Arzneimittel-Forschung[JOURNAL]
Sun
200 papers
Simultaneous extraction of acetylsalicylic acid and salicylic acid from human plasma and simultaneous estimation by liquid chromatography and atmospheric pressure chemical ionization/tandem mass spectrometry detection. Application to a pharmacokinetic study.
Nirogi R, Kandikere V, Mudigonda K … +3 more , Ajjala D, Suraneni R, Thoddi P
Arzneimittelforschung · 2011 · PMID 21755814 · Publisher ↗
A simple analytical method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in atmospheric chemical ionization mode (APCI) for the simultaneous estimation of acetylsalicylic acid (ASA, CAS 50-78-2) and its...
A simple analytical method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in atmospheric chemical ionization mode (APCI) for the simultaneous estimation of acetylsalicylic acid (ASA, CAS 50-78-2) and its active metabolite salicylic acid (SA, CAS 69-72-7) in human plasma has been developed and validated. ASA and SA were analyzed simultaneously despite differences in plasma concentration ranges of ASA and SA after oral administration of ASA. In spite of having different chemical, ionization and chromatographic properties, ASA and SA were extracted simultaneously from the plasma sample using acetonitrile protein precipitation followed by liquid-liquid extraction. The analytes were separated on a reversed phase column with rapid gradient program using mobile phase consisting of ammonium acetate buffer and methanol. The structural analogue diclofenac was used as an internal standard. The multiple reaction monitoring (MRM) transitions m/z 179 --> 137 for ASA, m/z 137 --> 65 for SA and m/z 294 --> 250 for IS were used. The assay exhibited a linear dynamic range of 0.02-10 microg/mL for ASA and 0.1-50 microg/mL for SA. The between-batch precision (%CV) ranged from 2.1 to 7.9% for ASA and from 0.2 to 5.2% for SA. The between-batch accuracy ranged from 95.4 to 96.7% for ASA and from 94.6 to 111.3% for SA. The validated method was successfully applied for the evaluation of pharmacokinetics of ASA after single oral administration of 650 mg test formulation versus two 325 mg reference formulations of ASA in human subjects.
Synthesis and analgesic effects of new pyrrole derivatives of phencyclidine in mice.
Ahmadi A, Solati J, Hajikhani R … +1 more , Pakzad S
Arzneimittelforschung · 2011 · PMID 21755813 · Publisher ↗
Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP, I) and many of its analogues have shown some pharmacological effects. In this study, new pyrrole derivatives of I (1-(1-phenylcyclohexyl)pyrrole, II and...
Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP, I) and many of its analogues have shown some pharmacological effects. In this study, new pyrrole derivatives of I (1-(1-phenylcyclohexyl)pyrrole, II and 1-[1-(4-methylphenyl)(cyclohexyl)]pyrrole, III) and their intermediates were synthesized and the acute and chronic pains were examined on mice using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests and the results were compared with the PCP and control groups. The results indicated that III generated higher analgesic effects in the tail immersion test compared to the PCP and control (dimethyl sulfoxide, DMSO) groups, demonstrating a marked and significant increase in tail immersion latency, but this effect was not observed for II in the dose of 1 mg/kg. The formalin test showed that III was effective in acute chemical pain (phase I, 0-5 min after injection), but was not effective for II at the same dosage compared to the PCP and control groups. Also chronic pain will be significantly attenuated by III but II was not effective as compared to the other groups. It is concluded that substitution of the aromatic pyrrole ring instead of piperidine in the PCP molecule will not be effective alone in tail immersion and formalin tests but the addition of a methyl group (with high electron donating and dipole moments) on the phenyl group plus substitution of the aromatic pyrrole ring can be effective in acute and chronic pain compared to the PCP and control groups.
Determination of cetirizine in human plasma using high performance liquid chromatography coupled with tandem mass spectrometric detection: application to a bioequivalence study.
Ren XL, Tian Y, Zhang ZJ … +3 more , Chen Y, Wu LL, Huang J
Arzneimittelforschung · 2011 · PMID 21755812 · Publisher ↗
A rapid, sensitive and selective HPLC-MS/ MS method was developed and validated for the quantification of cetirizine dihydrochloride (CAS 83881-51-0) in human plasma using mosapride citrate as internal standard (IS, CAS...
