Central effects of prostaglandin E1 in adult fowls

(1) Adult fowls (Callus domesticus) with cannulae chronically implanted into the 3rd cerebral ventricle and various other sites of the brain received infusions or injections of prostaglandin E₁ (PGE₁). The effects of this drug on behaviour, electrocortical activity and body temperature were studied.(2) PGE₁ given into the 3rd cerebral ventricle and into the hypothalamus produced sedation and/or sleep and increased body temperature.(3) Behavioural, electrocortical and body temperature changes were dose-dependent. The doses required to elicit hyperthermia were smaller than those affecting behaviour and electrocortical activity.(4) Infusion of PGE₁ into other cerebral areas, e.g. paleostriatum augmentatum, telencephalon and mesencephalon lacked effects on behaviour, electrocortical activity and body temperature.(5) The site through which behavioural, electrocortical and body temperature effects of PGE₁ were mediated appears to be the hypothalamus.     

Cardiac and microcirculatory effects of different doses of prostaglandin E1 in man

Summary A cumulative dose response to intravenous PGE₁ was established in 12 healthy volunteers. Systolic time intervals, including pre-ejection period (PEP), the ventricular ejection time (VET) and the RR-interval, were continuously determined, and transcutaneous oxygen pressure (tcpO₂) was recorded.RR-intervals fell in a dose dependent manner, reaching a significantly lower level at 128 ng·kg^–1·min^–1 of PGE₁ (basal value 842 ms falling to 756 ms). PEP decreased from 89 ms to 74 ms and the ratio PEP/VET decreased from 35% to 30%, indicating increased myocardial contractility. The maximal increase in tcpO₂ was 125% on the calf and 60% on the foot. The peak tcpO₂ was observed at an infusion rate of 16 ng·kg^–1·min^–1 PGE₁. A decline in tcpO₂ was seen at infusion rates >64 ng·kg^–1·min^–1 PGE₁, indicating a decrease in skin perfusion.The results indicate that the effects of intravenous PGE₁ on skin perfusion occur at a lower threshold than the increase in myocardial contractility. A maximal increase in skin perfusion can be achieved with doses of PGE₁ devoid of systemic haemodynamic effects.     

Prostaglandin E1 and noradrenaline at the neuromuscular junction

The effects of prostaglandin E₁ (PGE₁) on neuromuscular transmission in the frog nerve-sartorius muscle preparation were studied with intracellular recording techniques. PGE₁ was inactive in all concentrations examined; both spontaneous miniature end-plate potentials and evoked end-plate potentials were unchanged after preparations were bathed in up to 2·2×10^-5M (8 μg/ml) PGE₁. PGE₁ did not prevent the increase in end-plate potential amplitude which frequently occurred on addition of noradrenaline to the bathing solution.     

Acetylcholine release from the myenteric plexus of guinea-pig ileum by prostaglandin E1

Release of acetylcholine (ACh) by prostaglandin E₁ from the nerve terminals of the guinea-pig longitudinal muscle strip was studied in order to reveal the effect of PGE₁ on myenteric plexus activity. The ACh released was collected in the presence of physostigmine (2·1 μg ml^?1) and choline (0·1 μg ml^?1) at 38° C. Five to 100 ng ml^?1 PGE₁ enhanced the release dose-dependently. The effect was maintained during the presence of PGE₁ in the organ bath, while rapid tachyphylaxis was observed with the ACh-releasing action of nicotine. Tetrodotoxin or morphine almost completely inhibited the effect of PGE₁ on ACh release. Hexamethonium, in a concentration which completely blocked the effect of nicotine, partially inhibited the effect of PGE₁. In the late phase of nicotine action, the tissue was still sensitive to PGE₁ despite the continued exposure to nicotine. These data suggest the presence in the myenteric plexus of PG receptors which can increase ACh release.     

