The Therapeutic Effect of Pancreatic Kininogenase on Treatment of Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes.

Background: To determine the therapeutic efficacy and cost-effective of pancreatic kininogenase (PKase) on treatment of diabetic peripheral neuropathy (DPN) compared with Prostaglandin E1 (PGE1) in patients with type 2 diabetes. Methods: 104 patients with DPN receiving standard glucose control therapy were randomly assigned into 3 groups: Group-A received PKase treatment, Group-B received PGE1 treatment, and Group-C received only standard glucose control therapy. Michigan neuropathy screening instrument (MNSI) score, neurophysiology examination, and nerve conduction velocity were measured. Results: Standard glucose control therapy significantly reduced hyperglycemia to a similar level in all groups. Questionnaire grading and neurophysiology examination both indicated that no significant difference was found at the end of treatment between Groups -A and -B. Except for the ulnar nerve sensory conduction velocity that was significantly improved in Group-B, the remaining nerve conduction velocity (regardless of sensory or motor nerve conduction velocities) was improved to a similar level in Groups -A and -B. Group-A had significantly reduced questionnaire grading and better improvement in motor nerve conduction velocity of the common peroneal nerve, ulnar nerve, and sensory nerve conduction velocity of the sural nerve as compared with Group-C. However, the medical cost of PKase was only 18.9% of that of PGE1 during one course of treatment. Conclusions: PKase has the similar therapeutic efficacy as PGE1 on treatment of DPN in patients with type 2 diabetes. However, the medical cost of PKase is one fifth of that of PGE1. Thus, PKase is a cost-effective drug for treatment of DPN.

Assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus.

BACKGROUND: An established macaque model to assess HIV interventions against penile transmission is currently not available. Physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (PK). Here, we identify methods to establish erections in macaques to evaluate penile transmission, PK, and efficacy under physiologic conditions. METHODS: Penile rigidity and length were evaluated in eight rhesus macaques following rectal electrostimulation (RES), vibratory stimulation (VS), or pharmacological treatment with Sildenafil Citrate (Viagra) or Alprostadil. RESULTS: Rectal electrostimulation treatment increased penile rigidity (>82%) and length (2.5 ± 0.58 cm), albeit the response was transient. In contrast, VS alone or coupled with Viagra or Alprostadil failed to elicit an erection response. CONCLUSION: Rectal electrostimulation treatment elicits transient but consistent penile erections in macaques. High rigidity following RES treatment demonstrates increased blood flow and may provide a functional model for penile PK evaluations and possibly simian immunodeficiency virus (SIV) transmission under erect conditions.

Assessment of VerifyNow P2Y12 assay accuracy in evaluating clopidogrel-induced platelet inhibition.

The emergence of point-of-care assays enabling bedside testing such as the VerifyNow P2Y12 system might prove useful in clinical settings. The aim of this study was to evaluate the ability of the VerifyNow P2Y12 assay to estimate the inhibition of platelet aggregation provided by clopidogrel in the absence of baseline off-drug aggregation data. Sixty-eight patients with coronary artery disease scheduled to initiate clopidogrel therapy underwent platelet aggregation testing by VerifyNow P2Y12 at baseline and after clopidogrel administration. The inhibition reported by the VerifyNow assay (relative to thrombin receptor activating peptide-induced platelet aggregation, serving as baseline) was compared with that calculated with the actual adenosine diphosphate-induced baseline obtained with the same methodology. The postclopidogrel thrombin receptor activating peptide-induced aggregation showed a great discordance with that induced by adenosine diphosphate before clopidogrel with a bias of 24 units (95% limits of agreement from -142 to 190 units). Moreover, the inhibition reported by the assay overestimated the standard before-and-after testing data by an average of 8% (95% limits of agreement from -49% to 65%), making its use without a true baseline comparator unsatisfactory. The VerifyNow P2Y12 assay fails to accurately quantify platelet inhibition achieved by clopidogrel compared with before-and-after testing. Further studies are required to establish the clinical usefulness of the VerifyNow P2Y12 assay to accurately predict the occurrence of major adverse cardiovascular events in patients with reduced clopidogrel efficacy before it can be implemented in clinical practice. At present, the use of this assay in clinical care cannot be recommended for monitoring clopidogrel therapy.

Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study.

INTRODUCTION: Clopidogrel inhibits platelet P2Y12 ADP receptors, while ADP, as an inductor of aggregation, stimulates both P2Y12 and P2Y1 platelet receptors. Despite a clinical loading dose routine with clopidogrel, some patients still experience coronary stent thrombosis suggesting persistent platelet activation. The VerifyNow-P2Y12 is a rapid assay that test platelet activity over 3 min and uses of the combination of ADP and prostaglandin E1 (PGE1) to directly measure the effects of clopidogrel on the P2Y12 receptor. ADP is used to maximally activate the platelets by binding to the P2Y1 and P2Y12 platelet receptors, while PGE1 is used to suppress the ADP-induced P2Y1-mediated increase in intracellular calcium levels. OBJECTIVE: The VERIfy Thrombosis risk ASsessment (VERITAS) was a prospective study designed to measure platelet response to clopidogrel therapy in subjects with multiple risk factors or history of vascular disease using this novel point-of-care assay. METHODS: 166 participants were enrolled in 4 participating sites. Data from 147 participants were analyzed after exclusion of 19 patients due to protocol violations. Platelets were assessed twice at baseline (before clopidogrel) and at 24 h post-loading 450 mg (110 participants) or 7 days after chronic clopidogrel treatment (75 mg/day) (37 patients). All participants received aspirin 81-325 mg for at least 2 days before the study enrollment. Results from the VerifyNow-P2Y12 assay are reported in P2Y12 reaction units (PRU). RESULTS: Clopidogrel therapy resulted in a mean 64.0+/-25.3% PRU reduction. No participant reached PRU inhibition below 10% of baseline. Distribution of PRU values for the VerifyNow-P2Y12 assay shows a separation from baseline to post-clopidogrel assay values with some overlap due to high inter-individual variations in response. CONCLUSIONS: VerifyNow-P2Y12 is a reliable, fast and sensitive device suitable for monitoring of platelet inhibition during clopidogrel therapy.

Microvascular in vivo assessment of reperfusion injury: significance of prostaglandin E(1) and I(2) in postischemic "no-reflow" and "reflow-paradox".

BACKGROUND: Microvascular ischemia-reperfusion (I/R) injury is characterized by failure of capillary perfusion ("no-reflow") and reoxygenation-associated phenomena ("reflow-paradox"), including activation of leukocyte-endothelium interaction with cytotoxic mediator-induced loss of endothelial integrity. The objectives of this study were to elucidate the impact of both prostaglandins E(1) (PGE(1)) and I(2) (PGI(2)) in microvascular reperfusion injury, with special focus on the distinct pathophysiology of no-reflow- and reflow-paradox phenomena. MATERIALS AND METHODS: By use of the hamster dorsal skinfold preparation and in vivo fluorescence microscopy, the microcirculation of a striated skin muscle was assessed before 4 h of pressure-induced ischemia and 0.5, 2, and 24 h after onset of reperfusion. RESULTS: I/R was characterized by enhanced leukocyte-endothelium interaction in postcapillary venules, increase of macromolecular leakage, and reduction of functional capillary perfusion (P < 0.05). Intravenous 2-h infusion of PGE(1), starting with onset of reperfusion, reduced leukocyte adhesion and macromolecular leakage in postcapillary venules during early reperfusion (P < 0.05), while 6-h infusion, given during ischemia and early reperfusion, showed no significant effects. PGI(2) infusion also attenuated postischemic leukocyte adhesion, which was significant by a 6-h prolonged administration (P < 0.05), but did not influence the increase of microvascular permeability. Both prostaglandins were unable to prevent the postischemic failure of capillary perfusion (no-reflow). CONCLUSIONS: Both prostaglandins did not significantly influence postischemic no-reflow phenomena, but appeared as potent inhibitors of reflow-paradox under the experimental circumstances of this study.

The assessment of vasoactive properties of CGRP and adrenomedullin in the microvasculature: a study using in vivo and in vitro assays in the mouse.