A rapid, sensitive and selective HPLC-MS/ MS method was developed and validated for the quantification of cetirizine dihydrochloride (CAS 83881-51-0) in human plasma using mosapride citrate as internal standard (IS, CAS 112885-42-4). Following liquid-liquid extraction, the analytes were separated using a mobile phase consisting of methanol and aqueous ammonium acetate solution (10 mM) (60:40, v/v) on a reverse phase C18 column and analyzed by a triple-quadrupole mass spectrometer in the selected reaction monitoring (SRM) mode using the respective [M+H]+ ions, m/z 398 --> 201 for cetirizine and m/z 422 --> 198 for mosapride. The analysis time for each run was 8.0 min. The assay exhibited a linear dynamic range of 0.5-500 ng/ml for cetirizine dihydrochloride in human plasma. The lower limit of quantification (LLOQ) was 0.5 ng/ml with a relative standard deviation of less than 15% (all the concentration data in this study related to the salt (cetirizine dihydrochloride)). Acceptable precision and accuracy were obtained for concentrations over the standard curve range. It is the first time that the validated HPLC-MS/MS method has been successfully applied to a bioequivalence study in 20 healthy male Chinese volunteers.
Pharmacodynamic equivalence study of two preparations of eye drops containing dorzolamide and timolol in healthy volunteers.
Gatchev E, Petrov A, Kolev E … +6 more , Hristova R, Demircheva I, Koytchev R, Richter W, Tegel F, Thyroff-Friesinger U
Arzneimittelforschung · 2011 · PMID 21755811 · Publisher ↗
OBJECTIVE: The aim of the present study was to assess the pharmacodynamic equivalence (lowering of intraocular pressure) of two preparations of eye drops containing 20 mg dorzolamide (CAS 120279-96-1) and 5 mg timolol (C...
OBJECTIVE: The aim of the present study was to assess the pharmacodynamic equivalence (lowering of intraocular pressure) of two preparations of eye drops containing 20 mg dorzolamide (CAS 120279-96-1) and 5 mg timolol (CAS 26839-75-8). METHOD: The study was conducted as a monocentric, observer-blinded, randomized, single-dose, two-period crossover study in 38 healthy volunteers. Each volunteer received on day 1 in each period in a random way a single dose of 1 drop of the test or the reference formulation in the conjunctival sac of the right eye separated by a wash-out period of 7 days. Measurement of intraocular pressure (IOP) of the right eye (by a blinded observer) was performed on day 1 of each study period pre-dose and 2 h post dosing by means of Goldmann applanation tonometry. In order to investigate the pharmacodynamic equivalence of both products, the two-sided 95% confidence interval was calculated for the difference of the primary target parameter (absolute decrease in IOP 2 h post dose), by means of a parametric (ANOVA) statistical method. RESULTS: The results of the statistical evaluation of the primary target parameter "absolute decrease in IOP 2 h post dose" demonstrated a decrease in the IOP of 4.72 mmHg for the eye treated with the test formulation (dorzolamide 20 mg/ml + timolol 5 mg/ml eye drops) and 4.61 mmHg for the treated with the reference formulation. The mean difference was 0.11 mmHg. The 95% confidence interval was between -0.33 and 0.55 mmHg and thus entirely within the pre-defined equivalence range (+/- 1.5 mmHg). The results of the statistical evaluation of the secondary target parameter relative (as % of baseline) decrease in IOP 2 h post dose demonstrated essentially similar effectiveness in lowering the IOP by 27.63% (test formulation) and 27.12% (reference formulation), respectively. Both drug products were well tolerated. CONCLUSION: Both formulations showed comparable results obtained at a time probably equal to the maximum effect concerning the primary target parameter lowering of IOP 2 h post dose. The safety profile of both preparations showed no difference.
Reverse-phase liquid chromatography with electrospray ionization/mass spectrometry for the quantification of pseudoephedrine in human plasma and application to a bioequivalence study.
Kim JK, Jee JP, Park JS … +2 more , Kim HT, Kim CK
Arzneimittelforschung · 2011 · PMID 21755810 · Publisher ↗
A sensitive and selective reverse-phase liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) method was developed and validated to quantify pseudoephedrine (CAS 90-82-4) in human plasma. Phenacetin...