Elimination from the circulation of cats of 6-keto-prostaglandin E1 compared with prostaglandins E2 and I2

6-keto-PGE₁, when injected intravenously (i.v.) or into the aortic arch of cats, produced similar dose-dependent decreases in mean arterial blood pressure. The hypotensive effect of PGI₂ was slightly less pronounced compared with that of 6-keto-PGE₁, but was equally potent after i.v. and intra-arterial administration. PGE₂ had a more potent depressor effect than the two other compounds when injected into the aortic arch, but was much less effective after i.v. injection. Plasma concentrations of 6-keto-PGE₁, 6-keto-PGF_1α and PGE₂ were measured by radioimmunoassay after bolus injections of 6-keto-PGE₁, PGI₂ and PGE₂. The half-life (t 1/2) of the initial rapid decrease in immunoreactivity, indicating the rate of elimination, was found to be 1˙04-2˙19 min for 6-keto-PGE₁, 1˙16-2˙01 min for PGI₂ and 0˙29-1˙08 min for PGE₂. We have confirmed in the cat that 6-keto-PGE₁, like PGI₂ but unlike PGE₂, is not substantially inactivated by the lungs and thus could act as a circulating hormone. However, despite its higher chemical stability, the t 1/2 of 6-keto-PGE₁ in the circulation is similar to that of PGI₂. PGE₂ has a shorter t 1/2, probably due to its extensive pulmonary inactivation. Thus 6-keto-PGE₁ seems to be removed from circulation as quickly as PGI₂ by organs other than the lung and is unlikely to mediate prolonged effects of PGI₂ in the systemic circulation.     

Effect of intracisternal administration of prostaglandin E1 on waking and sleep in the rat.

Intracisternal injection of 50 μg/kg prostaglanclin E₁ (PGE₁) to rats was followed by a marked decrease of the paradoxical phase of sleep in the second and third hour after prostaglandin injection. The administration of 6-hydroxydopamine, which lowered the total level of noradrenaline to 40% and dopamine to 50% of control value, decreased the total time the animals spent in paradoxical sleep by 50%. The injection of PGE₁ to 6-hydroxydopamine-treated rats further decreased the time that animals spent in paradoxical sleep. However, the total time of paradoxical sleep in intact and 6-hydroxydopamine-treated animals injected with PGE was about equal i.e. 10–15% of control values.     

Effect of prostaglandin E1 and its biosynthesis inhibitor indomethacin on drinking in the rat

In the rat, injection of prostaglandin E₁ (PGE₁)0.5, 1.0 or 2.0 μg into the 3rd brain ventricle (3rd b.v.) inhibited the water deprivation-induced water intake in a dose-related fashion. The 1.0 μg dose of PGE₁ also inhibited the intake of 1.8% sodium chloride in rats depleted of body sodium by intraperitoneal dialysis, and of food in food deprived rats during a 60 min test period. Prostaglandin E₁ (1 μg) depressed the dipsogenic effect of angiotensin II (AII) or carbachol injected through the same cannula. Water-deprived rats pretreated with the PG synthetase inhibitor indomethacin, in two different doses, showed enhanced water intake. The pretreatment with indomethacin also enhanced the dipsogenic effect of various doses of AII injected into the 3rd b.v. The antagonistic action of PGE₁ on water-deprivation, or AII-induced water intake, and the enhancement of water intake after blocking PGs synthesis, suggests the involvement of PG in the regulation of thirst.     

Protection of the ischemic myocardium from reperfusion injury by prostaglandin E1 inhibition of ischemia-induced neutrophil activation

Summary This study investigates the action of intravenous PGE₁ on myocardial reperfusion injury and the possible involvement of antineutrophil activities. Cats were subjected to 3 h of temporary ligation of the left anterior descending coronary artery, followed by 2 h of reperfusion. Animals were treated with PGE₁ (5 g/kg x min) or vehicle (saline solution), starting 0.5 h after coronary artery occlusion. Vehicle-treated cats exhibited a significant loss of cardiac creatine phosphokinase specific activity at 5 h, accompanied by a significant ischemia-induced rise in the ST segment of the ECG and development of a Q wave after starting reperfusion. All of these alterations were largely prevented by PGE₁ treatment. PGE₁ exerted some blood-pressurelowering activity at 5 h (P > 0.05) but did not reduce myocardial contractile force and oxygen consumption. PGE₁ modestly antagonized ischemia-induced formation of platelet aggregates. However, PGE₁ prevented the rise in peripheral white blood cell count during ischemia and reperfusion and inhibited the generation of reactive oxygen species (myeloperoxidase assay) from zymosan-stimulated whole blood ex vivo. The ratio of generation of reactive oxygen species/white blood count remained unchanged. It is concluded that PGE₁ protects the ischemic myocardium from acute reperfusion injury and that this effect involves an action of the compound on neutrophils, probably by improved myocardial tissue preservation, resulting in reduced formation of chemotactic products and, consequently, less local neutrophil accumulation and release of noxious metabolites.Parts of these results have been presented to the 29th Spring meeting of the Deutsche Gesellschaft für Pharmakologie und Toxikologie, Mainz, 1988 Send offprint requests to K. Schrör at the above address     

