Pharmazie

A special single dose collector and a multi stage liquid impinger were used to assess the consistency of delivered dose and fine particle fraction respectively, of the Novopulmon 200 Novolizer (Viatris, Frankfurt, Germany) and Budesonid-ratiopharm Jethaler (Ratiopharm, Ulm, Germany). The obtained average delivered dose from the Jethaler at 4 kPa is 199 microg (99.5% of the label claim) versus 219 microg (109.6%) for the Novolizer (mean of 90 doses from the same device). The corresponding relative standard deviation (RSD) for the Jethaler is on average 14.05% (maximal and minimal dose are 289 and 148 microg respectively), versus an RSD of 5.56% for the Novolizer (max. is 240; min. is 187 microg). It can be shown that the rather extreme spread in the delivered dose from the Jethaler is caused by a variation in metered mass, and to less extent by a poor content uniformity of the drug-lactose compact. The fine particle fractions (FPFs, as percent of label claim, for particles <5.1 mi...

Receptor-binding studies using cloned human muscarinic receptors (M1-M4 subtypes) were performed on newly synthesized soft anticholinergics (F-828, F-838, SGM, SGE, SA-A) that are isosteric/ isoelectronic analogs of glycopyrrolate. The receptor binding pK(i) values of the new soft drugs were in the 5.5-9.5 range; with the majority being in the 7.0-8.5 range. As previously observed for similar structures, the pK(i) values tended to decrease with increasing molecular size, and with the introduction of three structural indicator variables, a QSAR equation accounting for close to 75% of the variability could be established. Confirming the known stereospecificity of these receptors, pure 2R isomers were found more active than the corresponding isomeric mixtures. In agreement with soft drug design principles, acid metabolites (SA-A) were found considerably less active than their parent esters. The more active, 2R isomer of SA-A showed some muscarinic subtype selectivity (M3/M2), which was...

Entire seeds of Chenopodium quinoa Willd are a rich protein source and are also well-known for their high saponin content. Due to their amphiphily quinoa saponins are able to form intricate micellar aggregates in aqueous media. In this paper we study the aggregates formed by self-association of these compounds from two quinoa saponin fractions (FQ70 and FQ90) as well as several distinctive nanostructures obtained after their complexation with different ratios of cholesterol (CHOL) and phosphatidylcholine (PC). The FQ70 and FQ90 fractions were obtained by reversed-phase preparative chromatography. The structural features of their resulting aggregates were determined by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM). Novel nanosized spherical vesicles formed by self-association with mean diameter about 100-200 nm were observed in FQ70 aqueous solutions whereas worm-like micelles an approximate width of 20 nm were detected in FQ90 aqueous solutions. Under exp...

Silymarin isolated from Silybum marianum is a mixture of three isomers, silybin (1), silydianin (2) and silychristin (3). Silybin is the most active antihepatotoxic agent, and contains a 1,4-dioxane ring in addition to a flavonoid moiety. Based on the skeleton of silybin, we prepared some flavones and coumarins containing the 1,4-dioxane ring system and evaluated them for antihepatotoxic activity against carbon tetrachloride induced hepatotoxicity in albino rats. The degree of protection was determined by measuring biochemical parameters such as serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), alkaline phosphatase (ALKP), total protein (TP) and total albumin (TA). The compounds namely 3',4'(1",4"-dioxino) flavone (4f), and 3',4'(2-hydroxy methyl, 1",4"-dioxino) flavone (4g) were found to exhibit a significant activity comparable to standard drug silymarin (silybon-70). Other compounds also exhibited good...

Esters of Cytarabine-N4-carboxylates 2a-i and succinamates 3a-f were synthesized as prodrugs of cytarabine (Ara-C) with the aim of developing improved derivatives for oral or parentral administration. At pH 2 series 2 showed relative higher stability than 3, while both series of esters revealed matched stability at pH 7. All esters were susceptible to enzymatic hydrolysis by rat plasma and liver homogenate with half lives ranged from 0.14 h to 12 d, and showed improved stability against cytidine deaminase. A parabolic relation was shown between Kobs of enzymatic hydrolysis and Vw. All compounds are more lipophilic than the parent drug, Ara-C.