A sensitive and selective reverse-phase liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) method was developed and validated to quantify pseudoephedrine (CAS 90-82-4) in human plasma. Phenacetin was used as the internal standard (I.S.). Sample preparation was performed with a deproteinization step using acetonitrile. Pseudoephedrine and I.S. were successfully separated using gradient elution with 0.5% trifluoroacetic acid (TFA) in water and 0.5% TFA in methanol at a flow-rate of 0.2 mL/min. Detection was performed on a single quadrupole mass spectrometer by a selected ion monitoring (SIM) mode via electrospray ionization (ESI) source. The ESI source was set at positive ionization mode. The ion signals of m/z 166.3 and 180.2 were measured for the protonated molecular ions of pseudoephedrine and I.S., respectively. The lower limit of quantification (LLOQ) of pseudoephedrine in human plasma was 10 ng/mL and good linearity was observed in the range of concentrations 10-500 ng/mL (R2 = 1). The intra-day accuracy of the drug containing plasma samples was more than 97.60% with a precision of 3.99-11.82%. The inter-day accuracy was 99.36% or more, with a precision of 7.65-18.42%. By using this analytical method, the bioequivalence study of the pseudoephedrine preparation was performed and evaluated by statistical analysis of the log transformed mean ratios of pharmacokinetic parameters. All the results fulfilled the standard criteria of bioequivalence, being within the 80-125% range which is required by the Korea FDA, US FDA, and EMEA to conclude bioequivalence. Consequently, the developed reverse-phase LC-ESI-MS method was successfully applied to bioequivalence studies of pseudoephedrine in healthy male volunteers.
Differences in spontaneously reported hypersensitivity and serious adverse events for intravenous iron preparations: comparison of Europe and North America.
Bailie GR, Hörl WH, Verhoef JJ
Arzneimittelforschung · 2011 · PMID 21755809 · Publisher ↗
Spontaneously-reported rates of adverse events (AEs) of intravenous (i.v.) iron products have not been compared since 2007. AEs in Europe (Eur) and North America (NA) have never been compared. New products have been mark...
Spontaneously-reported rates of adverse events (AEs) of intravenous (i.v.) iron products have not been compared since 2007. AEs in Europe (Eur) and North America (NA) have never been compared. New products have been marketed and many changes in prescribing habits have occurred since then, and the effect on AEs reporting is unclear. It was hypothesized that changing practices for i.v. iron products has caused changes in the rates of serious AEs and large differences exist between Eur and NA. Rates of AEs for three i.v. iron preparations (iron sucrose [IS], ferric gluconate [FG] and high and low MW iron dextran [HMWID, LMWID]) were compared by product and continent from January 1, 2003 to June 30, 2009 for selected countries in Eur and NA, using the Uppsala Monitoring Center's database. Rates of total, anaphylaxis and other serious allergic AEs were calculated as number of AEs divided by i.v. iron sales standardized to 100 mg dose equivalents (DEq) of iron. Quarterly sales (millions of 100 mg DEq of iron) increased from the first quarter 2003 to the end of the second quarter of 2009 by 1% for FG, 16% for IS and 2% for ID. Total AEs for NA plus Eur were similar for FG and IS, but total AEs were 6- to 7-fold higher for ID. Rates of anaphylaxis were 6- to 11-fold higher in Eur plus NA combined for ID than for IS or FG. In NA, there were substantially higher reports for total, anaphylaxis and other serious allergic AEs with FG compared to IS, whereas the reverse was the case in Eur. Odds ratios (OR) showed higher risks of anaphylaxis with FG in NA vs. Eur (OR = 4.40, P < 0.0001) and lower risks with IS (OR = 0.24, P < 0.0001). Odds of anaphylaxis with LMWID in Eur vs. FG and IS were 42.08 and 16.92 (both P < 0.0001), respectively. In NA, odds of anaphylaxis with ID vs. FG and IS were 2.36 and 17.73 (both P < 0.0001), respectively. Differences between NA and Eur may be related to varied treatment practices. ID had the highest rates of all types of AEs, and IS and FG had a continued trend for lowest rates of AEs.
Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomised, double blind, placebo controlled clinical trial.
Petersen EE, Genet M, Caserini M … +1 more , Palmieri R
Arzneimittelforschung · 2011 · PMID 21650086 · Publisher ↗
A randomised, double blind, parallel groups, placebo controlled clinical trial was conducted to assess the efficacy and safety profile of 250 mg ascorbic acid (Vit. C, Vagi C) in women with bacterial vaginosis (BV). Over...
