[Ocular hypotensive effect of systemic beta-blockers in patients with primary glaucoma and arterial hypertension]. / Oftal'mogipotenzivnyĭ éffekt sistemnogo primeneniia beta-blokatorov pri pervichnoĭ glaukome i arterial'noĭ gipertenzii.

AIM: to evaluate the ocular hypotensive efficacy of systemic beta-blockers in primary glaucoma patients suffering from arterial hypertension (AH). MATERIAL AND METHODS: The study included 29 patients with POAG (58 eyes) aged from 47 to 83 years. Patients with stage I-III POAG received instillations of prostaglandin analogs and carbonic anhydrase inhibitors. All POAG patients also suffered from arterial hypertension and were prescribed selective beta-blockers (metoprolol, bisoprolol, or nebivalol) as monotherapy or as part of combination therapy (if the target arterial pressure had not been achieved under the initial treatment). After the start of oral beta-blockers therapy, the patients were re-examined at 2 and 4 weeks, 3 months, 6 months, and 1 year. RESULTS: A clinically significant reduction of IOP in the most seriously affected eye - by 3.3 mmHg (p<0.05), or 14% - occurred four weeks after the start of selective beta-blockers. Over three months of combination therapy, IOP in the 'worst' eye decreased by 4.4 mmHg (18.5%). At 1 year, IOP in the 'worst' eye was 6.2 mmHg (26%) lower than at baseline (p<0.05). CONCLUSION: Aged and senile patients with primary glaucoma usually suffer from polypathy (on average, they have 6.3±0.6 concurrent somatic diseases). To reduce the risk of polypharmacy and the frequency of side effects in the treatment of POAG and AH patients, it is advised that the treatment includes oral selective beta-blockers able to provide target levels of arterial pressure and IOP. In this study, oral beta-blockers in POAG and AH patients enabled IOP reduction as great as 18.5%-26% of baseline values over a 1-year follow-up period.

Rotación de análogos de prostaglandinas y fluctuaciones diurnas de la presión intraocular / Switching prostaglandin analogues and 24-hour iop fluctuations

Objetivos: Evaluar la eficacia de la rotación de análogos de prostaglandinas sobre las fluctuaciones de la presión intraocular (PIO) en 24h. Métodos: Se evaluó a 14 pacientes con glaucoma primario de ángulo abierto mediante curvas mensuales de presión intraocular de 24h, realizando un patrón de cambios mensuales del tratamiento hipotensor entre brinzolamida y análogos de prostaglandinas durante un período de tres años. Resultados: Tanto el promedio de PIO como el promedio de variación (diferencia entre el pico y el valle) durante las curvas fueron significativamente mayores con la brinzolamida que con cualquiera de los tres análogos. Tanto el promedio de PIO como el promedio de fluctuaciones fueron similares entre los tres análogos, independiente del orden en que se usaron o de si se intercaló un mes de brinzolamida entre uno y otro análogo. Conclusiones: La brinzolamida fue menos efectiva para reducir la PIO promedio y sus fluctuaciones durante 24h. No hubo un cambio significativo al rotar los análogos(AU)

Objectives: To evaluate the fluctuations in 24h mean intraocular pressure (IOP) when switching prostaglandin analogues in patients with glaucoma. Methods: Fourteen patients with primary open angle glaucoma were evaluated with monthly 24-hour IOP curves, using a monthly switching pattern of prostaglandin analogues and brinzolamide during 3 years of follow-up. Results: Average IOP and average fluctuation (peak to through difference) were significantly higher with brinzolamide than with any of the analogues. There was no significant difference in either parameter with the different prostaglandin analogues, regardless of the order in which they were evaluated, or even if a month on brinzolamide was intercalated between the analogues. Conclusions: Brinzolamide was less effective than prostaglandin analogues in reducing 24-hour mean IOP and its fluctuations. Switching analogues had no significant effect on mean IOP or mean IOP fluctuations(AU)

Pharmacokinetics of prostaglandins.