The potent neuropeptide vasodilator, calcitonin gene-related peptide (CGRP), and the vasoactive peptide adrenomedullin (AM) are structurally related. Evidence from our laboratory has demonstrated that these peptides have potent microvascular actions of relevance to cardiovascular and inflammatory effects in health and disease. We wish to further investigate the actions of these peptides through studies in genetically modified mice. We have developed techniques to enable the quantitative analysis of CGRP and AM responses in the mouse microvasculature. A mouse isolated mesentery system was developed that measures changes in perfusion pressure used as an index of microvascular relaxation in the precontracted mesenteric microvascular bed. Bolus injections of CGRP and AM caused dose-dependent decreases in perfusion pressure that were proportional to vascular relaxation. An in vivo mouse skin assay was also used in which agents were injected intradermally into the dorsal skin. The effects of these agents was assessed by the extravascular accumulation of intravenously injected 125I-albumin for their ability to potentiate plasma extravasation induced by a mediator of increased microvascular permeability. CGRP and AM are not directly active in this assay, because it does not directly measure blood flow. However, the vasodilators acted in a potent and dose-dependent manner to significantly potentiate edema formation. The results demonstrate the potent activity of CGRP and the activity (although 100- to 300-fold less potent) of AM. Furthermore, the results demonstrate the increased potency of CGRP in the microvasculature when compared with the structurally distinct peptide VIP and PGE1.

Duplex Doppler ultrasound assessment of clitoral hemodynamics after topical administration of alprostadil in women with arousal and orgasmic disorders.

There are limited hemodynamic data in women with arousal or orgasmic disorders and even fewer normative control hemodynamic data in women without sexual dysfunction. In addition, there is limited experience with topical vasoactive agents (used to maximize genital smooth muscle relaxation) applied to the external genitalia during hemodynamic evaluations. The aim of this study was to report duplex Doppler ultrasound clitoral cavernosal arterial changes before and after topical PGE-1 (Alprostadil) administration in control women and in patients with arousal and orgasmic sexual disorders. We found that women with sexual arousal and orgasmic disorders had significantly (p < 0.05) diminished clitoral peak systolic and end diastolic velocity responses compared to controls. Further research is needed to establish the diagnostic role of topical vasoactive agents in the hemodynamic evaluation of women with sexual dysfunction.

[Analysis of costs and results of prostaglandin (PGE1 alpha-cyclodestrin) therapy of peripheral arterial diseases]. / Analisi di costi e risultati del trattamento con prostaglandine (PGE1 alpha-ciclodestrina) in pazienti con arteriopatie periferiche.

BACKGROUND: In this study patients with peripheral vascular disease were treated with PGE1 alpha-ciclodestrina. In the intermittent claudication group (walking distance at inclusion between 200-600 m) we included 55 patients treated with PGE1 alpha-ciclodestrina (15 diabetics) and 22 controls (not treated with PGE1 alpha-ciclodestrina). In the critical ischemia group 46 patients were treated and 47 patients followed up as controls (rest pain or necrotic lesions had been present for more than 2 weeks). METHODS: Patients with intermittent claudication were evaluated by a treadmill test (walking distance was the endpoint) and in those with critical ischemia the number of minor and major amputations in 12 months were considered as endpoints. A dose of PGE1 alpha-ciclodestrina (60-80 micrograms/day for 2 days) was repeated either every 6 or, in alternative, every 10 weeks. In the control group only antiplatelet agents, support treatment (control of risk factors) and exercise were used. RESULTS: All subgroups of patients treated with PGE1 alpha-ciclodestrina with intermittent claudication increased their walking distance (including the subgroup of diabetics). In critical ischemia there were no major amputations (only 2 minor amputations) in the PGE1 alpha-ciclodestrina group vs 10.6% (of major amputations) in the control group. Also an evaluation of laser Doppler flow, volume flow and transcutaneous PO2 indicated in subgroups of patients an improvement of microcirculation and limb perfusion with PGE1 alpha-ciclodestrina. CONCLUSIONS: The cost analysis and the quality of life evaluation indicated a benefit of preserving limbs from amputation.