A randomised, double blind, parallel groups, placebo controlled clinical trial was conducted to assess the efficacy and safety profile of 250 mg ascorbic acid (Vit. C, Vagi C) in women with bacterial vaginosis (BV). Overall, 277 out-patients with at least three of the following signs (white discharge that smoothly coats the vaginal walls, pH of vaginal fluid > 4.5, a fishy odour of vaginal discharge before or after addition of 10% KOH and presence of clue cells on microscopic examination) were randomised to apply a tablet deeply into the vagina once daily for 6 days. The primary efficacy endpoint was the cure rate, defined as the recovery of all inclusion criteria. In the intent-to-treat (ITT) population, cure was achieved by 55.3% of patients with Vit. C (n=141) and by 25.7% of patients with placebo (n=136). The between-group difference was 29.6% (p < 0.001). In the per-protocol (PP) population, cure rate was 66.4% with Vit. C (n=116) and 27.1% with placebo (n = 118), respectively. Between-group difference was 39.3% (p < 0.001). In a subset of patients with centralised evaluation of the vaginal swab, cure in ITT was achieved by 86.3% of patients with Vit. C (n=51) and by 7.6% of patients with placebo (n=53), the between-group difference was 78.7% (p < 0.0001). Cure rate in PP was 86.0% with Vit. C (n=50) and 6.1% with placebo (n=49), between-group difference was 79.9% (p < 0.0001). Both Vit. C and placebo were well tolerated and no differences in safety profile were evident between groups. The results support an effective and safe use of silicon-coated Vit. C vaginal tablets in the management of BV.
In vitro and in vivo chemosensitizing activity of LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase and polo-like kinases, against human leukemic B-cell precursors.
Uckun F, Dibirdik I, Sarkissian A … +1 more , Qazi S
Arzneimittelforschung · 2011 · PMID 21650085 · Publisher ↗
The present study documents the chemosensitizing anti-leukemic activity of the leflunomide metabolite (LFM) analog, LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase (BTK) and Polo-like kinases (PLK), agains...
The present study documents the chemosensitizing anti-leukemic activity of the leflunomide metabolite (LFM) analog, LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase (BTK) and Polo-like kinases (PLK), against human leukemic B-cell precursors. The results in 135 xenografted NOD/SCID mice regarding the anti-leukemic activity of GMP-grade LFM-A13, obtained with only 4-days of LFM-A13 therapy at nontoxic dose levels corresponding to 1-20% of its NOAEL (no observable advserse effect level), alone or in combination with the standard chemotherapy drug vincristine, demonstrate the potential of LFM-A13 as a new anti-leukemic drug candidate. All 82 LFM-A13-treated mice, including those receiving a combination of vincristine + LFM-A13 at the highest dose level of LFM-A13, tolerated their treatments well without weight loss, diarrhea, lethargy/ paralysis, other signs of morbidity, or mortality. The present study provides preclinical proof-of-principle for the development of LFM-A13 as a new chemosensitizing and apoptosis-promoting anti-leukemic agent and lends support to the hypothesis that the chemoresistance of relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be overcome by using LFM-A13 in combination with chemotherapy. Also presented are the results of a comprehensive meta-analysis of the overexpression of genes for LFM-A13 targeted kinases and their downstream effector molecules in B-lineage lymphoid malignancies utilizing the Oncomine database.
Relative bioavailability of prasugrel free base in comparison to prasugrel hydrochloride in the presence and in the absence of a proton pump inhibitor.
Seiler D, Doser K, Salem I
Arzneimittelforschung · 2011 · PMID 21650084 · Publisher ↗
Prasugrel (CAS 150322-43-3), an inhibitor of platelet activation and aggregation, is indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome. If a proton pump inhibitor i...
Prasugrel (CAS 150322-43-3), an inhibitor of platelet activation and aggregation, is indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome. If a proton pump inhibitor is co-administered with prasugrel, a pH dependent salt-to-base conversion rate of prasugrel could become clinically meaningful. In an open-label, randomized, four-period, 2 x two-way crossover study, the relative bioavailability of tablets containing prasugrel free base compared to prasugrel hydrochloride (originator product) both in the presence and in the absence of the proton pump inhibitor lansoprazole (CAS 103577-45-3) was investigated. In the absence of lansoprazole, the extent of absorption (AUC) of prasugrel free base was about 8-9% lower, while the rate of absorption (Cmax) after administration of prasugrel free base was 20% lower when compared to prasugrel hydrochloride. When lansoprazole was used to raise the pH level in the upper gastro-intestinal tract, AUC was decreased by 25% after administration of prasugrel hydrochloride and by 41% after prasugrel free base. In addition, the peak plasma levels were decreased by 52% and 72%, respectively (geometric means). The relative bioavailability of the prasugrel free base compared to prasugrel hydrochloride, both in the presence and in the absence of the proton pump inhibitor lansoprazole, differs so much that most probably a generic formulation containing prasugrel free base will not be equivalent in all aspects to the originator product.
