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E. Valverde Molina, V. González Muñiz, J. Gómez-Maldonado, and I. Muñoz Castillo Servicio de Farmacia, Hospital Carlos Haya, Málaga, Spain Abstract
el inhibidor de la bomba de protones más estable a pH ácido, seevaluó la posibilidad de adicionarlo a las UNP con objeto de facilitar Introduction: Pantoprazole is a weak base (pka ~ 4) with its stability
in aqueous solution dependent on pH. Keeping in mind that the pH Métodos: Se determinó por cromatografía líquida de alta resolu-
of the parenteral nutrition units (PNU) can range between 6.0 and ción (HPLC, del inglés high performance liquid chromatography) la 6.5 and since pantoprazole seems to be the most stable proton pump riqueza de pantoprazol en una UNP a diferentes intervalos de tiem- inhibitor (PPI) for pH acid, we want to assess the possibility of adding it to PNU with the aim of simplifying its administration to patients.
Resultados: La determinación cromatográfica de las concentracio-
Methods: Using high performance liquid chromatography (HPLC) to
nes de pantoprazol reflejó un rápido y progresivo envejecimiento measure pantoprazole content in PNU at different time intervals.
de la muestra. Pasadas 24 h la cantidad de fármaco detectado en la Results: The chromatographic determination of pantoprazole
UNP es inferior al 50% del total adicionado.
concentration reflected a rapid and progressive aging of the sample.
Conclusiones: A la vista de estos resultados se desaconseja este ve-
After 24 h the quantity of drug detected in the PNU was below 50% hículo para la administración de pantoprazol, ya que puede poner en riesgo la seguridad de los pacientes al infradosificar la medica- Conclusions: In view of these results, we therefore do not suggest
ción que requieren y exponerlos a los posibles efectos desconoci- this as a suitable vehicle for pantoprazole administration as it could dos de los diferentes productos de degradación del fármaco.
put patients at risk of being under-dosed and therefore exposing themto potential unknown side effects of the different drug degradation Palabras clave: Estabilidad fisicoquímica. HPLC. Pantoprazol. Nutrición pa-
Key words: Drug stability. HPLC. Pantoprazole. Parenteral nutrition.
Estabilidad de pantoprazol en unidades para nutrición

Introducción: El pantoprazol es una base débil (pka ~ 4) y su esta-
Pantoprazole, one of the most used proton pump inhibitors, is bilidad en solución acuosa es dependiente del pH. Teniendo en a weak base (pka ~ 4) with its stability in aqueous solution cuenta que el pH de las unidades de nutrición parenteral (UNP) dependent on pH. Its hydrolysis increases as pH decreases. At puede oscilar entre 6,0 y 6,5, y puesto que pantoprazol parece ser room temperature, its degradation half-life varies to a few minutesat pH 1.0-2.01 and 220 h to pH 7.8,2 with optimal stability atpH 9.
All benzimidazoles used as PPI are unstable in acid environments, but previous studies have shown significantdifferences in the degradation time of different molecules based Correspondence: E. Valverde Molina.
Servicio de Farmacia. Hospital Carlos Haya.
on the pH levels in which they are found. Pantoprazole is the PPI Camino de Antequera, s/n. 29011 Málaga. España.
least sensitive to acid pH.3 Keeping in mind that the pH of E-mail: [email protected] parenteral nutrition units (PNU) can range between 6.0 and 6.5, Accepted for publication: September 16, 2008.
the possibility of adding pH to the units was evaluated.
