Misoprostol y embarazo / Misoprostol and pregnancy

Se analiza el uso de la droga Misoprostol en el área obstétrica: Aborto. Inducción de parto. Sangramiento post parto. Se describen ventajas, desventajas, dosificación y contraindicaciones

Preparación cervical en el aborto del primer trimestre: médica versus mecánica / Cervical priming in first trimester abortion: medical versus mechanical

Objetivo: El objetivo fue comparar la efectividad en la preparación cervical antes de la evacuación quirúrgica de los análogos de prostaglandinas E2 (PGE2) con los tallos higroscópicos (dilapan, lamicel, laminaria) intracervicales en abortos del primer trimestre.Diseño: Se diseñó un estudio prospectivo randomizado con enfermas ingresadas en el Servicio de Obstetricia del Hospital Universitario La Fe de Valencia por aborto.Método: El material lo integran un grupo de 140 gestantes a las que se le administró una dosis intracervical de 0,5 mg de PGE2 (dinoprostona) en forma de gel y otro grupo de 135 embarazadas a las que se les insertó intracervicalmente tallos osmóticos al menos 8 horas antes del legrado quirúrgico. Se valoró el efecto sobre la dilatación inicial y los efectos secundarios (náuseas, vómitos, diarrea, sangrado, fiebre, etc.), así como las complicaciones en abortos incompletos y diferidos antes de la semana 14 de gestación. También se valoró el impacto económico.Resultados: Hubo diferencias significativas en la capacidad de dilatar el cérvix entre las PGE2 y los tallos (p 0,05). La frecuencia de efectos adversos digestivos fue significativamente mayor en las prostaglandinas, tanto en vómito y diarrea (p < 0,05) como en náuseas (p < 0,01). Las complicaciones sistémicas sólo se observaron en las PGE2, mientras que las locales se objetivaron únicamente con los tallos, siendo mayores con el dilapan que con el lamicel (p < 0,05). La necesidad de dilatación posterior en abortos incompletos fue sólo significativamente mayor con PGE2, en amenorreas inferiores a 9 semanas (p < 0,01) tanto en primigestas (p < 0,01) como plurigestas (p < 0,05). En los abortos diferidos las diferencias sólo fueron significativamente mayores con PGE2 en amenorrea inferior a 9 semanas (p < 0,05), primigestas (p < 0,01) y con BhCG sérica menor de 5.000 mU/ml (p < 0,01). No hubo diferencias en cuanto a edad mayor o menor de 35 años. El coste económico por paciente fue menor con dilapan y lamicel que con laminaria (p < 0,05).Conclusiones: La inserción de tallos osmóticos sintéticos supera a las PGE2 en rapidez de dilatación, pero no los osmóticos naturales (laminaria). Las prostaglandinas se asocian a mayores efectos secundarios. Los tallos son económicamente más baratos, pero las PGE2 son más fáciles de administrar. En aborto incompleto los tallos osmóticos sintéticos superan a las PGE2 en primigestas de embarazos precoces. En aborto diferido los tallos sólo superan a las PGE2 si la primigesta de corta edad gestacional tiene gonadotrofina coriónica (BhCG) sérica baja (AU)

Thermospray liquid chromatography/mass spectrometry of prostaglandin methyl ester derivatives: application to the determination of prostaglandins E2 and D2 in rat gastric mucosa.

Methyl ester derivatives of 6-keto prostaglandin (PG) F1 alpha, PGF 2 alpha, PGE2 and PGD2 as well as methyl oximes of 6-keto PGF1 alpha, PGE2 and PGD2 have been analysed by thermospray high-performance liquid chromatography mass spectrometry. These compounds are eluted in a gradient of ammonium acetate buffer-acetonitrile at pH 3.4 using a 5 micron ODS-2 reversed-phase column. The mass spectral patterns of the PG derivatives are discussed relative to those of non-derivatized PGs. In general, the methyl ester derivatives show better characteristics than the non-derivatized PGs for the analysis of these compounds in a biological matrix, both from a chromatographic as well as from a mass spectrometric standpoint. Detection limits between 100 and 600 pg on-column can be achieved. Response curves in the selected ion monitoring mode for PGF2 alpha, PGE2 and PGD2 are linear in the range from 100 pg to 10 ng. The technique has been applied to the analysis of PGE2 and PGD2 in rat gastric mucosa.

