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Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E1 (PGE1) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic reaction. Prostanit pharmacokinetics, however, remains poorly investigated. Thus, the object of this study was to investigate the pharmacokinetics of Prostanit-related and -affected metabolites in rabbit plasma using the liquid chromatography-mass spectrometry (LC-MS) approach. Besides, NO generation from Prostanit in isolated rat aorta and human smooth muscle cells was studied using the Griess method. In plasma, Prostanit was rapidly metabolized to 1,3-dinitroglycerol (1,3-DNG), PGE1, and 13,14-dihydro-15-keto-PGE1. Simultaneously, the constant growth of amino acid (proline, 4-hydroxyproline, alanine, phenylalanine, etc.), steroid (androsterone and corticosterone), and purine (adenosine, adenosine-5 monophosphate, and guanosine) levels was observed. Glycine, aspartate, cortisol, and testosterone levels were decreased. Ex vivo Prostanit induced both NO synthase-dependent and -independent NO generation. The observed pharmacokinetic properties suggested some novel beneficial activities (i.e., effect prolongation and anti-inflammation). These properties may provide a basis for future research of the effectiveness and safety of Prostanit, as well as for its characterization from a clinical perspective.

Retention and migration of a specially designed alprostadil transdermal cream was assessed after single-dose administration to the glans meatus of the penis. Seven men were enrolled in this two-way crossover study. Three subjects self-administered the radio-labeled alprostadil transdermal cream (∼100 mg of cream containing 300 μg alprostadil) by inserting the tip of the dispenser into the meatus. In three others, the dose was administered by dispensing the cream dropwise into the metal opening without touching the penis (the preferred and directed method). Retention and migration of the cream mass was measured in the penis with a gamma scintillation camera. The alprostadil transdermal cream was retained in the fossa navicularis at or near 99% in five of six subjects regardless of the method of dosing, thus indicating that the cream formulation performed as designed. A mild, transient burning sensation in the penis was the most common adverse event.

Background and Objectives Limaprost, a prostaglandin E1 analogue, is used to treat various symptoms in patients with ischemic diseases. The present study was designed to determine the pharmacokinetics and tolerability of single and multiple oral doses of limaprost 5 μg tablets in healthy Chinese subjects. Methods Single and multiple doses of 5-μg limaprost were orally administered to 12 healthy Chinese subjects. There was a 2-week washout period between single and multiple dosing. Blood samples were collected at various times. Indomethacin and aspirin were added to the blood samples to inhibit the endogenous release of prostaglandins during the sample processing. Plasma limaprost was measured by a two-dimensional liquid chromatography-tandem mass spectrometry method. Results After single dosing, limaprost was rapidly absorbed (time to reach maximum plasma concentration [ t max ] = 22.50 min) and eliminated (elimination half-life [ t ½ ] = 21.70 min), with the maximum plasma concentration ( C max ) being 2.56 pg/mL and area under the concentration-time curve (AUC) from time 0 to the last quantifiable time point (AUC 0–t ) being 70.68 pg·min/mL. There were significant inter-individual variations in the AUCs for both single- and multiple-dose regimens. The values of C max , AUC , t ½ and t max were not statistically different between single and multiple dosing. The accumulation factor R was 0.609 ± 0.432 ( R  < 1), indicating that there was no accumulation after multiple dosing. There were no statistically significant differences in pharmacokinetic parameters for both single and multiple dosing between female and male subjects. The drug was well tolerated, with no severe adverse events being observed. Conclusions Limaprost is rapidly absorbed after oral administration and is rapidly eliminated, with no accumulation after multiple dosing. The drug is well tolerated and no serious adverse events occurred.

Prostaglandins have potent and diverse biologic activities, but their clinical application is severely restricted, mainly due to rapid inactivation in vivo. In order to modulate the pharmacokinetics of prostaglandin E(1) (PGE(1)), we prepared biodegradable nanoparticles as a drug carrier. Nanoparticles encapsulating PGE(1) were prepared from a blend of poly(lactic acid) homopolymer and poly(ethylene glycol)-poly(lactide) block copolymer by the solvent diffusion method in the presence of iron. PGE(1) was efficiently and stably embedded in the nanoparticles through interaction with iron, despite being relatively hydrophilic and having unstable chemical properties. Depending on the isomers and molecular weight of poly(lactic acid) selected, PGE(1) was gradually released from the nanoparticles at various rates into diluted serum in vitro. Both stable retention of PGE(1) in the nanoparticles and coating of the nanoparticles with poly(ethylene glycol) led to an extremely extended blood residence time of PGE(1), as well as preferential accumulation in vascular lesions. These results suggest that the present strategy is useful to advance the clinical application of PGE(1) as a therapeutic agent for vascular disorders.