Ameliorative effect of astaxanthin on endothelial dysfunction in streptozotocin-induced diabetes in male rats.
Zhao ZW, Cai W, Lin YL … +4 more , Lin QF, Jiang Q, Lin Z, Chen LL
Arzneimittelforschung · 2011 · PMID 21650083 · Publisher ↗
The present study was designed to examine whether astaxanthin (ASX, 3,3-dihydroxybeta, beta-carotene-4,4-dione, CAS 472-61-7), a dietary antioxidant carotenoid that is naturally present in algae, crustaceans, and fish, h...
The present study was designed to examine whether astaxanthin (ASX, 3,3-dihydroxybeta, beta-carotene-4,4-dione, CAS 472-61-7), a dietary antioxidant carotenoid that is naturally present in algae, crustaceans, and fish, has a protective effect on endothelial dysfunction of aortas in diabetic rats and the possible molecular mechanism involved. Male Wistar rats were randomly divided into four groups: control rats, diabetic rats, diabetic rats treated with ASX (10 mg/kg/d), and control rats treated with ASX. Type 1 diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/ kg). STZ-induced diabetes in rats was complicated with excessive oxidative stress and endothelial dysfunction, increased serum oxidized low-density lipoprotein (ox-LDL) and aortic malondialdehyde (MDA) levels, inhibited endothelium-dependent vasorelaxation to acetylcholine (ACh) and unaffected endothelium-dependent vasorelaxation to sodium nitroprusside (SNP). Simultaneously, lectin-like oxLDL receptor-i (LOX-1) expression was enhanced and endothelial nitric oxide (NO) synthase (eNOS) expression was reduced in the aortas of diabetic rats. ASX treatment could significantly decrease serum oxLDL and aortic MDA levels, attenuate blunted endothelium-dependent vasodilator responses to ACh, upregulate eNOS expression, and decrease LOX-1 expression. These results indicated that ASX could ameliorate diabetic endothelial dysfunction by inhibiting the ox-LDLLOX-1-eNOS pathway. Treatment with ASX might be clinically useful for diabetic complications associated with endothelial dysfunction.
Bioequivalence study of two perindopril erbumine tablet formulations in healthy volunteers.
Setiawati E, Deniati SH, Yunaidi DA … +5 more , Handayani LR, Santoso ID, Arland JA, Setiawati A, Lian LY
Arzneimittelforschung · 2011 · PMID 21650082 · Publisher ↗
The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blin...
The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.
Effects of agmatine on the survival rate in rats bled to hemorrhage.
Gill F, Pelit T, Terzioğlu B … +2 more , Ekinci O, Gören MZ
Arzneimittelforschung · 2011 · PMID 21650081 · Publisher ↗
Agmatine (CAS 2482-00-0), an amine formed by decarboxylation of L-arginine, interacts with several targets like alpha2-adrenergic, imidazoline and N-methyl-D-aspartic acid (NMDA) receptors and besides it is involved in t...
Agmatine (CAS 2482-00-0), an amine formed by decarboxylation of L-arginine, interacts with several targets like alpha2-adrenergic, imidazoline and N-methyl-D-aspartic acid (NMDA) receptors and besides it is involved in the nitric oxide mediated effects. It has also been proposed that it possesses vasodilator effects and increases glomerular filtration rate in rats. The aim of this study was to supply evidence for the effects of agmatine in a rat model of hemorrhagic shock and explain the possible mechanisms of action. The iliac arteries and veins of Sprague-Dawley rats were catheterized under urethane anesthesia and around 2 ml/100 g blood was withdrawn within 20 min until the mean arterial blood pressure was stabilized around 25 mmHg. The rats were either pretreated with physiological saline, yohimbine (an alpha2-adrenergic receptor antagonist) or L-arginine (a nitric oxide donor) intravenously before administration of agmatine (300 microg/kg). Agmatine restored blood pressure in rats pretreated with physiological saline where all rats survived. Pretreatment with L-arginine abolished the increase in blood pressure produced by agmatine and the 1 h survival rate decreased to 67% (p < 0.01). Yohimbine pretreatment also suppressed agmatine induced restoration of blood pressure; however, the survival rate was found to be 17% for 3 min. No statistically significant effect was observed in the heart rate responses. These results may suggest that agmatine may increase survival through alpha2-adrenergic receptors and restores blood pressure through nitric oxide and adrenergic mechanisms in rats bled to hemorrhage.