The objective of this research was to develop a kinetic spectrophotometric method for determination of ramipril in pure form and pharmaceutical formulations. The method was based on the reaction of carboxylic acid group of the drug with a mixture of potassium iodate (KIO3) and potassium iodide (KI) in aqueous medium at room temperature. The reaction is followed spectrophotometrically by measuring the increase in absorbance at 352 nm as a function of time. The initial-rate and fixed-time methods were adopted for constructing the calibration curves. Both the calibration curves were linear in the concentration range of 10.0–70.0 μg mL−1. The detection limits were 0.02μg mL−1 and 0.15-μg mL−1 for initial rate and fixed time methods, respectively. The proposed methods are validated statistically and through recovery studies. The point and interval hypothesis tests have been performed confirming that there is no significant difference between the proposed methods and the reference method. The experimental true bias of all samples is less than ±2%. The methods have been successfully applied to the determination of ramipril in tablets and capsules.

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug (NSAID) widely used in humans and animals. There are limited published studies evaluating diclofenac's skin permeation following topical administration. The aim of our study was to evaluate and compare the in vitro permeation of three different diclofenac-containing formulations (patch, gel, solution) over 24 hours. These formulations were applied (n = 6 per formulation) to pig skin sandwiched between the two chambers in a static Franz diffusion cell and aliquots from the receptor medium were sampled at pre-defined time points. An HPLC method with UV detection was developed and validated with the aim of characterizing the transepidermal penetration in the in vitro system. Using this assay to determine the permeation parameters, results at 24 hours showed that the Flector patch released the highest drug amount (54.6%), whereas a lower drug amount was delivered with the Voltaren Emulgel (38.2%) and the solution (34.4...

Cardiovascular diseases are frequent complications of end-stage kidney disease. The aim of the present study was to prove the arrhythmogenic effect of dialysis using signal averaged ECG. The ECG changes and laboratory parameters (sodium, potassium, urea and creatinine levels) were detected during hemodialysis treatment in 26 patients suffering from end-stage kidney disease. The tests and the ECG were performed four times, before (0. minute), during (at 15 and 90 min), and eventually after dialysis (at 240 min). The duration of the QRS complex, high-frequency low-amplitude signals (HFLA), and root-mean-square voltage of the terminal 40 ms of the filtered QRS (RMS) were determined. We considered test results to be positive when two of the three tested parameters were outside the normal range: QRS > 120 ms, RMS < 20 uV, HFLA > 39 ms. Signal averaged ECG was positive in two cases (8%) before and after the dialysis. The duration of the QRS-complex increased significantly during the dialysis (predialysis: 109 +/- 7.6 ms, postdialysis: 116 +/- 8.0 ms, p < 0.0001). Serum urea nitrogen (predialysis: 26.2 +/- 5.4, postdialysis: 11.4 +/- 3.3 mmol/l, p <0.0001) and serum creatinine levels (predialysis: 931 +/- 212, postdialysis: 434 +/- 120 micromol/I, p < 0.0001) decreased significantly during the treatment. Significant and continuous decrease in the potassium levels were detected (predialysis: 5.30 +/- 0.72, postdialysis: 3.91 +/- 0.42 mmol/I, p < 0.0001) during the dialysis. Serum sodium levels (predialysis: 139 +/- 2.7, postdialysis: 141.4 +/- 2.2 mmol/I) had not changed during the dialysis. A significant negative correlation was found between decreasing potassium levels and increasing QRS duration (r = - 0.48, p = 0.01). Our results support our primer assumption that the metabolic changes during dialysis treatment can lead to considerable risk of cardiac arrhythmias.

Inhalation is an attractive delivery route for systemic and local therapy. High local drug concentrations may permit non-invasive delivery, lower therapeutic doses, reduced systemic side-effects, and reduced metabolic degradation of the drug in the liver. In our earlier study, carrier-based microcomposites were prepared and investigated. The present study introduces studies of the cytotoxicity of meloxicam-containing microcomposites on monolayers of Calu-3 cells, in order to acquire information on its availability in pulmonary formulations. By relating cytotoxicity and drug dissolution, the appropriate amount of meloxicam for dry powder inhalation could be determined.

