Targeting therapeutics to bone by conjugation with bisphosphonates.

Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate conjugate prodrugs to deliver a wide variety of drug molecules selectively to bones. It is important that conjugates be stable in the blood stream and that conjugate that is not taken up by bone is eliminated rapidly. The prodrugs should release active drug at a rate appropriate so as to provide efficacy. Radiolabelling is the best method to quantify and evaluate pharmacokinetics, tissue distribution, bone uptake and release of the active drug(s). Recent reports have described bisphosphonate conjugates derived from the antiresorptive drug, alendronic acid and anabolic prostanoid drugs that effectively deliver prostaglandins and prostaglandin EP4 receptor agonists to bone and show enhanced anabolic efficacy and tolerability compared to the drugs alone. These conjugate drugs can be dosed infrequently (weekly or bimonthly) whereas the free drugs must be dosed daily.

Inducción mecánica del parto: doble balón o sonda de Cook® / Mechanical induction of labour: double balloon or Cook® catheter

Los procedimientos mecánicos para la maduración de un cérvix desfavorable se están configurando como una alternativa eficaz frente a los farmacológicos, especialmente en los casos donde estos están contraindicados. En la actualidad se despierta el interés sobre el uso de estos métodos por tratarse en general de dispositivos que generan bajo coste, son seguros, simples, cómodos, reversibles, sin fármacos y, fundamentalmente, por sus pocos efectos adversos y repercusiones maternas y/o fetales. Con el objetivo de dar a conocer dicho método mecánico de inducción de parto, se realizó el seguimiento de una mujer gestante con patología asmática y con indicación de finalización del embarazo mediante doble balón de Cook®; este concluye con un parto eutócico y sin incidencias

Mechanical procedures for ripening an unfavourable cervix are positioning as an effective option vs. pharmacological methods, particularly in those cases where the latter are contraindicated. There is current interest about the use of these methods, as these are overall low-cost devices, simple, convenient, reversible, drug-free, and most of all, they cause few adverse effects and low impact on the mother and/or the foetus. With the objective to create awareness about said mechanical method for labour induction, follow-up was conducted for a pregnant woman with asthma and indication of end of pregnancy through Cook® double balloon, resulting in a normal delivery without incidences

Imbalance of endogenous prostanoids in moderate-to-severe asthma.

BACKGROUND: Inhalation studies suggested "protective" roles of exogenous prostaglandin E2, but the clinical relevance of endogenous prostanoids in asthma is poorly known. The objective of this study is to measure sputum levels of prostanoids in asthmatic patients to correlate with clinical indices. METHODS: Mild (n = 41) or moderate-to-severe (19) asthmatics and 27 normal controls were examined for pulmonary function (FEV1 and mid-forced expiratory flow), sputum cell differentials, and sputum levels of prostaglandins D2, E2, F2α, and thromboxane B2 measured by sandwich enzyme immunoassay. RESULTS: Each prostanoid level did not differ among the three groups. Sputum number of bronchial epithelial cells was greater in moderate-to-severe asthmatics than in the other two groups, suggesting epithelial desquamation. Levels of prostaglandin F2α, D2, and thromboxane B2 positively correlated with the severity of airflow obstruction in the 60 asthmatic patients, whereas prostaglandin E2 levels were unrelated to pulmonary function. The ratio of combined "contractile" prostanoids (prostaglandin D2/prostaglandin F2α/thromboxane B2) to prostaglandin E2 was 2.5-fold greater in moderate-to-severe asthmatics than in controls (p = 0.001) or in mild asthmatics (p = 0.0002) but did not differ between the latter two groups. In the two asthmatic groups combined, this ratio positively correlated with the sputum number of epithelial cells. The combined "contractile" prostanoids levels positively correlated with prostaglandin E2 levels in controls and in mild asthmatics but not in moderate-to-severe asthmatics. CONCLUSIONS: An imbalance in production, breakdown, or both between prostaglandin E2 and other prostanoids possibly due to epithelial damage may be involved in the pathogenesis of moderate-to-severe asthma.

The intake of broccoli sprouts modulates the inflammatory and vascular prostanoids but not the oxidative stress-related isoprostanes in healthy humans.