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Valverde Molina E et al. Stability of Pantoprazole in Parenteral Nutrition Units Pantoprazole is widely used in hospitals. In hospitals, patients HPLC water (Merck S.A.), and its stability was determined for with a significant amount of fluid therapy due to the high quantity at least 1 week at room temperature (variation coefficient of of intravenous medication they need is frequently seen. The 3.47%). An aliquot of IS (20 µg/mL) was injected at each time reduction of perfusion volumes for patients who require restricted interval with no changes in the appearance of the peak and no fluid therapy is very helpful for clinics. A regular way of decreasing fluid volume is by adding drugs to the PNU, and this also decreases The standard solution prepared was with a pantoprazole concentration of 160 µg/mL, and the preparation of sodium After reviewing bibliographic information, studies on PPI pantoprazole in commercial freeze-dried powder was dissolved stability in various solutions were found,4-6 but no study made into an injectable solution of 250 mL of PNU. As has occurred with other authors,5 pure pantoprazole could not be obtained bythe manufacturer for use as a reference standard. Therefore,“Anagastra®” the commercial product for injections, was used to prepare the standards. Five calibrators were prepared by dilutingthe standard solution of pantoprazole with the PNU solution at Preparation of the Parenteral Nutrition Unit
concentrations of 2, 5, 10, 15, and 30 µg/mL. Both thepropylparaben and pantoprazole standard solutions were evaluated Standard type PNU was used (Table 1) and prepared according Analysis of Samples by Using High Performance
Preparation of the Sample
Liquid Chromatography
To prepare the sample, 40 mg vials of sodium pantoprazole in The original method by Dentinger et al5 was used for pantoprazole freeze-dried powder for injectable solutions were used determinations by HPLC, with small modifications made by (Anagastra®, Altana Pharma AG). Ten mL of the PNU solution Johnson.4 Equipment from HPLC Waters Corporation 1525, a was put into each vial and shaken in a vortex; later, 3 L of PNU binary pump and a VIS-UV W 2487 detector was used. For data were added to the bottle by syringe, and a final concentration of acquisition and processing, Breeze (Waters Corporation) software 13.3 µg/mL was drawn. The sample time interval was set at 3, was used. Chromatographic conditions used included the reversed 6, 9, 12, 24, and 48 h. PNU were kept at room temperature and phase Symmetry 300™ C18 column 3.3 µm 4.6×150 mm used at protected from the light. The PNU pH was determined before room temperature and with a wavelength of 280 nm. The mobile the addition of pantoprazole and at 0, 24, and 48 h after its phase consisted of a 40% (v/v) proportion of HPLC grade addition. Samples were prepared aseptically, but their sterility acetonitrile (Merck SA) in a 50 mM (pH 7) phosphate buffer (Merck S.A. Lot 4871). The phosphate buffer was prepared withHPLC grade water and was filtered by 0.2 µm filter membranes Preparation of the Calibration Curve and Internal
(Millex® GS. Millipore). The mobile phase was degassed using Standard
helium, and the flow rate was set at 1 mL/min. The final injectionvolume was 30 µL, and determinations were carried out in An internal standard solution was prepared (IS), with propylparaben duplicate. For integrating the chromatograms, the retention times (Farmaquímica Sur SL), at a final concentration of 0.2 mg/mL for pantoprazole and the IS were set after reevaluating the methodat 3.5 and 5.7 min, respectively.
Analysis of Samples
Table 1. Quantitative Composition of Parenteral Nutrition
For each analysis, 500 µL of PNU with added pantoprazole were drawn together, and this was placed in a centrifuge tube.
Subsequently, 100 µL of IS solution (0.2 mg/mL) and 400 µL of acetonitrile were added. This was shaken for 20 s in a vortex and centrifuged for 10 min at 10 000 rpm and at room temperature.
The supernatant was collected in a centrifuge tube, and 100 µL were placed in microvials for later analysis by HPLC. Data Analysis
Pantoprazole stability was determined through evaluation of the concentration at each time interval.
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Valverde Molina E et al. Stability of Pantoprazole in Parenteral Nutrition Units Table 2. Pantoprazole Concentration Data in the Parenteral
For finding pantoprazole determinations, the HPLC method Nutrition Unit at Time Intervals of the Trial was selected because of its efficacy, sensitivity, and repeatability.