Assessment of the penile vascular system with color-coded duplex sonography and pharmacocavernosometry and -graphy in impotent men.

OBJECTIVE: To examine the extent to which color-coded duplex sonography permits complete clarification of vessel-dependent erectile dysfunction (ED). MATERIAL AND METHODS: A total of 215 patients with ED were examined. All patients underwent pharmacocolor-coded duplex sonography (PHCCDS; 20 micrograms of prostaglandin E1, PGE1, intracavernosally) as well as pharmacocavernosometry and -graphy (PHCM and PHCG; 20 micrograms of PGE1 intracavernosally). The penile vessels were visualized, i.e. the dorsal arteries, the cavernosal arteries, and the anastomoses between them, as well as the venous pathways. Peak flow and end-diastolic flow in all arteries and, when present, anastomoses were determined after stimulation. Induction flow to achieve maximal tumescence/rigidity as well as maintenance flow were determined during PHCM. Finally, for the morphological visualization of the cavenous body and possible venous insufficiencies, a radiography in 2 planes was produced with infusion of a water-soluble contrast medium. RESULTS: In 145 patients with a grade 0-III tumescence after stimulation with 20 micrograms of PGE1, PHCCDS revealed an end-diastolic flow of > 5 cm/s, with a peak flow velocity > 25 cm/s in the 2 cavernosal and 2 dorsal arteries. The deep dorsal vein of the penis was visualized in 110 of these 145 patients with a blood flow > 5 cm/s, and in 35 cases with a blood flow < 5 cm/s. Venous drainage to the corpus spongiosum was visualized in 80 patients with a blood flow > 10 cm/s. All patients had a pathologically increased induction (normal value < 100 ml/min) and maintenance venous flow (normal value < 10 ml/min) in the PHCM as well as venous drainage in the PHCG. Sixty patients with a tumescence grade of IV-V (rigidity) had a peak flow velocity clearly > 25 cm/s, an end-diastolic flow < 5 cm/s in the 2 cavernosal and 2 dorsal arteries in the PHCCDS, as well as induction values < 100 ml/min and maintenance flow values < 10 ml/min in the PHCM, without visible insufficient efferent venous pathways on the PHCG. In 29 patients (13.5%) hemodynamically active anastomoses perforating the tunica albuginea could be detected. Ten patients with a tumescence grade of III had a peak flow velocity < 25 cm/s and an end-diastolic flow < 5 cm/s without venous leakage in PHCM and PHCG. CONCLUSION: PHCCDS allows for the assessment of arterial flow disorder as well as of venous leakage in ED. PHCM and PHCG should only be carried out in patients in whom surgical or radiological interventional procedures at the efferent venous pathways are planned.

Clinical assessment of oxygen delivery and consumption during hypotensive anaesthesia--a clinical application of The Deep Picture.

Usual evaluation of the relationship between oxygen delivery (DO2) and oxygen uptake (VO2) is based on the arterial oxygen tension (pO2), oxygen saturation (sO2), haemoglobin concentration (ctHb), the same indicators in mixed venous blood and cardiac output, sometimes supplemented by the expiratory carbon dioxide concentration. And, so far, the relationship among DO2, VO2 and the new parameters for an evaluation of oxygen status (oxygen extraction tension: px, concentration of extractable oxygen: cx, oxygen compensation factor: Qx) (1) has not been discussed enough. Therefore, this study was designed to evaluate whether the new parameters give the clinically significant information to analyse the relationship between DO2 and VO2 during the acute haemodynamic change with intentionally induced hypotension in anaesthetized adult patients.

Assessment of blood flow in different segments of the penis by duplex sonography in subjects with normal erectile potency.