Chronic constipation is a common and costly health problem occurring in ∼4.5 million Americans. Current management of constipation is suboptimal and requires a stepwise approach using a combination of laxatives to decrease symptoms. The objective of this review was to describe the efficacy and safety of a new therapeutic entity, lubiprostone, recently approved by the US Food and Drug Administration for the treatment of chronic idiopathic constipation. Computerized searches of MEDLINE and International Pharmaceutical Abstracts were conducted (1966–July 10, 2006). Search terms utilized were lubiprostone, RU-0211, and chronic constipation. References of selected articles were searched for additional articles or abstracts. All relevant published literature regarding lubiprostone was included in this review. Pertinent abstracts presented at meetings of the American College of Gastroenterology and Digestive Diseases Week were also included. Lubiprostone activates a chloride channel (ie, subtype 2) and increases chloride and fluid secretion into the intestines, resulting in relief of constipation. It is poorly absorbed after oral administration, and its metabolism occurs primarily in the stomach and jejunum. Lubiprostone was evaluated in 6 placebo-controlled, double-blind, randomized Phase II or III clinical trials. Overall, in clinical trials, >1400 patients were exposed to 24 μg of lubiprostone BID for up to 48 weeks. It improved the number of bowel movements, stool consistency, bloating, and global assessment of constipation compared with placebo ( P < 0.05). Nausea was the most common adverse effect reported in clinical trials, occurring in 30.9% of patients. However, nausea was dose dependent and decreased when lubiprostone was given with food. Lubiprostone is the first in its class of chloride channel activators that results in improvement of symptoms of constipation. It has not been compared with other laxatives but, based on the available placebo-controlled studies, its efficacy is superior to placebo and its safety is acceptable. Considering the currently available laxatives, lubiprostone will become an additional option for the treatment of patients with chronic constipation.

Limaprost, a prostaglandin E1 analogue, with a strong vasodilatory and antiplatelet activity has been used to release from the symptoms of thromboangiitis obliterans (TAO), which is more prevalent in Korea and Japan, and lumbar spinal canal stenosis (LSCS). In spite of many uses of limaprost, the pharmacokinetics (PK) of it has not been studied in the Korean population. Therefore, a preliminary PK study was designed at a clinical oral dosage of 30-μg limaprost in 5 healthy Korean volunteers. Blood samples were obtained at 14 consecutive time points for 12 hours after dosing and analyzed by liquid chromatography—tandem mass spectrometry with electrospray ionization (LC-ESI/MS/ MS) at a very low detection limit of 0.5 pg/mL of limaprost in human plasma with considerably short run time (18 minutes). Pharmacokinetic characteristics resulted in ‘‘time for maximal concentrations (Tmax 0.5 hour),’’ ‘‘elimination half-life (T1/2 1.64 hours),’’ ‘‘maximal concentration (Cmax 13.37 pg/mL),’’ ‘‘area under the curve (AUC12 hours 18.60 pg · h/mL),’’ ‘‘AUC extrapolated to infinity (AUCinfinity 22.98 pg · h/mL),’’ ‘‘extrapolation (AUCinfinity — 12 hours/AUCinfinity 0.15%),’’ ‘‘elimination rate constant (ke 0.68 h—1),’’ ‘‘systemic clearance (CL 1.77 L/h),’’ and ‘‘mean residence time (MRT 1.74 hours).’’ These results showed that orally administered 30-μg limaprost was rapidly and highly absorbed, and it was considerably eliminated fast from the blood stream in the healthy Korean volunteers.

