Hakan Ergün

Intestinal Ischemia and Reperfusion Impairs Vasomotor Functions of Pulmonary Vascular Bed

OBJECTIVE To investigate the effects of intestinal ischemia and reperfusion (I/R) on the pulmonary vascular endothelium and smooth muscle. SUMMARY BACKGROUND DATA Respiratory failure is an important cause of death and complications after intestinal I/R. Although the mechanism of respiratory failure in this setting is complex and poorly understood, recent studies of lung injury suggest that endothelial dysfunction may play a significant role. METHODS A rat model of acute lung injury was studied after 60 minutes of superior mesenteric arterial occlusion followed by either 120 or 240 minutes of reperfusion. The pulmonary vasomotor function was examined in isolated lungs perfused at a constant flow rate. RESULTS Sixty minutes of intestinal ischemia followed by 120 or 240 minutes of reperfusion led to a significant reduction in the ability of the pulmonary vasculature to respond to angiotensin II, acetylcholine, and calcium ionophore but not to nitroglycerin. The vasoconstriction response to N(G)-nitro-L-arginine methyl ester, which is a measure of basal nitric oxide release, was diminished in the 240-minute reperfusion group. Intestinal I/R was also associated with pulmonary leukosequestration and increased pulmonary microvascular leakage. CONCLUSIONS Basal and agonist-stimulated release of nitric oxide from the pulmonary vascular endothelium and the ability of pulmonary smooth muscle to contract in response to angiotensin II were impaired by intestinal I/R. Such functional impairment in both pulmonary vascular endothelium and smooth muscle may contribute to the alveolocapillary dysfunction and pulmonary hypertension found in acute lung injury after intestinal I/R.

Role of integrins and intracellular adhesion molecule-1 in lung injury after intestinal ischemia-reperfusion

BACKGROUND We tested the hypothesis that lung injury after intestinal ischemia-reperfusion (IR) requires the activation of CD11/CD18 glycoprotein complex and its ligand, intracellular adhesion molecule-1 (ICAM-1), on pulmonary endothelial surface. METHODS Rats were assigned to one of six groups including sham operation, intestinal IR (60/120 min) and IR plus treatment with one of the following monoclonal antibodies against CD11a, CD11b, CD18, and ICAM-1. Pulmonary microvascular permeability, neutrophil accumulation, and expression of adhesion molecules were evaluated. RESULTS Intestinal IR resulted in lung injury characterized by a marked increase in microvascular permeability, neutrophil accumulation and upregulated expression of leukocyte integrins and ICAM-1. The increase in pulmonary microvascular permability and neutrophil accumulation elicited by intestinal reperfusion was effectively prevented by administration of blocking antibodies against ICAM-1, CD11, and CD18. CONCLUSIONS These results indicate that adhesion molecules contribute to the lung injury after intestinal IR. Immunoneutralization of certain of these adhesion molecules may prevent intestinal IR-induced lung injury.

THE EFFECTS OF L-ARGININE AND ILOPROST ON THE VIABILITY OF RANDOM SKIN FLAPS IN RATS

The effects of an intravenous infusion of L-arginine as a physiological precursor of endothelium-derived relaxing factor/nitric oxide (EDRF/NO), iloprost (a stable prostacyclin (PGI2) analogue), and L-arginine combined with iloprost on skin viability were studied in 9 x 3 cm random pattern skin flaps in rats. Intravenous infusion of all drugs was started at the beginning of the operation and continued for 60 minutes. At the end of infusion period the depth of fluorescein dye penetration in the skin flap was assessed visually from photographic records, and the flap survival area was measured by the grid method at the seventh postoperative day. There was a significant reduction in distal necrosis of random skin flaps after intravenous infusion of L-arginine, iloprost, and L-arginine combined with iloprost (p < 0.01). Possible mechanisms that may be responsible for impairment of endothelium-dependent vasodilation and vasospasm in the microvasculature of random skin flap and their prevention with L-arginine and iloprost include restoration of the depleted stores of NO which in turn causes vasodilatation and has an antithrombotic effect.

Pharmacological characterization of metamizol-induced relaxation in phenylephrine-precontracted rabbit thoracic aorta smooth muscle.

