasma but also in hyperlipemic plasma due to IV LE and in dialysates resulting from the extracorporeal circuitry of MARS ® . Hence, the analytical method must be validated for all the involved matrices. Irrespective of LE rates in plasma and albumin concentrations in physiologic serum, all QCs fulfilled acceptability criteria for precision and accuracy according to EMA. Furthermore, similar intensities of AA were found in blank plasma, PLE and D. Thus, combination of protein precipitation, TF-LC-MS/MS and use of deuterated IS contributes to a polyvalent and robust analytical method. In conclusion, our method initially validated to monitor A, Nic, Nif and/or Neb in plasma was also applicable to patients severely poisoned and treated with non-conventional therapies such as LE and MARS ® .

Effect Of epigallocatechin-3-gallate on the pharmacokinetics of amlodipine in rats

This study investigates the effect of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, on the pharmacokinetics of amlodipine in rats.The pharmacokinetics of orally administered amlodipine (1 mg/kg) with or without EGCG pretreatment (30 mg/kg/day for 10 days) were investigated. Plasma concentrations of amlodipine were determined by using a sensitive and reliable liquid chromatography with tandem mass spectroscopy (LC-MS/MS) method. The effects of EGCG on the metabolic stability of amlodipine were investigated by using rat liver microsome incubation systems.The results indicated that when the rats were pretreated with EGCG, the Cmax of amlodipine increased from 16.32 ± 2.57 to 21.44 ± 3.56 ng/mL (p < 0.05), the Tmax decreased from 5.98 ± 1.25 to 4.01 ± 1.02 h (p < 0.05), and the AUC0–t increased from 258.12 ± 76.25 to 383.34 ± 86.95 μg h L−1 (p < 0.05), which suggested that the pharmacokinetic behavior of amlodipine was affected after oral co-administration of EGCG. Additionally, the metabolic half-life was prolonged from 31.3 ± 5.6 to 52.6 ± 7.9 min (p < 0.05) with the pretreatment of EGCG.It can be speculated that the drug-drug interaction between EGCG and amlodipine might occur, which might have resulted from the metabolism inhibition of amlodipine by EGCG when they were co-administered.

INFLUENCE OF AMLODIPINE ON RESISTANCE TO ENROFLOXACINE IN SALMONELLA ENTERICA

In recent years, there has been an increase in the number of strains of salmonellae resistant to antibiotics of fl uoroquinolone series. The occurrence of Salmonella resistant to enrofl oxacin was assessed at poultry farms of the Russian Federation in 2007 and 2017. In 2007 sensitivity of 23 salmonella cultures to enrofl oxacin was studied and in 2017 the same study was done with 15 salmonella cultures isolated from agricultural birds. Antibiotic resistance was determined by the disc-diffusion method in compliance with the generally accepted requirements. From 2007 to 2017 the frequency of salmonella isolation resistant to enrofl oxacin increased from 0 to 23.08%. Evaluation of the effl ux (active removal of antimicrobial substances by a bacterial cell) was carried out using a classical test with ethidium bromide. It was established that the presence of effl ux in Salmonella cultures was associated with an insignifi cant increase in resistance to enrofl oxacin, trimethoprim with sulfamethoxazole and trimethoprim with sulfadimezine. The effect of amlodipine on the sensitivity of salmonella to enrofl oxacin was evaluated by cultivation of Salmonella in the presence of various concentrations of amlodipine. It was revealed that the specifi c proportion of strains of salmonella with higher sensitivity to enrofl oxacin increased with the simultaneous rise in concentrations of amlodipine (Pearson correlation, r = 0.9). Administration of amlodipine in concentration of 250 μg/ml to Salmonella enterica cultures, in the presence of subinhibitory concentrations of enrofl oxacin, increased their sensitivity to enrofl oxacin in 87.5% of cases.

Moderate hypothermia and responses to calcium channel blockers - Role of the nitric oxide.

Moderate hypothermia (25-31°C) may have a significant influence on vascular tone. At present, very little is known about the role of endothelial nitric oxide on the hypothermia-induced responses. In this study, we investigated the effect of hypothermia (to 28°C) on the vasodilatation induced by verapamil, a phenylalkylamine calcium channel blocker (10-9-3 × 10-4M) and dihydropyridines, amlodipine (10-9-3 × 10-4M), and benidipine (10-9-10-3M) on 5-hydroxytryptamine (5-HT or serotonin) precontracted calf cardiac veins. Furthermore, the role of nitric oxide in the hypothermia-induced responses was analyzed. Ring preparations of veins obtained from calf hearts were suspended in organ baths containing 15ml of Krebs-Henseleit solution, maintained at 37°C, and continuously gassed with 95% O2-5% CO2. After a resting period, verapamil, amlodipine, and benidipine were applied cumulatively on serotonin (10-6M) precontracted calf cardiac vein rings and induced concentration-dependent relaxations. In another part of the study, the medium temperature was decreased to 28°C after the preparations were contracted with 5-HT, then cumulative concentrations of verapamil, amlodipine, or benidipine were added. During hypothermia, the pIC50 value, but not the maximal response, to all blockers were significantly higher than at 37°C. Hypothermia in the presence of NG-nitro-l-arginine methyl ester (L-NAME, 10-4M) decreased the pIC50 and Emax values to verapamil, amlodipine, and benidipine. Only one blocker was tested in each preparation. These results suggest that nitric oxide may play a role in the hypothermia-induced changes in vasodilation caused by verapamil, amlodipine, and benidipine in calf cardiac vein, but further research is needed to explain the complete mechanism.

Single-Pill Triple Fixed Dose Combination Therapy with Single Component Drug Monitoring in Treatment-Resistant Hypertension: A Pilot Study.

Single-pill fixed dose combination (FDC) therapies are widely used in the treatment of arterial hypertension. This pilot study aimed to evaluate the effects of a FDC therapy combined with therapeutic drug monitoring (TDM) on blood pressure (BP) in patients with treatment resistant hypertension. The study population included patients with suspected treatment-resistant hypertension during treatment with at least 3 antihypertensive drugs. We evaluated the effect of switching all patients to a regime including a single-pill triple FDC containing olmesartan, amlodipine and hydrochlorothiazide. Adherence was evaluated by measuring serum concentrations of amlodipine in a single-blinded fashion. We enrolled 13 patients (mean age 57.2±9.1 years, 8 males) with resistant hypertension (office systolic and diastolic BP 158.3±17.3 and 94.8±11.1 mmHg); mean use of antihypertensive drugs was 3.8±1.1. Medication intake of FDC was confirmed in all patients at 18 weeks. Systolic and diastolic office BP were significantly lower (-22.8 and -13.6 mmHg) after 18 weeks of treatment with triple FDC (135.5±20.1 and 81.2±6.3 mmHg, p<0.01, respectively); mean use of antihypertensive drugs was 3.8±0.9. In 9 patients with 24-h ambulatory BP monitoring (ABPM) both at baseline and after 18 weeks, 24-h mean arterial pressure decreased (-9.3 mmHg, p=0.055). Overall, 9 (69%) patients achieved BP control in office BP and 4 (31%) in 24-h ABPM. Our results support the use of single-pill triple FDC therapy in combination with TDM for the management of patients with suspected treatment-resistant hypertension and further testing in clinical studies.