A simple method based on capillary electrophoresis with a capacitively coupled contactless conductivity detector (CE-C(4)D) was developed for the determination of potassium, sodium, calcium and magnesium in parenteral nutrition formulations. A hydro-organic mixture, consisting of 100 mM Tris-acetate buffer at pH 4.5 and acetonitrile (80:20, v/v), was selected as the background electrolyte. The applied voltage was 30 kV, and sample injection was performed in hydrodynamic mode. All analyses were carried out in a fused silica capillary with an internal diameter of 50 microm and a total length of 64.5 cm. Under these conditions, complete separation between all cations was achieved in less than 4 min. The CE-C(4)D method was validated, and trueness values between 98.6% and 101.8% were obtained with repeatability and intermediate precision values of 0.4-1.3% and 0.8-1.8%, respectively. Therefore, this method was found to be appropriate for controlling potassium, sodium, calcium and magnesium in parenteral nutrition formulations and successfully applied in daily quality control at the Geneva University Hospitals.

Statins have been widely used for the treatment of hypercholesterolemia, and recent studies have shown that these drugs also affect bone metabolism. The aim of this experiment was to follow the effect of atorvastatin on bone metabolism in male albino Wistar rats. Our study was carried out on 16 rats (240 +/- 10g) which were randomly divided into 2 groups of 8 animals. The control group (CO) was given aqua pro injectione (0.2 mL/100 g BW; gavage) and the experimental group atorvastatin suspension (AT; 0.3 mg in 0.2 mL aqua pro inj./100 g BW; gavage) daily for 8 weeks. We examined serum markers of bone turnover using ELISA - C-terminal crosslinking telopeptide of type I collagen (CTX-I), total osteocalcin (total OC), procollagen type I N propeptide (PINP) and bone alkaline phosphatase (bone ALP). We investigated bone morphogenetic protein-2 (BMP-2) in the proximal tibia using Western blot analysis. Additionally, we measured bone mineral density (BMD). The femurs were used for a three-...

The solubility of nalidixic acid in water-ethanol mixtures has been determined at 25 degrees C. The generated solubility data sets have been used to assess the accuracy of different numerical analyses for the excess free energy model and a new numerical method for solubility prediction in water-ethanol mixtures based on four experimental determinations is proposed. The accuracy of a previously presented numerical method to fit all data points is compared with that of a proposed analysis using average percentage deviation (APD). The APD obtained are 14.6 (+/- 8.0) and 8.4 (+/- 4.1), respectively for previous and proposed methods. A minimum number of three and four data points employed to train the original forms of the excess free energy model and the solubility at other solvent compositions were predicted. The APDs obtained were 61.4 and 23.0%, respectively. The APD produced for the proposed numerical method was 16.1%.

Four new phenolic anionic conjugates have been isolated from the whole plant aqueous alcohol extract of Frankenia laevis L. Their structures were established, mainly on the basis of ESI-MS, 1D and 2D NMR spectroscopic evidence, as gallic acid-3-methyl ether-5-sodium sulphate, acetophenone-4-methyl ether-2-sodium sulphate, ellagic acid-3,3'-dimethyl ether-4,4'-di-sodium sulphate and ellagic acid-3-methyl ether-4-sodium sulphate.

In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished ...

Clinical studies have suggested that metformin, a widely used antidiabetic agent, exerts a direct cardioprotective effect on cardiovascular disease in addition to its blood glucose-lowering activity. This study was designed to identify the role of metformin in rats with isoproterenol (ISO)-induced myocardial injury and to investigate its underlying mechanism. A rat model of myocardial ischemic injury was established by the subcutaneous injection of a high dose of ISO, a beta-adrenergic agonist. The results showed that pretreatment of metformin significantly reduced rat mortality induced by ISO, attenuated the increased plasma lactate dehydrogenase activity and myocardium malondialdehyde level, alleviated the hemodynamic disturbance, inhibited the upregulated gene expression of myocardial probrain natriuretic peptide and alleviated the myocardial morphological injury and apoptosis induced by ISO. Furthermore, western blot analysis showed that metformin suppressed the overexpression o...

Drug efflux by intestinal P-glycoprotein (P-gp) is recognized as a significant biochemical barrier affecting oral absorption for a number of drugs apart from the cytochrome P450 3A enzyme. Various conflicting reports have been published regarding the effects of grapefruit juice (GFJ) on P-gp mediated drug efflux, in which GFJ has been shown to have no effect, as an inhibitor effect or activation of the enzyme. Therefore the present study's objective was to provide clarification of previous findings, adopting a two-way approach, involving both single dose and multiple dosage regimens. Diltiazem (DTZ) 15 mg/kg was administered concomitantly with 5 ml/kg of GFJ to one group (n = 6) of male Wistar rats and another group (n = 6) of animals were provided distilled water with DTZ (the control). A third group of rats was administered GFJ orally for six days and on seventh day GFJ and DTZ were administered concomitantly. The Cmax and AUC of DTZ were decreased significantly in the presenc...