Current evidence supports the positive association between the consumption of plant foods and health. In this work, we assessed the effect of consuming a half-serving (30 g) or one serving (60 g) of broccoli sprouts on the urinary concentrations of biomarkers of oxidative stress (isoprostanes) and inflammation (prostaglandins and thromboxanes). Twenty-four volunteers participated in the project. A quantitative determination of sulforaphane and its mercapturic derivatives, eicosanoids, and total vitamin C in urine was performed. The intake of broccoli sprouts produced an increase in the urinary concentrations of sulforaphane metabolites and vitamin C. Among the 13 eicosanoids analyzed, tetranor-PGEM and 11ß-PGF2α as well as 11-dehydro-TXB2 showed a significant decrease in their urinary concentrations after the ingestion of broccoli sprouts. Therefore, the consumption of broccoli sprouts modulated the excretion of biomarkers linked to inflammation and vascular reactions without exerting a significant influence on the oxidation of phospholipids in vivo.

Evaluation of the stability, bioavailability, and hypersensitivity of the omega-3 derived anti-leukemic prostaglandin: Δ(12)-prostaglandin J3.

Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, Δ(12)-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of Δ(12)-PGJ3. The stability of Δ(12)-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of Δ(12)-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. Δ(12)-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. Δ(12)-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that Δ(12)-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while Δ(12)-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared Δ(12)-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of Δ(12)-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. Δ(12)-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest Δ(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.

Aclaramiento lagrimal y sintomatología ocular en pacientes tratados con prostaglandinas sin conservantes / Tear clearance and ocular symptoms in patients treated with preservative-free prostaglandins

Objetivos: Evaluar el efecto en los síntomas de sequedad ocular y en la dinámica lagrimal que se produce al sustituir una prostaglandina con conservante por una prostaglandina sin conservante. Material y métodos: Estudio prospectivo no controlado en el que se seleccionaron 28 ojos de 14 pacientes con síntomas de ojo seco en tratamiento con latanoprost, travoprost o bimatoprost con conservante. Se evaluaron los síntomas oculares con un cuestionario validado de enfermedad de la superficie ocular y los signos mediante el test de aclaramiento lagrimal, el Schirmer y el índice de función lagrimal (TFI, TFI=Schirmer/aclaramiento). En todos los pacientes se cambió el tratamiento hipotensor a tafluprost sin conservante. Al mes, se repitieron los tests. En el análisis estadístico se utilizó el test de Wilcoxon y el coeficiente de correlación de Spearman. Resultados: No encontramos diferencias en la presión intraocular (PIO) al cambiar a tafluprost. La PIO inicial era 20,4mmHg (DE2,2) y la PIO al mes era 19,96mmHg (DE2,6) (p>0,05). La puntuación del cuestionario disminuyó de forma significativa desde 9,7 (DE3,7) hasta 5,4 (DE2,7) al mes del tratamiento (p<0,001). No encontramos diferencias significativas en el aclaramiento, en el Schirmer, ni en el TFI (p>0,05). Inicialmente, aclaramiento=0,13 (DE0,07), Schirmer=10,7mm (DE6) y TFI=80 (48-156). Al mes, aclaramiento=0,1 (DE0,07), Schirmer=9,5mm (DE3,9) y TFI=104 (48-216). Hemos encontrado una asociación significativa entre la puntuación del cuestionario y el aclaramiento al mes (coeficiente de correlación=0,62; p=0,014). Conclusiones: La sustitución de una prostaglandina con conservante por tafluprost sin conservante mejora los síntomas de sequedad ocular y sugiere una mejoría en el test de función lagrimal(AU)

Objectives: To assess the effects on dry eye symptoms and tear dynamics of switching from a prostaglandin with a preservative to a preservative-free prostaglandin. Material and methods: Fourteen patients (N=28 eyes) with open-angle glaucoma and dry eye symptons, treated with preserved latanoprost, travoprost or bimatoprost were included in this uncontrolled prospective study. Ocular symptoms were analysed using a validated ocular surface disease questionnaire and ocular signs were assessed with tear clearance, Schirmer and tear function index test (TFI=Schirmer/clearance). Patients were assigned to preservative-free tafluprost treatment, and measurements were repeated 4 weeks after change of medication. Wilcoxon test and Spearman correlation coefficient were used in the statistical analysis. Results: No statistically significant difference in intraocular pressure (IOP) was observed after switching to tafluprost. Mean IOP at baseline was 20.4mmHg (SD2.2) and after 4 weeks 19.9mmHg (SD2.6), (P>0.05). The mean questionnaire score significantly decreased from 9.7 (SD3.7) at baseline to 5.4 (SD2.7) after one month (P<0.001). No significant differences in tear clearance, Schirmer or TFI were found (P>0.05). At baseline, tear clearance=0.13 (SD0.07), Schirmer=10.7mm (SD6) and TFI=80 (48-156). After 4 weeks, tear clearance=0.1(SD0.07), Schirmer=9.5mm (3.9) and TFI=104 (48-216). A significant association between questionnaire score and tear clearance after 4 weeks was observed (Spearman coefficient=0.62; P=0.014). Conclusions: Switching from preservative prostaglandin with a preservative to preservative-free tafluprost treatment improves dry eye symptoms and suggests an improvement in TFI(AU)

Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists.

To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.

Inhibidores de la ciclooxigenasa-2 en la prevención del cáncer / COX-2 inhibitors in cancer prevention

La quimioprevención del cáncer es hoy en día una realidad. Se considera de uso clínico asistencial la prevención del cáncer de mama con tamoxifeno, del cáncer escamoso cutáneo con queratitis actínica mediante diclofenaco en gel y en poliposis familiar con el antiinflamatorio inhibidor de ciclooxigenasa-2 (COX-2) celecoxib. Este último, ha recibido una enorme atención por investigadores de cáncer por lo atractivo de su mecanismo de acción y sus posibilidades de uso clínico futuro en diversas neoplasias. Otros antiinflamatorios como ácido acetilsalicílico o sulindac también tienen un papel probado en quimioprevención del cáncer mediante la inhibición de ciclooxigenasas o de sustancias relacionadas. La revisión de los mecanismos por los que actúan estas sustancias nos da una clara idea de lo que es y lo que será la quimioprevención (AU)

Chemoprevention of cancer is a reality today. Prevention of breast cancer with tamoxifen, of squamous cell skin cancer with actinic keratosis by diclofenac gel and in familial polyposis with anti-inflammatory drug (COX-2) celecoxib is considered of health care clinical use. The latter has received enormous attention by cancer investigators due to the attractiveness of its action mechanism and its possibilities of future clinical use in different neoplasms. Other anti-inflammatory drugs such as aspirin and sulindac also have a proven role in chemoprevention of cancer by cycloosygenase inhibition or of related substances. The review of the mechanisms by which these substances act gives us a clear idea of what it is and what the chemoprevention will be (AU)

Propiedades del subcitrato de bismuto coloidal (SBC) en el tratamiento de desórdenes gastrointestinales / Properties of colloidal bismuth subcitrate (CBS) in the treatment of gastrointestinal disorders

Durante dos siglos las preparaciones de bismuto han sido útiles en una variedad de desórdenes gastrointestinales. Una renovada atención sobre la terapia con bismuto surgió cuando se demostró que los compuestos de bismuto son efectivos contra la infección por Helicobacter pylori. La necesidad de su erradicación total ha potenciado el uso del subcitrato de bismuto coloidal (SBC). En este sentido, parece actuar por varios mecanismos. El presente trabajo de revisión describe la farmacología del SBC en el tratamiento de descontroles gastrointestinales. El uso prolongado de compuestos de bismuto a dosis elevadas, que se produjo en el pasado, dio lugar a la aparición de efectos adversos serios. Los estudios sobre la administración oral de SBC sugieren que, utilizado en las dosis recomendadas, ha sido efectivo y seguro. No obstante, la posible toxicidad de las preparaciones de bismuto debe tenerse presente. En el presente trabajo se muestra una descripción de absorción, distribución, eliminación y toxicidad del SBC. Años atrás no había ningún estudio sistemático sobre las relaciones de estructura-actividad del SBC. Sin embargo, recientemente se ha producido un importante progreso en esta área. Así que, otro aspecto interesante de esta revisión es que resume, discute y describe las principales propiedades físicas, químicas y estructurales de SBC