Correct evaluation of erectile potency requires careful assessment of the hemodynamics of the cavernous area. Pulsed Doppler flow velocity measurement of cavernous arteries after intracavernous injection of vasoactive drugs represents an effective, repeatable and minimally invasive technique. However, doubts remain concerning the procedures employed and the results obtained. Based on the assumption that all flowing viscous fluids are subjected to a significant decrease in pressure and, hence, velocity the smaller the vessel diameter is, the pulsed Doppler flow velocity measurement was used to evaluate such a decrease in three consecutive segments of the penis (a,b and c). A statistically significant decrease in velocity (P < 0.0001 on the right and left) was observed between the arterial segments a, b and c in cavernous arteries of subjects with normal erectile function. Therefore, we stress that in the vascular evaluation of the penis, one should take into account the values obtained in each penile segment because a reduction in flow velocity in a proximo-distal direction can be regarded as physiologic. Misinterpretation of results can thus be prevented, avoiding a wrong diagnosis of arteriogenic erectile insufficiency.

Experience with intracavernosal tri-mixture for the management of neurogenic erectile dysfunction.

Using papaverine, papaverine/phentolamine, or prostaglandin E1 (PGE1), intracavernosal pharmacotherapy has been successful in treating erectile dysfunction. The limiting factor of using these medicines is intracorporeal fibrosis with the first two and a high cost with PGE1. Our experience with intracavernosal therapy in patients with impotence secondary to neurogenic disease has included 35 men, 30 of whom are spinal cord injured, 3 after radical prostatectomy, 1 with multiple sclerosis, and 1 with lower extremity weakness after surgery. Patients ranged in age from 22 to 59 years, with an average of 36.3 years; mean follow-up was 13.8 months. Intracavernosal therapy has been performed with a tri-mixture of papaverine hydrochloride (smooth muscle relaxant), phentolamine mesylate (alpha-adrenergic blocking agent) and alprostadil (PGE1- a vasodilator and smooth muscle relaxant). Of the patient population, all 35 patients were able to have adequate erections for sexual relations with minimal complications. Acting synergistically, the ingredients promote erectile activity using small doses and without a significant incidence of priapism or fibrosis. Techniques of injection, dosing and followup are discussed.

A comparative study with intracavernous injection of prostaglandin E1 versus papaverine for the diagnostic assessment of erectile impotence.

The intracavernous injection of vasoactive drugs is a valuable diagnostic aid and an important tool for the treatment of erectile failure. A comparative study with intracavernous injection of prostaglandin E1 (PGE1) and papaverine was performed in 60 patients with impotence. We evaluated the efficiency and side effects of both agents. The overall positive response rate was 85.0% in the PGE1 group and 65.0% in the papaverine group which suggests PGE1 has a stronger vascular effect. The mean onset of maximal erection was after 9.6 minutes in the PGE1 group and after 6.5 minutes in the papaverine group. The mean maintenance of erection was for 53.2 minutes in the PGE1 group and for 38.6 minutes in the papaverine group. There were no systemic side effects of either agent. Three instances of injection pain and 2 of burning sensation in the penis were noted in the PGE1 group, while in the papaverine group, there were 21 reports of injection pain, 4 of prolonged erection and 2 of burning sensation in the penis. These results suggest that PGE1 is a more desirable vasoactive alternative for the diagnosis of impotence.

Effect of prostaglandin E1 on myocardial contractility in dogs anesthetized with halothane: load-independent and noninvasive assessment using transesophageal echocardiography.

The presence of an inotropic action of prostaglandin E1 (PGE1) in vivo is controversial, and there are conflicting results obtained by various indices of myocardial contractility. In this study, a direct effect of PGE1 on contractility was investigated in dogs by use of a load-independent contractile index: left ventricular end-systolic wall stress (LVESWS) versus the velocity of circumferential fiber shortening with rate-corrected (Vcfc) relationship using transesophageal echocardiography (TEE). Hemodynamics, arterial blood gas, and TEE data were obtained before PGE1 infusion (control), and with a 10%, 20%, and 30% decrease in mean arterial pressure (MAP) following intravenous PGE1 administration. PGE1 infusion rates were 0.19 +/- 0.03 at 10%, 0.82 +/- 0.17 at 20%, and 2.32 +/- 0.36 micrograms/kg/min at a 30% decrease in MAP. Pulmonary capillary wedge pressure, systemic vascular resistance index, and left ventricular stroke work index significantly decreased, and heart rate, cardiac index, and stroke volume index were not significantly altered. Analysis of the TEE data showed LVESWS (index of afterload) significantly decreased from 92.0 +/- 11.2 g/cm2 to 72.7 +/- 7.8 at 10%, 59.3 +/- 7.8 at 20%, and 44.6 +/- 6.2 at a 30% decrease in MAP, and Vcfc significantly increased from 0.595 +/- 0.065 circ/sec of control value to 0.670 +/- 0.056 at 10%, 0.824 +/- 0.049 at 20%, and 0.939 +/- 0.070 at a 30% decrease in MAP. In the LVESWS versus Vcfc relationship, no significant difference could be detected between the control state and the 10%, 20%, and 30% decrease in MAP, and no inotropic effect was found.(ABSTRACT TRUNCATED AT 250 WORDS)