Effect of piperine on CYP2E1 enzyme activity of chlorzoxazone in healthy volunteers

1.?The purpose of the present study was to investigate the effect of piperine (PIP) on CYP2E1 enzyme activity and pharmacokinetics of chlorzoxazone (CHZ) in healthy volunteers.

2.?An open-label, two period, sequential study was conducted in 12 healthy volunteers. A single dose of PIP 20?mg was administered daily for 10 days during treatment phase. A single dose of CHZ 250?mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected at predetermined time intervals after CHZ dosing and analyzed by HPLC.

3.?Treatment with PIP significantly enhanced maximum plasma concentration (C_max) (3.14–4.96?μg/mL)_, area under the curve (AUC) (10.46–17.78?μg h/mL), half life (T_1/2) (1.26–1.82?h) and significantly decreased elimination rate constant (K_el) (0.57–0.41?h?^??¹), apparent oral clearance (CL/F) (24.76–13.65?L/h) of CHZ when compared to control. In addition, treatment with PIP significantly decreased C_max (0.22–0.15?μg/mL), AUC (0.94–0.68?μg h/mL), T_1/2 (2.54–1.68?h) and significantly increased K_el (0.32–0.43?h?^??¹) of 6-hydroxychlorzoxazone (6-OHCHZ) as compared to control. Furthermore, treatment with PIP significantly decreased metabolite to parent (6-OHCHZ/CHZ) ratios of C_max, AUC, T_1/2 and significantly increased K_el ratio of 6-OHCHZ/CHZ, which indicate the decreased formation of CHZ to 6-OHCHZ.

4.?The results suggest that altered pharmacokinetics of CHZ might be attributed to PIP mediated inhibition of CYP2E1 enzyme, which indicate significant pharmacokinetic interaction present between PIP and CHZ. The inhibition of CYP2E1 by PIP may represent a novel therapeutic benefit for minimizing ethanol induced CYP2E1 enzyme activity and results in reduced hepatotoxicity of ethanol.     

Synthesis and biodistribution study of liver-specific prostaglandin E1 polymeric conjugate

We synthesized a polymeric prodrug of prostaglandin E₁, (PGE₁) using galactosylated poly-(l-glutamic acid) (Gal-PLGA) as a biodegradable and targetable carrier to the liver parenchymal cells. PLGA was reacted with ethylenediamine followed by coupling with 2-imino-2-methoxyethyl-1-thiogalactosides to obtain Gal-PLGA. PGE₁ was activated with N,N′-carbonyldiimidazole (CDI) then the PGE₁ ester obtained was attached to Gal-PLGA. After intravenous injection in mice at a dose of 1 mg/kg PGE₁ conjugates with Gal-PLGA (PGE₁-PLGA-Gal) labeled with [¹¹¹In] or [³H]PGE₁ rapidly accumulated in the liver up to 65 and 50% of the dose respectively. The hepatic uptake of [¹¹¹In]PGE₁-PLGA-Gal was remarkably inhibited by the co-administration of Gal-BSA indicating that the PGE₁ conjugates were taken up by the liver via the asialoglycoprotein receptor-mediated endocytosis. These findings suggest that PGE₁ can be effectively targeted to the liver parenchymal cells by covalently conjugating with Gal-PLGA.     

Effect of prostaglandin E1 on ouabain-induced arrhythmia

Prostaglandin E₁ (PGE₁) was infused i.v. to a total dose of 50 μg/kg to cats anesthetized with pentobarbital. PGE₁ increased significantly the dose of ouabain necessary to produce premature ventricular complexes, ventricular tachycardia and death. All of the animals in both the control and PGE₁-treated group died in ventricular fibrillation. PGE₁ did not produce any significant change in blood pressure or heart rate nor did it affect the cardiac slowing prior to ventricular tachycardia produced by ouabain. In addition, the maximum rate of ventricular tachycardia produced by ouabain was not different in either the control or PGE₁-treated animals.     