Bismuth preparations have been useful in a variety of gastrointestinal disorders for two centuries. A renewed attention in bismuth therapy arose when it was shown that bismuth preparations are effective against Helicobacter pylori infection. The need for its total eradication has resulted in the use colloidal bismuth subcitrate (CBS). In this sense, it appears to act via several mechanisms. Present review describes CBS pharmacology in the treatment of gastrointestinal disorders. The prolonged use of high dose bismuth compounds in the past has shown some serious side effects. The studies on CBS oral administration suggests that, utilized in recommended dosages, it has been effective and safe. Nevertheless, the possible toxicity of bismuth preparations should be kept in mind. A description about CBS absorption, distribution, elimination and toxicity are shown in the present review. In the past, there had been no systematic study of the structure-activity relationships of CBS. Recently, however, there has been important progress in this area. So, another interesting aspect of this review is that summarizes, discusses and describes the main physical, chemical and structural properties of CBS

Mammary uptake and excretion of prostanoids in relation to mammary blood flow and milk yield during pregnancy-lactation and somatotropin treatment in dairy goats.

Mammary arterious-venous differences (A-V) and excretion into milk of four prostanoids were related to changes in milk yield and milk vein blood velocity (MBV) in goats at different stages of pregnancy and lactation, and during somatotropin (ST) treatment in mid-lactation. Arterial concentrations and mammary A-V for the vasodilators prostacyclin (PGI(2)) and prostaglandin (PG) E(2) (measured as 6-keto-PGF(1 alpha) and bicyclic PGE(2), respectively) decreased from late pregnancy to lactation. A-V were negatively correlated to MBV (r = -0.32 to -0.34). Arterial concentrations of the vasoconstrictors PGF(2 alpha) and TXA(2) (measured as TXB(2)) changed similarly, but no A-V across the mammary gland were found. The vasodilator to vasoconstrictor ratio in plasma was around 1:1, and in skimmed milk around 0.29-0.49 due to significantly higher TXB(2) levels in milk compared to plasma. Close linear correlations were established between milk yield and excretion of TXB(2) into milk (r = 0.80, P < 0.001), and between MBV and PGE(2) excretion into milk (r = 0.69, P < 0.001). ST treatment stimulated MBV and mammary prostanoid supply, and decreased prostanoid concentration in milk vein plasma. The high arterial levels of prostaglandins during pregnancy most likely reflected uterine synthesis. Our results support a role for PGI(2) and PGE(2) in local mammary blood flow regulation during lactation. Increased mammary uptake of these two prostanoids may be involved in the mammary blood flow response to ST. TXA(2) may be synthesized by mammary epithelial as well as vascular cells, and TXA(2) may be an important factor in regulation of mammary function.

Augmented heme oxygenase-1 induces prostaglandin uptake via the prostaglandin transporter in micro-vascular endothelial cells.

Previous studies show that expression of heme oxygenase-1 (HO-1) in endothelial cells results in decreased cyclooxygenase expression and prostaglandin (PG) levels through limiting heme availability. Regulation of PGs, important inflammatory mediators, may contribute to the anti-inflammatory potential of HO-1. Here we examine the effects of HO-1 expression on PG clearance via the prostaglandin transporter (PGT). Endothelial cells expressing human HO-1 via retroviral transfer exhibit approximately 7-fold higher levels of PGT RNA and equivalently elevated uptake of [(3)H]PGE(2). The pattern and extent of uptake and the substrate inhibitory constants of PGE(2), PGF(2alpha), and thromboxane B(2) are similar to those of cloned PGT. Treatment of cells with stannous chloride, an inducer of HO-1, results in increased expression of PGT while incubation of cells expressing human HO-1 with stannic mesophorphyrin, a substrate inhibitor of HO-1, decreases PG uptake. Therefore, PG clearance via PGT may contribute to the cellular regulation of PG levels by HO-1.

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.

Identification of lactate as a driving force for prostanoid transport by prostaglandin transporter PGT.

We previously characterized the prostaglandin (PG) transporter PGT as an exchanger in which [(3)H]PGE(2) influx is coupled to the efflux of a countersubstrate. Here, we cultured HeLa cells that stably expressed human PGT under conditions known to favor glycolysis (glucose as a carbon source) or oxidative phosphorylation (glutamine as a carbon source) and studied the effect on PGT-mediated [(3)H]PGE(2) influx. PGT-expressing cells grown in glutamine exhibited a 2- to 4-fold increase in [(3)H]PGE(2) influx compared with the antisense control, whereas cells grown in glucose exhibited a 14-fold increase. In the presence of 10 vs. 25 mM glucose during the uptake, there was a dose-dependent increment in [(3)H]PGE(2) influx. Cis inhibition of [(3)H]PGE(2) influx occurred with lactate at physiological concentrations (apparent K(m) = 48 +/- 12 mM). Preloading with lactate caused a dose-dependent trans stimulation of PGT-mediated [(3)H]PGE(2) uptake, and external lactate caused trans stimulation of PGT-mediated [(3)H]PGE(2) release. Together, these data are consistent with PGT-mediated PG-lactate exchange. Cells engaged in glycolysis would then be poised energetically for prostanoid uptake by means of PGT.