Treatment of arterial hypertension in the very elderly: a meta-analysis of clinical trials.
Schall P, Wehling M
Arzneimittelforschung · 2011 · PMID 21650080 · Publisher ↗
The benefits of lowering blood pressure are obvious for the population up to the age of 65 years, but whether and, if so, which treatment is beneficial in the very elderly population remains still a matter of debate. We...
The benefits of lowering blood pressure are obvious for the population up to the age of 65 years, but whether and, if so, which treatment is beneficial in the very elderly population remains still a matter of debate. We conducted a meta-analysis of randomised controlled clinical trials with duration of at least 12 months and the analysis of cardio- and cerebrovascular endpoints in participants aged 75 years and over. MEDLINE, CENTRAL (Cochrane Central Register of Controlled Trials) and the WHO-ISH Collaboration register were searched until October 20, 2009. Further, references from reviews, trials and previously published meta-analyses were analysed. A total of 10 studies were included providing morbidity and mortality data with a total of 8667 participants in the meta-analysis, with separate analyses for studies on isolated systolic hypertension. There were 148 non-fatal strokes and 287 cardiovascular morbidity and mortality events among treated patients, compared with 176 non-fatal strokes (p = 0.02) and 366 cardiovascular morbidity and mortality events (p = 0.0001) among control patients. Rates of heart failure were significantly reduced (64 vs. 121 events; p = 0.00001), total mortality remained unchanged (odds ratio 0.97). Further, 9 studies with 6933 participants were included in the systematic review of blood pressure reduction trials. The average blood pressure achieved at the end of the studies was 164/83 mmHg in the placebo group and 150/83 mmHg in the treatment group. At the beginning of the study blood pressure was 170.6/ 88.6 mmHg in the placebo group and 175.4/94.6 mmHg in the treatment group. Changes were only significant for systolic blood pressure in the treatment group (p = 0.0008). Treating healthy subjects aged 75 years and older with moderate to severe hypertension reduces non-fatal strokes, cardiovascular morbidity and mortality and the incidence of heart failure but does not change total mortality.
Critical considerations into the new EMA guideline on bioequivalence.
Marzo A, Fontana E
Arzneimittelforschung · 2011 · PMID 21650079 · Publisher ↗
The market of generic drugs has been greatly developing during the last 15 years in various European Union (EU) member states, mainly in the Mediterranean area, including non-EU countries, i.e., in the Middle East. This...
The market of generic drugs has been greatly developing during the last 15 years in various European Union (EU) member states, mainly in the Mediterranean area, including non-EU countries, i.e., in the Middle East. This has required a more detailed support from EMA (European Medicines Agency) as guidelines are concerned. Previous EU guidelines on bioavailability and bioequivalence neglected some relevant issues often met in bioequivalence trials, defined in the literature as "open questions on bioequivalence". In the absence of EU specific directives these problems were managed by EU investigators in compliance with U.S. FDA (Food and Drug Administration) guidelines that had already considered some of these "open problems". The latest EMA guideline operating from August 1, 2010 focuses on various relevant issues, including directions on orodispersible tablets, how to operate in the case of high variability, or how to manage the carryover effect of plasma concentrations, but, e.g., it is still neglecting the issue of the multiple-peak phenomenon. In addition, comprehensive directions are still needed on how to manage clinical studies in which endogenous substances are involved. The present review focuses on situations now appropriately discussed in the latest EU guideline, as well as other situations that still need to be defined and need further attention by the regulatory agency in order to give additional adequate directions to the investigators.
Improved RP-HPLC method to determine biapenem in human plasma/urine and its application to a pharmacokinetic study.
Zhao L, Liu Y, Kou Z … +6 more , Bayasi A, Cai H, Zhang C, Wang Q, Li Y, Fang Y
Arzneimittelforschung · 2011 · PMID 21528646 · Publisher ↗
Existing methods to determine biapenem (CAS 120410-24-4), a carbapenem, either lacked sensitivity/reproducibility or had no internal standard as a control. Here an improved reversed-phase high-performance liquid chromato...