Naturally occurring prostaglandins (PGs) are rapidly metabolized in the human circulation. For clinical use a number of PG analogues have therefore been developed which are resistant to rapid inactivation. Among these are carboprost, gemeprost and misoprostol. Following intramuscular injection of carboprost, plasma levels peaked after 20 minutes and declined slowly thereafter. In amniotic fluid the half-life was between 31 and 37 hours. Gemeprost is administered vaginally, and maximum plasma levels were reached after 2-3 hours, with detectable levels for at least 6-8 hours. Pharmacokinetic data on misoprostol are available following oral, vaginal and sublingual administration. Following oral treatment, plasma levels peaked at about 30 minutes, while after vaginal administration of the tablets the levels increased gradually and reached maximum levels after 70-80 minutes, but remained detectable for a significantly longer time. After sublingual administration the peak concentration was the same as for oral treatment but declined significantly more slowly. Endocervical administration of PGE(2) might be regarded as a local therapy, while following vaginal administration increased plasma levels of metabolites can generally be found. The plasma profile varies with the vehicle used.

Labor induction with misoprostol versus dinoprostone: a meta-analysis of seven randomized trials

Comparar a eficácia e a segurança de dois análogos das prostaglandinas, misoprostol e dinoprostone na indução do parto em gestações de terceiro trimestre com feto vivo e cérvice desfavorável ao uso de ocitocina, conforme relatos recentes na literatura...

Blood-brain-barrier transport of lipid microspheres containing clinprost, a prostaglandin I2 analogue.

Because the permeability of the blood-brain barrier to lipid microspheres (LMs) has not hitherto been demonstrated, blood-brain-barrier permeability to LM containing the prostaglandin I2 analogue clinprost has been evaluated for an in-vitro system of primary cultured monolayers of bovine brain capillary endothelial cells (BCECs), by a capillary depletion study in rats and by an in-situ brain perfusion study in normal and 4-vessel-occluded fore brain ischaemic rats. Although energy-dependency was not observed in [3H]clinprost uptake by BCECs, in accordance with results for simple diffusional transport, uptake of [3H]clinprost contained in lipid microspheres (denoted [3H]clinprost(LM)) was significantly inhibited by the endocytosis inhibitor, dansylcadaverine. The transport of LM into BCECs by endocytosis was also confirmed by fluorescence microscopy and flow-cytometric analysis using LM labelled with a fluorescent probe, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil). The absolute uptake of Dil(LM) by BCECs, measured by HPLC, was, however, almost 1/10 that of [3H]clinprost(LM), results which suggest the superiority of simple diffusion of clinprost over endocytosis of its LM form in the uptake of clinprost(LM) by BCECs. In the capillary-depletion study with rat-brain-perfused [3H]clinprost(LM) from the internal carotid artery, the parenchyma apparent distribution volume was about 45 times larger than that of the capillary, showing that [3H]clinprost(LM) was transported through the blood-brain barrier into the brain. The permeability coefficients of [3H]clinprost and [3H]clinprost(LM) determined by insitu brain perfusion in normal rats were considerably higher than those of the active metabolite [3H]isocarbacyclin and its LM form. In addition, the Blood-brain-barrier permeabilities to [3H]clinprost, [3H]isocarbacyclin and their LM forms in ischaemic rats were almost identical to those in normal rats. It was concluded that clinprost(LM) was transported through the blood-brain barrier by endocytosis of LM, simple diffusion of clinprost released from LM, and transport of isocarbacyclin generated by hydrolysis of clinprost. The blood-brain-barrier permeability of clinprost(LM) is not reduced in ischaemic conditions, because the simple diffusion of clinprost released from LM contributed mainly to clinprost(LM) transport.

Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure.

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/- 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of rioprostil in rats.