Fifteen patients who arrived between 6 and 24 hours after the onset of acute myocardial infarction and who were found to have totally occluded coronary arteries, received aspirin, heparin, and tissue plasminogen activator given over 3 hours. Eight patients were randomly assigned to receive intravenous prostaglandin E1, 20 ng/kg/min for 6 hours, while seven patients received placebo infusion. Coronary arteriography begun immediately before the start of tissue plasminogen activator and repeated every 15 minutes revealed restoration of antegrade flow in two of eight (25%) patients treated with prostaglandin E1 and in two of seven (28%) patients receiving placebo. Pharmacologic sampling of tissue plasminogen activator levels were performed at baseline and 30, 45, 60, 75, 90, 135, 180, 190, 210, and 240 minutes afterwards for assessment of tissue plasminogen activator antigen. There was no difference in fibrinogen levels and no difference in tissue plasminogen activator antigen levels at these time periods. Clearance values of tissue plasminogen activator were calculated and were not different between the two groups. These data do not support the use of prostaglandin E1 for the acceleration of reperfusion in patients receiving tissue plasminogen activator for acute myocardial infarction.

Lubiprostone, a locally acting highly selective type-2 chloride channel activator, has been US FDA approved since January 2006 for the treatment of adults with chronic idiopathic constipation and FDA approved since April 2008 for the treatment of woman aged 18 years or older suffering from irritable bowel syndrome (IBS) with constipation. Through activation of the type-2 chloride channels located on the luminal side of intestinal epithelial cells, it promotes fluid secretion, increasing the liquid content of stool and accelerating small bowel as well as colonic transit. Lubiprostone has demonstrated efficacy with respect to increasing weekly spontaneous bowel movements and improving stool consistency, straining and constipation severity, both in short- and long-term studies. It has also demonstrated efficacy in the treatment of IBS with constipation, with beneficial effects on global symptoms, abdominal pain, constipation-related symptoms and overall quality of life. There is no evidence of a rebound in constipation or IBS symptoms following cessation of lubiprostone. In general, lubiprostone is well tolerated, with the most common side effects including nausea, headache and diarrhea.

Intraurethral application of prostaglandin-E1 (MUSE™) is a well-tolerated pharmacotherapy for erectile dysfunction. However, the physiological mechanisms of drug transfer into the cavernous bodies are not completely clear. Using spongiosography in 35 patients, our study tried to elucidate existing shunt mechanisms. The X-rays show venous drainage through the deep dorsal vein up to the plexus Santorini. The circumflex veins are also contrasted and the cavernous bodies show opacification in their distal portion only. Structures shunting directly between the corpus spongiosum and the cavernous bodies were not demonstrable. Retrograde filling of the cavernous bodies through the deep dorsal vein and its circumflex braches seems to be the most relevant way of drug transfer after intraurethral application of prostaglandin-E1. Diffusion into the cavernous bodies or a systemic mechanism of action does not seem probable.

The therapeutic response to PGE1 is highly variable, and a contribution by variable formation of its active tertiary metabolite PGE0 is in question. Hence, the objective of this study was to assess the person-to-person variation of the reduction of the inactive intermediate metabolite 15-KD PGE1 by human liver and human erythrocytes in forming the active metabolite PGE0. Source of enzyme was lysed erythrocytes from 29 donors, and a bank of 37 donor livers including specimens from 15 children. Tritium-labelled 13,14-dihydro-15-keto-prostaglandin E1 (15-KD PGE1) was used at low nanomolar concentrations and found to be converted almost exclusively to the more polar compound 13,14-dihydro-prostaglandin E1 (PGE0) by an NADPH-dependent carbonyl reductase. The identity of the product PGE0 was established by comparison of its chromatographic and mass spectral characteristics with authentic PGE0. Lysed erythrocytes had readily measurable enzymatic activity; differences between the preparations from 29 subjects were very small with only a twofold range of variation. In contrast to lysed erythrocytes, intact erythrocytes did not catalyse the reaction so that the erythrocyte activity should be medically immaterial. 15-KD PGE1 15-ketoreductase activity of liver cytosol averaged 61.1 fmol.min-1.mg-1 protein in preparations from 37 human livers. Individual activities varied over an almost tenfold range, with indications of a non-normal distribution. Kinetic studies of selected specimens showed substantially different Vmax values but indistinguishable kM values, suggesting that the individual variation in 15-KD PGE1 15-ketoreduction is the result of differences in enzyme concentration rather than of structural enzyme variations. The activity in 15 livers from children was significantly lower than in those from adults. Inhibition data suggest that both the liver and the erythrocyte enzymes belong to the class of carbonyl reductases. The variations in hepatic enzyme activity may be expected to affect the transformation of 15-KD PGE1 to the active metabolite PGE0 in vivo. The clinical significance remains to be explored.