Prostaglandin analog treatment of glaucoma and ocular hypertension.

OBJECTIVE: To review available data related to the use of prostaglandin analogs (bimatoprost, latanoprost, travoprost, unoprostone) in the management of ocular hypertension and open-angle glaucoma. DATA SOURCES: Primary and review articles were identified from a MEDLINE search (1966-May 2001) and requested information from product manufacturers. STUDY SELECTION AND DATA EXTRACTION: All available information, including that published in articles and abstracts, which was deemed relevant was included in this review. Limited data have been published to date. DATA SYNTHESIS: The prostaglandin analogs appear to be effective, well-tolerated agents for the reduction of intraocular pressure (IOP) in patients with primary open-angle glaucoma and ocular hypertension. This drug class offers an alternative for patients who do not achieve control with another topical antiglaucoma agent or for those with a contraindication to first-line therapy with beta-adrenergic antagonists. Based on preliminary clinical data, bimatoprost, latanoprost, and travoprost appear to be at least as effective as timolol, while the effectiveness of unoprostone is similar or slightly less. Prostaglandin analogs may be used in conjunction with other antiglaucoma medications, although further studies must establish the optimal combination. Whether clinical experience will yield outcomes in favor of one of the prostaglandin analogs remains to be determined. Patients should be educated on adverse events associated with prostaglandin analogs, particularly the potential for changes in the pigmentation of the iris and eyelashes. CONCLUSIONS: Bimatoprost, latanoprost, and travoprost appear to be equivalent to the current standard of therapy in the topical treatment of elevated IOP. Further clinical data published in article versus abstract format is required to better assess potential differences among these 3 agents.

[Pharmacodynamics and pharmacokinetics of prostaglandins and their derivates in eye tissues]. / Farmakokinetyka i farmakodynamika prostaglandyn i ich pochodnych w tkankach oka.

This paper presents the classification of prostaglandins and their receptors. The ocular distribution of the receptors and the effects of their agonists are presented. The efficacy in lowering intraocular pressure of different prostaglandins and their derivatives, especially the PGF2a group, is discussed. The history of latanoprost development is also presented. Good therapeutic index characterises two antiglaucomatous PG-derivatives: latanoprost and unoprostone.

Structural determinants of substrates for the prostaglandin transporter PGT.

We recently identified a broadly expressed transporter, PGT, that transports primarily prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha). In the current study, we examined the structural determinants of potential PGT substrates in detail. Rat PGT was transiently expressed in HeLa cells, the timed uptake of tracer PGE2 was determined in the presence of various concentrations of unlabeled prostanoids; and the resulting inhibitory constants (Ki) were determined by curve-fitting. PGE2 and PGF2 alpha, both known to be transported, had similar affinities for PGT (Ki = 49-50 nM). The strongest interaction (Ki = 13-19 nM) was obtained with prostanoids lacking the 9- or 11-position oxygen groups. A relatively high affinity was also obtained for the bicycloendoperoxides U44069, PGH2, and U46619 (Ki = 29-39 nM). However, a radioactive representative from this group, U46619, was not transported. Structural modifications that produced a moderately reduced affinity relative to that of PGE2 (Ki = 56-286 nM) included reduction in C5 = C6, the addition of a benzene group at position C18, and isomerization at the C8 position. In complementary studies, tracer isoprostane B-iso-PGF2 alpha was found to be transported at approximately 13% the rate of tracer PGE2. Substantially weaker interaction (Ki = > 700 nM) was seen when the 1-position COO- anionic group was neutralized or when the 15(S)-OH group was changed to 15(R)-OH or to 15-keto. These results with the cloned rat PGT are very similar to those previously reported in the in vitro perfused rat lung and indicate that PGT probably represents the predominant route by which certain prostanoids, including F2 isoprostanes, are transported across plasma membranes.