We present a simple, accurate, stability-indicating nuclear magnetic resonance (NMR) method for determining active (S,S) and inactive (R,S) epimers of S-adenosyl-L-methionine (SAM) in tablets. The SCH3 resonances of SAM epimers were well resolved at 300 MHz. Individual assays of 5 SAM tablets gave SAM values of 101.3 +/- 1.7% of declared amounts. Tablet solutions were assayed at a level of 8.0 mg/mL, but the method was linear for SAM concentrations ranging from 64 to 1 mg/mL (correlation coefficient, 0.9996). Reproducibility was indicated by a relative standard deviation of 0.33% for 6 replicate assays for total SAM at a concentration of 8 mg/mL. In contrast to the propietary liquid chromatographic (LC) method, which requires SAM as an external standard, the NMR method uses sodium trimethylsilylpropionate-d4 (TSP) both as an internal standard and as a chemical shift reference. The method was used to test the stability of SAM analytes under various pH levels and temperatures. We found 8% inactivation of SAM due to epimerization over a 24 h period at room temperature and pH 5. SAM solutions showed no detectable inactivation after 14 days when stored below 0 degrees C.

We undertook the present study to evaluate the activity of the dried extract of Maytenus ilicifolia against stomach ulcers and in the increase of the volume and pH of the gastric juice of Wistar rats, as a model to evaluate the viability of the Jet Spouted Bed Dryer for the production of dry-extracts of medicinal Brazilian plants. The extract was obtained from the drying of a hydro-alcoholic extract with drying aid (40% of colloidal SiO2 related to solid content in the concentrated extract, at a concentration of 15.82% in water). The drying conditions employed were: Temperature of the spouting gas 150 degrees C, feed flow-rate of hydro-alcoholic extract 16.0 g/min, feed flow rate of the spouting gas 1.67 m3/min and static bed height 7.0 cm. Wistar rats received three different doses (140, 280 and 420 mg/kg) of the dried extract by intraperitoneal way and, after 60 minutes, were immobilized with wire screen and placed at temperature of 4 degrees C for two hours (cold-restraint stress...

The pH-dependent aggregation of the novel photosensitizer TPCS(2a) is investigated at low concentration (c = 10(-6) M) in aqueous media by means of time-correlated single-photon counting, and compared to that of the chemically related photosensitizer TPPS(2a). The efficacy of selected solubilizers, i.e., various nonionic Pluronic block copolymers and the nonionic surfactant Tween 80, in inhibiting aggregation of the two photosensitizers is evaluated, which is important for the further formulation of TPCS(2a).

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug (NSAID) widely used in humans and animals. There are limited published studies evaluating diclofenac's skin permeation following topical administration. The aim of our study was to evaluate and compare the in vitro permeation of three different diclofenac-containing formulations (patch, gel, solution) over 24 hours. These formulations were applied (n = 6 per formulation) to pig skin sandwiched between the two chambers in a static Franz diffusion cell and aliquots from the receptor medium were sampled at pre-defined time points. An HPLC method with UV detection was developed and validated with the aim of characterizing the transepidermal penetration in the in vitro system. Using this assay to determine the permeation parameters, results at 24 hours showed that the Flector patch released the highest drug amount (54.6%), whereas a lower drug amount was delivered with the Voltaren Emulgel (38.2%) and the solution (34.4...

Hairy roots of Salvia austriaca Jacq. transformed with Agrobacterium rhizogenes strain A4 were obtained and transgenic status of the roots was confirmed by polymerase chain reaction (PCR) using rolB and rolC specific primers. The root cultures growing in half-strength Gamborg (1/2 B5) liquid medium supplemented with sucrose (30 g L(-1)) under light conditions (photoperiod: 16 h light/8 h dark) were examined for their ability to produce diterpenoids. From n-hexane extract the abietane-type diterpenoids royleanone, 15-deoxyfuerstione and taxodione were isolated and identified. This is the first report on the genetic transformation of S. austriaca.