The selection of a sampling schedule for taking measurements Pantoprazole Concentration (SD), µg/mL
was done keeping in mind that approximately 6 h pass for parenteral nutrition preparation to be completed and administered to the patient. Also, considering that parenteral nutrition mixtures perfuse in less than 48 h and usually no more than 24 h, 48 h was established as the upper time limit and 24 h as the critical A yellow coloration was observed in the PNU tested, which in view of data obtained, seems to be related to the appearance of degradation products from pantoprazole. Nevertheless, the Johnson4 study concludes that the appearance of a yellow tonalityin pantoprazole solutions is not related to an unacceptable decreasein the concentration of the molecule. In consideration of these apparently contradictory results, it would be necessary to designnew studies which correlate the variation of pantoprazole solution Chromatographic determination of pantoprazole concentrations tonality with its percentage of degradation.
at different sampling times (Table 2) shows the sample’s aging Pantoprazole is one of the most stable PPI in terms of pH change.
(the decrease of pantoprazole over time). This activity loss is However, it has a very fast activity loss in PNU; its concentration related to the decrease of pantoprazole content. Less than 80% falls below the tolerable lower limits within a few hours after its of added pantoprazole could be detected in the PNU after 6 h, addition; and its concentrations reduce to less than 50% at 24 h.
and its concentration was reduced to less than 50% at 24 h.
Based on these results, this vehicle for pantoprazole administration With the aim of seeing if the added drug could destabilize the is not recommended, as it does not provide any benefit for patients, mixture, pH measurements of PNU were carried out simultaneously but could put them at risk of underdosing their needed medication, with the chromatographic determination of pantoprazole. No and could expose them to possible unknown effects from the significant modifications were detected in the pH evolution of PNU throughout the study, and an average pH of 6.11 (6.16-6.06) The results obtained in this study encourage pharmacy was established. However, PNU color changes were observed, departments to communicate the risk of adding unstudied drugs with a yellowish color at 12 h which had intensified after 24 h.
to parenteral solutions and also promote research on the stabilityof other compounds with the end of ensuring correct dosage andminimizing possible dangers of inappropriate drug use.
This study was designed to determine stability, and therefore References
suitability of pantoprazole inclusion in parenteral nutrition mixturesprepared daily in hospitals. Showing pantoprazole stability in 1. Ferron GM, Ku S, Abell M, Dnruh M, Getsy J, Mayer PR, et al. Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution.
parenteral nutrition mixtures provides medical departments with Am J Health-Syst Pharm. 2003;60:1324-9.
a new system for administering medication, and therefore, increases 2. Protonix (pantoprazole) delayed-release tablets, package inserto available treatment alternatives. This new administration method Philadelphia: Wyeth Laboratories; 2000.
3. Kromer W, Krüger D, Huber R, Hartmann M, Steinijans VW. Differences could provide significant advantages both clinically and for the in pH-dependent activation ratos of substituted benzimidazoles and biological in vitro correlates. Pharmacology. 1998;56:57-70.
In developing the study, a standard PNU without lipids was 4. Johnson CE. Stability of pantoprazole in 0.9% sodium chloride injection in polypropylene syringes. Am J Health-Syst Pharm. 2005;62:2410-2.
selected to simplify analysis. Although a limitation can be 5. Dentinger PJ, Swenson CF, Anaizi NH. Stability of pantoprazole in an considered, pantoprazole stability depends on the pH of the mixture.
extemporaneously compounded oral liquid. Am J Health-Syst Pharm.
The inclusion of the lipid mixture does not affect, a priori, the pH 6. Ekpe A, Jacobsen T. Effect of various salts on the stability of lansoprazole, of the mixture. Consequently, it can be assumed that pantoprazole omeprazole, and pantoprazole as determined by high-performance liquid stability in PNU is similar with and without lipids. chromatography. Drug Dev Ind Pharm. 1999;25:1057-65.


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