Existing methods to determine biapenem (CAS 120410-24-4), a carbapenem, either lacked sensitivity/reproducibility or had no internal standard as a control. Here an improved reversed-phase high-performance liquid chromatographic (RP-HPLC) method was established in human plasma and urine. After adding p-aminobenzoic acid as the internal standard to plasma or urine, plasma samples were ultra-filtrated and urine samples were diluted directly. Chromatographic separations were carried out on a 4.6 mm x 150 mm column with acetonitrile-0.1 mol/l sodium acetate (2:98, v:v; pH 4.38 or 4.00) as mobile phase and UV detection at 300 nm. The extraction recovery was 91.51% for biapenem at the concentration level of 5 microg /ml in human plasma. The linear quantification range of the method was 0.1 to approximately 50 microg /ml for plasma and urine, with linear correlation coefficients greater than 0.998. The intra-day and inter-day relative standard deviations (R.S.D.) for biapenem at low, middle and high levels in human samples were less than 12.51% for plasma and less than 7.05% for urine. The RP-HPLC method was successfully applied to pharmacokinetic studies, in which healthy subjects received multiple doses of biapenem (300 mg, i.v., b.i.d., for 5 continuous days). The pharmacokinetic results are presented.
Pharmacokinetic properties of a once-daily formulation of tacrolimus in patients with renal transplantation.
Imanishi Y, Matsui K, Ishida K … +4 more , Ito S, Matsuura K, Deguchi T, Itoh Y
Arzneimittelforschung · 2011 · PMID 21528645 · Publisher ↗
The present study was designed to determine the pharmacokinetic profiles of a once-daily formulation of tacrolimus (CAS 104987-11-3; TAC-once) in patients before and after introduction of renal transplantation. Pharmacok...
The present study was designed to determine the pharmacokinetic profiles of a once-daily formulation of tacrolimus (CAS 104987-11-3; TAC-once) in patients before and after introduction of renal transplantation. Pharmacokinetic parameters for tacrolimus were almost comparable among patients receiving TAConce before, 2 weeks after and 3 weeks after renal transplantation. Among various parameters, C(trough) correlated most closely with the area under the concentration-time curve during 24 h (AUCo-24) (R2 = 0.82, P < 0.001), while no consistent correlation was observed between AUCo_24 and concentrations at 2 h or 4 h, or the dose of TAC-once. The clinical outcomes such as the incidence of acute re-jection, renal tissue injury and cytomegalovirus infection were evaluated during the first 3 weeks and 3 months after transplantation, and the data were compared with the historical data obtained from patients who had received the conventional twice-daily formulation of tacrolimus (TAC-twice). There were no significant differences in the incidence of such clinical outcomes between the two groups. These findings suggest that C(trough) is useful for therapeutic monitoring of tacrolimus in patients receiving TAC-once. In addition, pharmacokinetics and clinical outcomes were comparable between TAC-once and TAC-twice formulations.
Synthesis and screening of cyclooxygenase inhibitory activity of some 1,3-dioxoisoindoline derivatives.
Cizmeciolu M, Pabuguoglu V, Ballar P … +2 more , Pabuççuoğlu A, Soyer Z
Arzneimittelforschung · 2011 · PMID 21528644
In this study, 15 compounds bearing N,N-phthaloylacetamide structure designed by the molecular simplification approach based on thalidomide structure were synthesized and evaluated for inhibitory potencies against cycloo...
In this study, 15 compounds bearing N,N-phthaloylacetamide structure designed by the molecular simplification approach based on thalidomide structure were synthesized and evaluated for inhibitory potencies against cyclooxgenase (COX) isoenzymes, namely COX-1 and COX-2. The results suggested that the N,N-phthaloylacetamide structure, as a primary amide, has inhibitory activity against cyclooxygenase isoenzymes with a higher COX-1 selectivity. The conversion of the primary amide to secondary or tertiary derivatives lowered the potency but favored the COX-2 selectivity thus yielding the compounds with stronger COX-2 inhibiting activity.
Design and synthesis of certain mesoionic sydnonyl styrylketones as potential nonsteroidal antiinflammatory agents.
Deshpande SR, Pai KV, Pai RS
Arzneimittelforschung · 2011 · PMID 21528643 · Publisher ↗
In an attempt to develop effective and safer analgesic anti-inflammatory agents, nine compounds belonging to 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(4-methoxyphenyl) sydnones, containing the structural features of m...