An ELISA for PGE2 utilizing monoclonal antibody.

An ELISA for PGE2 has been developed which is sensitive to concentrations of 0.5 to 20.0 ng PGE2/ml. Mouse monoclonal anti-PGE2 ascites is utilized in a binding competition between the test sample and an adsorbed conjugate of PGE2-BSA. The antibody which remains bound to the solid phase is quantitated colorimetrically by incubation with alkaline phosphatase-conjugated goat anti-mouse IgG followed by incubation with p-nitro-phenylphosphate. PGE1, PGA1, PGA2, PGB2, 6-keto-PGF1 alpha, PGF2 alpha, 13,14-dihydro-15-keto-PGE2, thromboxane B2 and arachidonic acid showed minimal cross-reactivity with the anti-PGE2. The PGE2 ELISA permits the quantitative analysis of large numbers of samples at a fraction of the cost and time required to process a commercial RIA kit. When linked to the appropriate computer software, data collection and analysis can be performed in less than 10 minutes per 96-well plate. Furthermore, the use of an ELISA system eliminates the radioactive and toxic chemical waste generated by RIA methods.

[High performance liquid chromatography of synthetic analogs of prostaglandin E]. / Vysokoéffektivnaia zhidkostnaia khromatografiia sinteticheskikh analogov prostaglandina E.

High-performance liquid chromatography was used for separation, identification and purification of synthetic analogues of prostaglandin E, about 30 various samples being analysed. Basing on the data obtained, recommendation are given on the preparative HPLC separation (up to 300 mg scale) of structural isomers and epimers of synthetic prostaglandins.

Evaluation of the 190H analogues of prostaglandins E1, E2, F1 alpha and F2 alpha as specific markers for the identification of human semen in body fluid mixtures.

The specificity of antisera raised against each of the prostaglandin series 190H E1/E2 and 190H F1 alpha/F2 alpha, produced in males, was evaluated by radioimmunoassay. Further, the ability of these antisera to detect semen specific prostaglandins in mixtures of body fluids was examined. Antisera directed against the 190H E1/E2 series cross-reacted with prostaglandin E1 and marginally with E2. Antisera raised to the 190H F1 alpha/F2 alpha series were, however, highly specific to the semen specific prostaglandins 190H F1 alpha/F2 alpha and 190H E1/E2. It was possible to detect picogramme quantities of contaminating 190H F1 alpha/F2 alpha on vaginal swabs taken up to 72 h after intercourse and on vaginal swabs stored at room temperature for up to 2 years. These prostaglandins were not detected on semen free vaginal swabs, in faecal material, saliva, urine or in a sample of human milk (stain). A limited study of casework material is also described. Detection of the 190H F series, as a group, has considerable potential in the identification of human semen at picogramme levels, eliminating the need for alternative chemical tests and extensive microscopic examination.

Multidimensional column-switching liquid chromatographic method for dissolution testing of enprostil soft elastic gelatin capsules.

Enprostil (methyl 7-[(1 R,2R,3R)-3-hydroxy-2-[(E)-(3R)-3-hydroxy-4- phenoxy-1-butenyl]-5-oxocyclopentyl]-4,5-heptadienoate), an E-type prostaglandin exhibiting anti-ulcer activity, is formulated as a propylene carbonate solution filled into soft elastic gelatin (SEG) capsules. Enprostil SEG capsules were maintained for timed intervals at 50 degrees C, 30 degrees C, and room temperature, and the quantity of drug released upon complete capsule dissolution was determined as a function of storage condition. The dissolution test adhered to USP XXI guidelines (paddle method) and used a multidimensional HPLC technique to provide a sensitive and selective enprostil assay. Parallel HPLC assays determined the enprostil concentration in the propylene carbonate fill that was physically expressed from initially manufactured and from aged capsules. This corrected for any enprostil loss via chemical degradation on storage. The study included six different aged samples (six replicates each), and for all six samples, the enprostil recovered from dissolved capsules averaged 104 +/- 1.4% of the enprostil physically expressed from the capsules. Similarly, the enprostil recovered from dissolved, aged capsules averaged 103 +/- 5% of the enprostil physically expressed from capsules at the initial time point. These findings exclude the possibility that interactions with the SEG capsule wall reduce drug availability during storage under normal conditions. The multidimensional HPLC technique should generally extend to analysis of other noncationic drugs formulated into soft gelatin capsules.