The pharmacokinetics of rioprostil in rats has been investigated following a single intravenous or oral dose of rioprostil between 0.004 and 10 mg/kg. Rioprostil is eliminated from plasma following an intravenous dose rapidly (t1/2 = 0.22 h) and nearly exclusively by biotransformation. The high total clearance (CL = 5.4 l.h-1.kg-1) indicates an additional extrahepatic metabolism. A systemic bioavailability of 2%, in spite of a rapid and nearly complete absorption (fa = 90%), indicates an extended first-pass effect. Twenty-four hours after the administration of [3H]rioprostil the residual radioactivity in the animal amounted to less than 1% of the dose administered.

Metabolic fate of rioprostil in the rat--in vivo and in liver perfusion.

The metabolic fate of rioprostil is investigated in the rat--in vivo and in liver perfusions--using the tritriated drug. Seven metabolites are isolated from the perfusion model and identified by 1H-NMR spectroscopy, mass spectrometry (EI/CI/FAB) and combined GC-MS (EI/CI). Rioprostil is extensively metabolized. The main metabolite in urine (81.2%) and bile (50.1%) is the tetranor-1,16-dicarboxylic acid. The tetranor carboxylic acid is isolated in smaller amounts (8.1 and 18.2% resp.). Rioprostil itself can be detected neither in the urine nor in the bile of the in vivo studies. Thus, the metabolism of rioprostil proceeds via the biotransformation pathways of the naturally occurring prostaglandins.

Pharmacokinetics of rioprostil in human plasma as assayed by combined capillary gas chromatography-negative ion chemical ionization mass spectrometry.

To investigate the pharmacokinetics of rioprostil in man an assay is developed to analyse levels of rioprostil in plasma. After extraction and purification by solid-phase cartridges rioprostil is measured by negative ion chemical ionization mass spectrometry using a deuterated internal standard. The method is validated by a recovery experiment. Levels of rioprostil in the plasma of four volunteers following a single oral dose of 600 micrograms rioprostil are found as always below 100 pg/ml. The data presented here suggest that rioprostil is transformed rapidly in man to its more polar metabolites.

Pharmacokinetic interactions between theophylline and rioprostil.

The study is of double-blind crossover design. The effects of rioprostil, an analogue of prostaglandin E1, at a dose of 300 micrograms b.d., and placebo on the kinetic of slow-release theophylline are investigated. Eight healthy male volunteers participate in the study, each study period lasting for one week. During the first period, the doses of theophylline are altered in response to measured theophylline levels, 200 mg or 400 mg b.d. Regardless of placebo or rioprostil treatment, side effects appear before day 6 and are related specifically to theophylline administration. Blood samples are taken on days 4 and 5 to check steady-state plasma levels of theophylline and on days 6 and 7 to determine the main pharmacokinetic parameters. The same schedule is used for the second period of treatment. The achievement of steady-state concentration is verified. The mean pharmacokinetic parameters do not show a significant difference when slow-release theophylline is given alone or with rioprostil. These results are likely to be clinically relevant and, therefore, the theophylline dose should not be changed if rioprostil is prescribed at the same time as the theophylline.

Evaluation of prostaglandin-receptors in human and rat liver: interspecies differences at the prostaglandin receptor-level.