Time-dependent stimulatory and inhibitory effects of prostaglandin E1 on exudative and tissue components of granulomatous inflammation in rats

1 The effects of prostaglandin (PGE₁), following local administration during different phases of developing sponge-induced granulomata, were studied in normal and essential fatty acid deficient (EFAD) rats.

2 In normal rats, a single dose of 1 μg PGE₁ on implantation (day 1) increased exudate production without altering total leucocyte counts after 6 h and stimulated granulomatous tissue formation after 8 days.

3 Repeated daily administration of the same dose of PGE₁ on days 1 to 3 had no effect, while administration on days 4 to 7 (i.e. when tissue growth is already in progress) inhibited granuloma formation.

4 In EFAD rats, which are known to produce only very small amounts of endogenous prostaglandins, acute (6 h) exudate formation was unaffected by 0.05 μg PGE₁. However, early stimulatory and later inhibitory effects of 0.05 μg PGE₁ per day were obtained on the granulomatous tissue, similar to those obtained with the 20 fold higher dose in normal rats.

5 The early stimulatory action of PGE₁ on granulomatous tissue formation was enhanced, in normal rats, by concomitant administration of 10 μg theophylline. This latter compound did not influence the later inhibitory effect of PGE₁.

6 These results indicate that PGE₁ exerts either pro- or anti-inflammatory actions on the proliferative (tissue) component of the inflammatory process, depending on the time of administration. While the stimulatory effect following early administration may have been secondary to an initial cyclic adenosine 3′,5′-monophosphate-mediated, vascular response, such a mechanism is unlikely to have been responsible for the later anti-inflammatory action of PGE₁.

7 The implications of these results are discussed in relation to the postulated negative-feedback role of endogenous PGE in chronic inflammation.

     

The antidipsogenic action of peripheral prostaglandin E2

Intraperitoneal (IP) injection of 50 μg/kg prostaglandin E₂ (PGE₂) suppresses water intake elicited by cellular dehydration, intracerebroventricular injection of angiotensin II (A II) and, for a shorter duration, water deprivation. At a dose of 100 μg/kg, IP PGE₂ reduces drinking to all of these stimuli as well as to hypovolemia. A 10 μg/kg dose of PGE₂ has not effect on drinking under any of the conditions tested. Intraperitoneal PGE₂, at either 50 or 100 μg/kg, does not support the formation of a conditioned taste aversion suggesting that PGE may act via specific inhibition of drinking rather than by producing a generalized malaise. Although both central and peripheral administration of PGE suppresses water intake, the findings that peripheral PGE₂ reduces drinking to cellular dehydration but has minimal effects on drinking due to hypovolemia are in marked contrast to the actions reported for intracranial PGE. In addition, peripheral PGE₂ reduces body temperature whereas centrally applied PGE induces thermogenesis. These data may indicate differential roles and/or mechanisms by which central and peripheral PGE may control water intake.     

Prostaglandin E1 decreases human arterial accumulation of radiolabeled apo B-containing lipoproteins in vivo

Objective: An increased apo B-containing lipoprotein influx and cholesterol ester accumulation in arteries are well-known events in human atherogenesis. In vitro and experimental animal studies have provided evidence of a beneficial effect of PGE₁ on both vascular apo B-containing lipoprotein accumulation and cholesterol ester content. Methods: We examined the effect of PGE₁ (administered via an intravenous portable infusion pump at a rate of 5 ng PGE₁ kg⁻¹ ·  min⁻¹ for 5 days a week, 6 h daily, over a total of 5 weeks) in ten patients (eight males, two females) on ¹²³I-apo B-containing lipoprotein accumulation into the large arteries in vivo. Apo B-containing lipoprotein isolation was carried out by immunoaffinity chromatography and radiolabeling with the iodine monochloride method. ¹²³I-apo B-containing lipoprotein accumulation was imaged and quantified by means of special computer software before and after 5 weeks of PGE₁ therapy Results: PGE₁ led to a significant decrease in maximal arterial apo B-containing lipoprotein retention. The mean decrease in the carotid and femoral arteries in type I lesions amounted to between 16.9% and 30.4%, and in type II lesions between 22.4% and 30.7%, 20 h after injection of radiolabeled apo B-containing lipoprotein. The type of arterial apo B-containing lipoprotein kinetic curves, however, remained unchanged. Conclusion: These findings indicate that PGE₁ decreases the apo B-containing lipoprotein influx in the large arteries and the vascular cholesterol content, suggesting that PGE₁ may lead to regression of lipid-rich lesions in human in vivo. Received: 2 June 1996 / Accepted in revised form: 5 December 1996     