Mucociliary function in patients with nasal polyps.

Patients with nasal polyposis complain of nasal blockage and rhinorrhoea, which may be due to impaired mucociliary clearance. The saccharine clearance time and ciliary beat frequency of samples of ciliated epithelium from patients with nasal polyps was measured. We also studied the effect of fluid from the oedematous stroma of nasal polyps and of histamine and prostaglandin (PG) D2, E2 and F2 alpha on the cilia from normal individuals. Polyp fluid was found to increase ciliary beat frequency. Histamine and PGD2 had no effect, but PGE2 and PGF2 alpha both increased ciliary beat frequency and so may cause the ciliostimulatory effect of polyp fluid. The saccharine clearance time was prolonged in three of nine patients, but ciliary beat frequency was only slightly reduced in one of these. Thus, where mucociliary clearance is reduced, it is likely to be due to abnormalities of mucus rather than impaired ciliary activity.

Dose-related effect of IGF-I on placental prostanoid release.

Prostanoids play an important role throughout all of pregnancy and during the initiation and progress of labor. The human placenta at term produces large quantities of prostanoids, yet little is known of the factors regulating their biosynthesis. In a previous study we observed that insulin-like growth factor I (IGF-I) specifically inhibits thromboxane B2 (TxB2) and prostaglandin F2 alpha (PGF2 alpha) from human term placental explants. In these studies we have defined the dose-related action of IGF-I on the release of placental prostanoids. With use of a perifusion system, the basal release of prostaglandin E2 (PGE2), PGF2 alpha, TxB2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) from human term placental explants increased from the fifth hour in culture, while the release of 13,14-dihydro-15-keto-PGF2 alpha (PGFM) remained constant. The addition of IGF-I (5.2-83.3 ng/mL) to the perifusing medium effected an inhibition of TxB2 and PGF2 alpha. The release of TxB2 was inhibited in a dose-related fashion from the initiation of IGF-I treatment and throughout the five hours of treatment, whereas the inhibition of PGF2 alpha was significant only at a dose of 83.3 ng/mL of IGF-I. Yet, the release of 6-keto-PGF1 alpha, PGE2, or PGFM was not altered by any dose of IGF-I studied. Because both TxB2 and PGF2 alpha are vasoconstrictors, we have proposed that IGF-I may enhance vasodilation in the placenta. Therefore, IGF-I may allow for increased blood flow, thus affecting the maintenance of pregnancy and the supply of nutrients available for the growth of the fetus.

Ocular absorption, distribution, and systemic absorption of a novel antiglaucoma medication, prostaglandin derivative, in male white rabbits.

A prostaglandin derivative, (5Z,9 alpha,11 alpha,13E)-9,11-dihydroxyprosta- 5,13-dienoic acid sodium salt (S-1033), that lowers intraocular pressure with little adverse effect, may have clinical value in the treatment of glaucoma. After [14C]S-1033 (0.2% solution) was instilled into the eye of a white rabbit, radioactivity and S-1033 appeared in systemic plasma so rapidly (tmax, 5 min) and S-1033 was eliminated very rapidly with half-lives of 2.8 and 11.0 min at alpha- and beta-phases, respectively. The metabolite, M-1, [1R-[1 alpha,2 beta-(1E),3 alpha,5 alpha]]-3,5-dihydroxy-2-(1- octenyl)-cyclopentanepropanoic acid (tetranor-S-1033), appeared in plasma very rapidly (tmax, 5 min), suggesting that a fast metabolism was a major factor in the rapid elimination of S-1033 from plasma. The values for the ratios of the area under the curve of ocular instillation to intravenous administration for radioactivity and S-1033 were 1.01 and 0.52, respectively, indicating that more than half of the S-1033 instilled was transported into the systemic circulation. To clarify the contributing pathway of the massive and rapid systemic absorption of S-1033 after topical dosing, plasma levels of S-1033 were investigated after instillation to rabbits in which the nasolacrimal ducts were occluded. Plasma concentrations of S-1033 were slightly higher than those in intact rabbits, suggesting that conjunctiva would be as important as nasal mucosae for the systemic absorption under the physiological condition. As for the intraocular distribution, the highest levels of radioactivity were found in the cornea, conjunctiva, and anterior sclera.(ABSTRACT TRUNCATED AT 250 WORDS)