In an attempt to develop effective and safer analgesic anti-inflammatory agents, nine compounds belonging to 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(4-methoxyphenyl) sydnones, containing the structural features of mesoionic sydnone and styrylketone, have been designed and synthesized by condensing 4-acetyl-3-(4-methoxyphenyl) sydnone with various substituted aryl aldehydes and characterized by spectral studies. They have been tested for analgesic activity by acetic acid induced writhing in mice and for anti-inflammatory activity by carrageenan induced rat paw edema at 100 mg/kg body weight p.o. The compounds containing furyl and chloro substituents showed highly significant analgesic effect, while those with dimethylamino, chloro and nitro substituents exhibited highly significant anti-inflammatory effect at the end of 3 h. The compounds that showed good analgesic and anti-inflammatory activities were evaluated for ulcerogenicity in rats to assess their gastric side effects at 100 mg/kg body weight p.o. They were found to be less ulcerogenic than the standard drug.
Beneficial effects of colchicine on 17alpha-ethynylestradiol-induced cholestasis in rats.
Zhou ZX, Wang T, Jiang ZZ … +9 more , Shang J, Liu L, Zhang Y, Zhu D, Huang X, Zhang S, Hu Y, Wang JY, Zhang LY
Arzneimittelforschung · 2011 · PMID 21528642 · Publisher ↗
Colchicine (CAS 64-86-8) is considered to have a hepatoprotective effect and play a role in biliary excretion. 17alpha-Ethynylestradiol (EE) (5 mg/kg, subcutaneously, daily, for 5 days) causes intrahepatic cholestasis by...
Colchicine (CAS 64-86-8) is considered to have a hepatoprotective effect and play a role in biliary excretion. 17alpha-Ethynylestradiol (EE) (5 mg/kg, subcutaneously, daily, for 5 days) causes intrahepatic cholestasis by reducing both the influx and efflux of bile acid in hepatocytes, resulting in a decrease in bile flow. The objective of this study was to evaluate whether colchicine has any effect on EE-induced cholestasis. The effects of colchicine treatment on EE-induced cholestasis in rats for 5 consecutive days were evaluated. The serum components and enzymatic activity were assayed. In addition, the bile flow and biliary excretion were determined. Furthermore, western blot analysis was used to measure the expression of farnesoid X receptor (FXR), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and cholesterol 7alpha-hydroxylase (CYP7A1). Colchicine not only significantly inhibited the elevation of cholestasis-related serum components and enzyme activity but also significantly attenuated the decrease of the bile flow and biliary excretion. Colchicine also remarkably increased the hepatic expression of FXR, BSEP and MRP2, but decreased that of CYP7A1. Our data indicates that colchicine treatment attenuated EE-induced cholestasis in rats, most likely by promoting bile flow and biliary excretion, and reduced the synthesis of bile acids.
Pharmacokinetics and bioequivalence study of two mosapride citrate formulations after single-dose administration in healthy Chinese male volunteers.
Huang J, Tian Y, Zhang ZJ … +2 more , Li J, Cao X
Arzneimittelforschung · 2011 · PMID 21528641 · Publisher ↗
The pharmacokinetics and relative bioavailability/bioequivalence of two formulations of mosapride citrate (CAS 112885-42-4) were assessed in this study. The study was conducted in 20 healthy Chinese male volunteers accor...
The pharmacokinetics and relative bioavailability/bioequivalence of two formulations of mosapride citrate (CAS 112885-42-4) were assessed in this study. The study was conducted in 20 healthy Chinese male volunteers according to an open, randomized, single-blind, 2-way crossover study design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 12 h post-dose, and mosapride citrate plasma concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Based on the plasma concentration-time data of each individual during two periods, pharmacokinetic parameters, Cmax, AUCo-t,, AUCo-infinity, and t1/2, were calculated by applying non-compartmental analysis. Pharmacokinetic data for test and reference formulations were analyzed statistically to test for bioequivalence of the two formulations. After oral administration, the values of Cmax, Tmax, t1/2, AUCo-t, AUCo-infinity for test and reference formulations were 68.48 +/- 22.95 and 70.69 +/- 23.78 ng/mL, 0.46 +/- 0.20 and 0.49 +/- 0.21 h, 2.30 +/- 0.30 and 2.24 +/- 0.28 h, 161.17 +/- 52.75 and 171.37 +/- 59.02 ng x h/mL, 165.76 +/- 54.34 and 175.77 +/- 60.54 ng x h/mL, respectively. Both primary target parameters, AUCo-infinity and AUCo-t, were tested parametrically by analysis of variance (ANOVA). Relative bioavailabilities were 95.3 +/- 11.3% for AUCo-infinity and 95.2 +/- 11.3% for AUo-t. Bioequivalence between test and reference formulations was demonstrated for both parameters, AUJCo-infinity and AUCo-t. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80-125%. That means that the test formulation is bioequivalent to the reference formulation of mosapride citrate.
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