Prostaglandin E1 increases binding of 123I-low-density lipoprotein to the human liver in vivo

Previous in vitro radioligand binding data have shown that prostaglandin E₁ (PGE₁) increases the number and the binding affinity of low-density lipoprotein (LDL) receptors of the human liver. Experimental data in normo- and hypercholesterolaemic rabbits have confirmed these findings, showing a significant increase in LDL-binding to the liver in vivo after prolonged PGE₁ therapy. Methods: This study aimed to confirm the experimental and animal data in human in vivo. ¹²³I-LDL binding to the liver was quantified in vivo in patients suffering from peripheral vascular disease, seven of them with heterozygous familial hypercholesterolaemia (HC) and five with normal total plasma cholesterol, after PGE₁ administration (5 ng·kg^–1·min^–1; 6 h daily for 5 days/week for 5 weeks). LDL uptake by the liver was quantified by single photon emission computer tomography (SPECT). Results: The amount of LDL trapped by the liver in normocholesterolaemics (45.6%) was significantly higher than in hypercholesterolaemics (22.0%). PGE₁ induced an increase in liver LDL binding, which was more pronounced in HC (+38.2%) than in normocholesterolaemic patients (+8.11%).     

Research on the comparison of the demethylvancomycin’s diffusion–deposition characteristics in the ocular solid tissues of sustained subtenon drug delivery with subconjunctival injection

Purpose: To compare the demethylvancomycin’s diffusion–deposition characteristics in the ocular solid tissues of sustained subtenon drug delivery with subconjunctival injection.

Method: Sixty adult white rabbits were randomly assigned to the subtenon drug delivery group and the subconjunctival injection group. The subtenon drug delivery group was continuously infused demethylvancomycin to the subtenon of rabbits. The subconjunctival injection group was injected demethylvancomycin to the subconjunctival of rabbits. Cornea, iris and sclera were collected for high-performance liquid chromatography analyses to determine drug concentrations at one hour, three hours, six hours, 12?h and 24?h of drug administration. WinNonlin 6.3 was used to calculate the parameters of cumulative area under the curve (AUC_cum) of demethylvancomycin.

Results: The peak levels of demethylvancomycin concentration of the subtenon drug delivery group and the subconjunctival injection group were 92.406?±?21.555 and 51.778?±?14.001?μg/g in cornea, 28.451?±?10.229?μg/g and 42.271?±?27.291?μg/g in iris, 153.166?±?51.738?μg/g and 57.423?±?18.480?μg/g in sclera. The differences of concentrations between the two groups in cornea and sclera were statistically significant (F?=?487.775, p?F?=?132.748, p?F?=?4.848, p?=?0.064). The maximum of AUC_cum of the subtenon drug delivery group and the subconjunctival injection group was 1808.23?h?*?μg/g and 273.73?h?*?μg/g in cornea, 489.12?h?*?μg/g and 216.16?h?*?μg/g in iris and 2166.34?h?*?μg/g and 392.57?h?*?μg/g in sclera at 24?h of drug administration.

Conclusion: The sustained subtenon drug delivery had a better drug permeability and accumulation in the intraocular solid tissue compared to subconjunctival injection, which demonstrated it was probably a promising and effective approach for treating posterior segment diseases and endophthalmitis.     

Evaluation of anti-inflammatory activity and standardisation of hydro-methanol extract of underground tuber of Dioscorea alata

Context The underground edible tuber of Dioscorea alata L. (Dioscoreaceae) is a functional food with high nutritive value and therapeutic potential. The tuber is known to possess anti-inflammatory properties in traditional medicine.