[Assessment for protective effects of CoQ10, PGE1 and TXA2 receptor antagonist (ONO-3708) on warm ischemic liver].

Metabolic disturbances in the canine liver during warm ischemia by Pringle's method for 60 minutes and the role of Coenzyme Q10 (CoQ10), Prostaglandin E1 (PGE1) and ONO-3708, TXA2 receptor antagonist, were studied. Mongrel dogs were divided into five groups; control group, group of liver ischemia without drugs, groups of liver ischemia with CoQ10, PGE1 and ONO-3708 pretreatment. Metabolic rates of PGI2, TXA2, insulin, glucagon and glucose and production of lipid peroxides in the five groups were measured at the points before Pringle's procedure, 5 minutes, 60 minutes and 120 minutes after declamping. In the group of ischemia without drug administration, the hepatic metabolism of PGI2, TXA2, insulin and glucose were decreased after declamping. The metabolism of glucagon, however, was not disturbed by warm ischemia. The production of lipid peroxides increased at 5 minutes after declamping. In the groups of CoQ10, PGE1 and ONO-3708 pretreatment, changes of PGI2, TXA2 and insulin metabolism in the liver were improved, and an increased production of lipid peroxides by warm ischemia was normalized. This study suggests that CoQ10, PGE1 and ONO-3708 protect liver damage by warm ischemia as results of improvement of metabolic disturbances of PGI2, TXA2, insulin and suppression of lipid peroxides production.

Misoprostol: a prostaglandin E1 analogue.

The pharmacology, pharmacokinetics, clinical efficacy, contraindications and precautions, adverse effects, dosage, and cost of misoprostol are reviewed. Misoprostol is a synthetic analogue of natural prostaglandin E1. It produces a dose-related inhibition of gastric acid and pepsin secretion and enhances mucosal resistance to injury. Misoprostol is extensively absorbed from the stomach and undergoes rapid de-esterification to its biologically active metabolite, misoprostol acid. The average absorption after an oral dose is 88%; peak plasma concentrations of misoprostol acid are achieved in less than 30 minutes. Clinical trials have demonstrated ulcer healing rates of approximately 60-80% in patients with duodenal ulcers who received misoprostol 800 micrograms daily for four weeks. Misoprostol was generally no more efficacious than conventional therapy with the H2-receptor antagonists cimetidine and ranitidine. The healing rate observed for gastric ulcers was less than that observed for duodenal ulcers. In trials involving healthy volunteers and patients with arthritis receiving aspirin, naproxen, tolmetin, ibuprofen, or piroxicam, misoprostol was consistently superior to placebo, cimetidine, and sucralfate in the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. The majority of these studies have been of short duration; however, long-term studies (up to three months) have corroborated superiority over placebo. Misoprostol is an abortifacient and is contraindicated in pregnant women and women of childbearing potential not using effective contraception. The most common adverse effect of misoprostol therapy is diarrhea, which is often mild and self-limiting and can be minimized by administration of misoprostol after meals and at bedtime. The cost (based on retail price) of four weeks of therapy with misoprostol is comparable to that of other antiulcer agents. Misoprostol has been shown to be an effective agent for the prevention of NSAID-induced gastric ulcers. However, there is no evidence that it offers any clinical advantage over H2-receptor antagonists for the treatment of gastric or duodenal ulcer disease.