Reactivity of enprostil stereoisomers in soft elastic gelatin capsules.

Enprostil (methyl 7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy-1-butenyl]- 5-oxocyclopentyl]-4,5-heptadienoate), a gastric acid secretion inhibitor and potent anti-ulcer drug, is formulated as a propylene carbonate solution which is filled into soft elastic gelatin capsules. The drug molecule features two unresolved asymmetric carbon atoms, and synthesis yields an equimolar mixture of four different optical isomers (two diastereomeric pairs of enantiomers). The objective of this study was to establish the degree to which enprostil does or does not degrade stereoselectively in the soft elastic gelatin capsule formulation. Accordingly, we developed an HPLC method capable of resolving enprostil diastereoisomers and applied the method to determining reaction rates of enprostil in soft elastic gelatin capsules maintained at 40 degrees C. The study included three soft elastic gelatin capsule lots: the first two contained an equimolar mixture of all four enprostil enantiomers; and the third contained an equimolar mixture of two individual diastereoisomers of known optical purity. Comparing enprostil degradation rates in the three capsule lots showed that reactivity ratios in all cases were (within the limits of experimental uncertainty) equal to unity. This observation conclusively excludes the possibility of significant enantioselectivity for enprostil degradation in the soft elastic gelatin capsule formulation. We also report kinetic equations for the general case of relating stereospecific reactivity ratios to drug product shelf life when drug concentrations are monitored with nonstereoselective analytical techniques.

Femtomole analysis of prostaglandin pharmaceuticals.

An analytical method is described whereby the major classes of prostaglandins are fully resolved by microcolumn liquid chromatography and detected at the subfemtomole level by laser-induced fluorescence. The prostaglandins are labeled with the fluorescent reagent 4-bromo-methyl-7-methoxycoumarin and are subsequently separated on a high-efficiency fused-silica microcolumn (0.2 mm i.d., 1.06 m length, 150,000 theoretical plates). The optimal chromatographic conditions consist of a 3-micron octadecylsilica packing material and an isocratic mobile phase of 47.6% methanol, 23.8% acetonitrile, and 28.6% water. The prostaglandin derivatives are detected directly on the microcolumn by laser fluorimetry, using a helium/cadmium laser (325 nm, 15 mW) as the excitation source together with a simple filter/photo-multiplier optical detection system. In real sample matrices, the prostaglandin PGF2 alpha is readily quantifiable from the detection limit (0.3 fmol) to the formulation strength of the therapeutic agent Lutalyse (Upjohn), spanning more than six orders of magnitude in concentration. The simplicity and general applicability of the present analytical methodology and instrumentation suggest that this technique can be used to attack a wide variety of biomedically important problems with exceptional sensitivity and selectivity.

A PGE2-derivative for quantitative gas chromatographic mass spectrometric measurement in the selected ion monitoring mode.

The quantification of prostaglandin PGE2 by gas chromatography mass spectrometry in the form of an easily prepared derivative is described. After extraction and purification of biological samples the compound was derivatized in two steps to 9-enol-PGE2- methylester - trimethylsilylether , 9-enol-PGE2-Me- TMS3 . The molecular ion at m/z 582 with 40% relative abundance and the fragment ion at m/z 492 with 100% relative abundance permit a specific and sensitive evaluation in the selected ion monitoring mode. The high masses selected lie above the biological background. The calibration curve produced by adding known amounts (10-200 ng) of PGE2 to blank human urine and with (2H4)-deuterated PGE2 as internal standard gave a linear correlation. The separation from biological impurities was obtained on a 50 m glass capillary column and resulted in sharp and symmetrical peaks.