Objective The present study explores the anti-inflammatory activity and standardisation of D. alata tuber hydromethanol extract.

Materials and methods Hydromethanol extract (70%) of D. alata tuber was chemically characterised using HPLC and GC-MS techniques. Murine lymphocytes were cultured for 48?h with six different concentrations (0–80?μg/mL) of the extract. The expression of nitric oxide (NO), TNF-α, COX-1, COX-2, and PGE₂ were evaluated using colorimetric and ELISA methods.

Results Dioscorea alata extract inhibited the expression of NO and TNF-α with an IC₅₀ value of 134.51?±?6.75 and 113.30?±?7.44?μg/mL, respectively. The IC₅₀ values for inhibition of total COX, COX-1, COX-2 activities and PGE₂ level were 41.96?±?3.07, 141.41?±?8.99, 32.50?±?1.69, and 186.34?±?15.36?μg/mL, respectively. Inhibition of PGE₂ level and COX-2 activity was positively correlated (R²?=?0.9393). Gallic acid (GA), 4-hydroxy benzoic acid (4HBA), syringic acid (SYA), p-coumaric acid (PCA), and myricetin (MY) were identified and quantified using HPLC. GC-MS analysis revealed the presence of 13 different phytocompounds such as hexadecanoic acid, methyl stearate, cinnamyl cinnamate, and squalene.

Conclusion The D. alata extract significantly down-regulated the pro-inflammatory signals in a gradual manner compared with control (0?μg/mL). Different bioactive phytocompounds individually possessing anti-inflammatory activities contributed to the overall bioactivity of the D. alata tuber extract.     

Combination effects of O-carboxymethyl-O-ethyl-β-cyclodextrin and penetration enhancer HPE-101 on transdermal delivery of prostaglandin E1 in hairless mice

An inclusion complex of prostaglandin E₁ (PGE₁) with β-cyclodextrin (β-Cyd) or O-carboxymethyl-O-ethyl-β-cyclodextrin (CME-β-CyD) was made as topical preparations in a fatty alcohol/propylene glycol ointment base. When the PGE₁ preparations were applied onto the skin of hairless mice, the vasodilating effect of the PGE₁-CME-β-CyD complex supplemented with a penetration enhancer, 1-[2-(decylthio)ethyl] azacyclopentane-2-one (HPE-101) was approximately 100 times that of the PGE₁ alone and approximately 10 times that of PGE₁ with HPE-101 or the PGE₁-β-CyD complex with HPE-101. The combination of CME-β-CyD and HPE-101 enhanced the percutaneous penetration of PGE₁ in a synergistic manner; CME-β-CyD assisted the release of HPE-101 from the ointment base and its entry into the skin which may facilitate the percutaneous penetration of PGE₁. Furthermore, this combination suppressed the bioconversion of PGE₁ to give less pharmacologically active metabolites during the passage through the skin, a situation delivering intact PGE₁ more effectively to the site of action. The present data suggest that the combination of CME-β-CyD and HPE-101 is particularly useful for improving topical bioavailability of PGE₁.     

Stimulation of insulin secretion after prostaglandin PGE 1 in the anesthetized dog

Overnight fasted anesthetized dogs were treated with prostaglandin PGE₁ infused at a rate of 0.5 or 1 μg/kg/min for 40 min and compared with saline-infused dogs. PGE₁ infusion caused a significant transient drop in arterial blood pressure (25–30 per cent) and in pancreaticoduodenal vein (PDV) blood flow (40–50 per cent). Total insulin output was unchanged during infusion. The cessation of PGE₁ infusion (1 μg/ kg/min) was accompanied by a slight tendency toward recovery of PDV blood flow and a highly significant (P < 0.01) increase in insulin output. No significant change in blood glucose was observed during PGE₁ infusion; however a moderate hypoglycemia was recorded at the time of maximal insulin output. These results (1), confirm that insulin output is relatively independant of gross changes in pancreaticoduodenal blood flow; and (2), demonstrate that insulin release is significantly increased in response to PGE₁ infusion. The relationship between the PGE₁-induced insulin increase and the adenylate cyclase system of the β-cell remains to be elucidated.