The properties of PGE1-, PGE2- and iloprost (stable PGI2-analogue)-binding sites on normal human and rat liver surface cell membranes were investigated. The specific binding of [3H]PGE1 to human (rat) liver surface cell membranes could be displaced most effectively by unlabeled PGE1 (IC-50:2.5 +/- 1.7, (6.1 +/- 2.1) microM) and the specific binding of [3H]PGE2 by unlabeled PGE2 (IC-50: 1.9 +/- 0.9 (2.0 +/- 0.8) microM. The Scatchard analysis on [3H]PGE1- as well as on [3H]iloprost-binding was curvilinear whereas it was clearly linear on [3H]PGE2-binding in both the species. The high-affinity [3H]PGE1-sites showed a Bmax of 36.3 +/- 5.2 (21.3 +/- 4.3) fmol/mg protein and a Kd of 2.1 +/- 1.8 (1.9 +/- 0.7) nM, the low-affinity [3H]PGE1-sites a Bmax of 93.4 +/- 18.2 (86.1 +/- 13.2) fmol/mg protein and a Kd of 10.5 +/- 2.9 (15.1 +/- 3.2) nM. The high-affinity [3H]iloprost-sites exhibited a Bmax of 71.4 +/- 13.9 (35.9 +/- 8.2) fmol/mg protein and a Kd of 4.1 +/- 1.2 (1.7 +/- 1.8) nM, the low-affinity [3H]iloprost-sites a Bmax of 217.3 +/- 42.1 (142.9 +/- 17.8) fmol/mg protein and a Kd of 16.3 +/- 4.9 (9.2 +/- 7.2) nM. The [3H]PGE2-sites showed a Bmax of 135.4 +/- 51.9 (38.8 +/- 7.4) fmol/mg protein and a Kd of 16.2 +/- 3.2 (2.5 +/- 1.2) nM. It is assumed that prostaglandins of the E-series are promising substances in the regulation of human and rat liver function since liver cells are able to bind reasonable amounts of these substances in a high affinity manner. However, interspecies differences in the affinity of the prostaglandins to their receptor-sites make it strange to assume that the same biological findings claimed several times for the rat liver are relevant for human too.

Disposition of 3H-enisoprost, a gastric antisecretory prostaglandin, in healthy humans.

1. After oral administration of 3H-enisoprost (450 micrograms) to five healthy men, as a solution in capsules, peak 3H levels of 5624 +/- 566 pg equiv./ml (mean +/- S.E.M.) were reached within one hour. No unchanged drug was detected in plasma. 2. Enisoprost was rapidly de-esterified to SC-36067 [(+/-)11 alpha, 16 zeta-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-dien-1-oic acid], a pharmacologically active analogue, which reached peak concentrations of 651 +/- 200 pg/ml within 20 min of dosing. SC-36067 was eliminated metabolically, with a half-life of 1.61 h, by a combination of beta-oxidation, omega-oxidation and 9-keto-reduction. 3. After nine days 59.0 +/- 2.98% and 17.4 +/- 1.57% of the dose was excreted in urine and faeces respectively. The majority of this excretion was complete in two days. 4. Five urinary metabolites were identified by GC-MS. These were (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (+/-)3-[3 alpha,5-dihydroxy-2 beta-(4-hydroxy-4-methyl-1E-octenyl)-1 alpha-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (+/-)3-[2 beta-(8-carboxy-4-hydroxy- 4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (+/-)3-[2 beta-(8-carboxy-4- hydroxy-4-methyl-1E-octenyl)-3 alpha,5-dihydroxy-1 alpha-cyclopentanyl] propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its gamma lactone (2.6% dose). 5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1 alpha- cyclopent-3-enyl]propanoic acid and (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1- propanoic acid. 6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11 alpha-hydroxy group in SC-36067 or its metabolites also occurred.

Deposition of viprostol (a synthetic PGE2 vasodilator) in the skin following topical administration to laboratory animals.

1. Topical application of 14C-viprostol, a synthetic prostaglandin E2 analogue, to laboratory animals resulted in a significant depot of radioactivity in the skin at the application site in all species studied: mouse, rat, guinea pig, rabbit and monkey, with longer residence times in the larger species. 2. The location of the 14C-label in the skin in mice and monkeys was determined by microscopic autoradiography. Evaluation of the autoradiograms show rapid penetration of the drug into the skin via the hair follicles. 3. In mouse distribution of radioactivity was evident in the stratum corneum and down the hair shafts by 30 min. after dosing. By 2 h radioactivity was also observed throughout the viable epidermis; in the dermis only the hair shafts contained significant radioactivity. At 72 h after dose removal, radioactivity was evident only in the hair follicles and hair shaft. 4. In monkey the residence time of radioactivity in the skin was significantly longer than in mouse, but the general distribution pattern was similar in both species. 5. The presence of viprostol in the hair follicles and epidermal layer after topical administration is consistent with its extensive skin metabolism previously reported.