A highly specific radioimmunological determination of sulprostone (1) using antisera against two different haptens.

A sensitive and specific radioimmunoassay for sulprostone in serum has been developed. The use of antisera raised against two different haptens allows the determination of sulprostone alone or together with its main metabolites. Radioactive tracers with high specific radioactivity were synthesized by coupling the haptens to [125I]-iodohistamine.

Radioimmunoassay for sulprostone.

The development of a radioimmunoassay for measuring subnanogram amounts of the prostaglandin uterine stimulant, sulprostone (N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 carboxamide), is described. The 9-carboxymethoxime derivative of sulprostone was coupled to keyhole limpet hemocyanin to prepare the immunogen, and to tyramine to yield a precursor suitable for radioiodination. The antiserum generated from rabbits was specific for sulprostone, showing cross reactivities of less than 0.1% against PGE2, PGF2 alpha, and known sulprostone metabolites. The range for routine assay of sulprostone was 10-300 pg which corresponded to 50-1500 pg/ml of plasma. The coefficient of variation for replicate analyses on the same sample was 8-12%. The assay was used to measure the plasma levels of sulprostone in patients who had received the drug intramuscularly.

Microcolumn chromatographic cleanup and GLC determination of 11-methyl-16,16-dimethylprostaglandin E2 in polyethylene glycol 400 solutions.

An analytical procedure is described for the GLC determination of 11-methyl-16,16-dimethylprostaglandin E2 in aqueous polyethylene glycol 400 solutions. Because of the nature of the carrier matrix, sample cleanup was required prior to GLC separation. Separation was achieved using a diethylaminoethylcellulose microcolumn. This procedure has proven to be amenable to routine analysis.

Prostaglandin prodrugs. I: Stabilization of dinoprostone (prostaglandin E2) in solid state through formation of crystalline C1-phenyl esters.

Dinoprostone para-substituted phenyl esters were synthesized in attempt to improve the solid-state stability of the parent prostaglandin. A phenol series covering a wide melting-point range was employed, and a linear relationship was observed between the phenol melting points and the resulting prostaglandin C1-ester melting points. The crystalline esters showed improved solid-state stability over the parent compound, and many esters were biologically active.

The use of immobilized ligands and [125I]protein a for immunoassays of thromboxane B2, prostaglandin D2, 13,14-dihydro-prostaglandin E2, 5,6-dihydro-prostaglandin I2, 6-keto-prostaglandin F1 alpha, 15-hydroxy-9 alpha, 11 alpha(epoxymethano)prosta-5,13-dienoic acid and 15-hydroxy-11 alpha,9 alpha(epoxymethano)prosta-5,13-dienoic acid.

Immunoassays were developed for quantitative determination of thromboxane B2, prostaglandin D2, 13,14-dihydro-prostaglandin E2, 5,6-dihydro-prostaglandin I2, 6-keto-prostaglandin F1 alpha, 15-hydroxy-9 alpha, 11 alpha (epoxymethano) prosta-5, 13-dienoic acid and 15-hydroxy-11 alpha, 9 alpha (epoxymethano) prosta-5,13-dienoic acid. Ligands immobilized by covalent linkage to a solid support, bound homologous rabbit antibodies. [125I] Protein A was used to measure the bound IgG antibody. Increments of homologous and heterologous fluid-phase ligand completed with solid-phase ligand for antibody and resulted in decreasing amounts of bound [125I]-Protein A. The serologic specificity for each immune system was determined. Immunoassays for thromboxane B2, 6-keto-prostaglandin F1 alpha, and 5,6-dihydro-prostaglandin I2 were used to identify their respective homologous ligands that were separated by normal phase and reversed phase high pressure liquid chromatography.