Metamizol produced a dose- and time-dependent relaxation in rabbit thoracic aorta smooth muscle that was precontracted by phenylephrine. Such a relaxation was not observed with indomethacin, which is also a nonsteroidal anti-inflammatory drug. The relaxing effect of metamizol was independent of the presence of vascular endothelium. Tetraethylammonium (a calcium-activated potassium channel inhibitor), glybenclamide (an ATP-dependent potassium channel inhibitor), indomethacin (a cyclooxygenase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) did not have any effect on metamizol-induced relaxation response. Metamizol did not produce any relaxation effect on aortic smooth muscle when KCl (30, 60, and 117 mM KCl) was used instead of phenylephrine to precontract the preparation. Ouabain (a Na-K ATPase pump inhibitor) showed a dose-dependent inhibition on metamizols relaxation response. However, in potassium-free medium, which is an alternative way to block the Na-K ATPase pump, no inhibition in metamizol-induced relaxation response was observed. When metamizol was incubated for 2 h in organ-bath conditions before evaluating its relaxing effect, it produced a relatively faster relaxation, indicating that the relaxing effect of metamizol is produced by one of its (active) spontaneous degradation products (possibly 4-methylaminoantipyrine).

The effect of dipyrone on survival of skin flaps.

The effect of dipyrone on the skin flap survival was studied in a model of an epigastric island flap with a random extension on the opposite side in 23 rats. Dipyrone was given intraperitoneally one hour before the skin flap was raised. At the end of the operation the depth of penetration of the fluorescein dye in the skin flap was assessed visually from photographic records and the flap survival area was measured by a grid method on the seventh postoperative day. There was a significant reduction in the amount of ischaemic necrosis of the skin flap after a single dose of dipyrone 50 mg/kg (p < 0.001). These data suggest that dipyrone is a useful agent in the prevention and treatment of ischaemia and necrosis of the skin flap.The effect of dipyrone on the skin flap survival was studied in a model of an epigastric island flap with a random extension on the opposite side in 23 rats. Dipyrone was given intraperitoneally one hour before the skin flap was raised. At the end of the operation the depth of penetration of the fluorescein dye in the skin flap was assessed visually from photographic records and the flap survival area was measured by a grid method on the seventh postoperative day. There was a significant reduction in the amount of ischaemic necrosis of the skin flap after a single dose of dipyrone 50 mg/kg (p < 0.001). These data suggest that dipyrone is a useful agent in the prevention and treatment of ischaemia and necrosis of the skin flap.

The effect of resveratrol on blood pressure in a rat model of preeclampsia

Objective: To examine the hypothesis that resveratrol administration could result in blood pressure and blood flow decrease in a rat preeclampsia model. Materials and Methods: Desoxycorticosterone acetate (DOCA) was used to produce hypertension. The Wistar albino rats were divided randomly into three groups: control (n = 12), DOCA injected (n = 11), and DOCA injected and resveratrol treated (n = 13). Rats were sacrificed on gestational day 16–20. The systolic blood pressure was measured by the tail-cuff method. Urine protein was expressed as protein/creatinine. Laser Doppler measurements of the blood flow were made in one placenta, the left kidney and both parietal lobes of brain. Placentas were examined by light microscopy. Results: DOCA injected group exhibited significant differences in blood pressure and protein/creatinine. Mean blood pressure in DOCA-treated rats was 130.1 ± 12.9 mmHg at baseline and 148.4 ± 20.1 mmHg at the time of euthanization (p = 0.044). Resveratrol did not significantly affect blood pressure, placental and renal blood flows. There were also no significant differences in placental pathology parameters among the three groups. Conclusion: The present study demonstrated that resveratrol did not decrease blood pressure, and did not result in a significant response in blood flows and placental pathology parameters.

Vancomycin elimination in human infants with intrauterine growth retardation

Background: Intrauterine growth retardation (IUGR) results in substantial decrease in nephron number and renal and hepatic organ mass in experimental animals and newborn infants. Because the liver and the kidneys are the major organs for drug biotransformation and elimination, any decrease in their size and function may lead to impaired metabolism and elimination of drugs in newborns with IUGR. Our objective was to test the hypothesis that IUGR results in prolonged renal elimination of vancomycin in newborns. Methods: Small for gestational age (SGA) infants (n = 20) were matched with appropriate for gestational age (AGA) infants (n = 123). Steady state peak and trough serum concentrations were used to calculate vancomycin clearance (Cl), volume of distribution (Vd) and half-life (t½) for each subject. Pharmacokinetic profiles were compared between groups. Results: Overall, Cl, Vd and t½ of vancomycin were the same between groups. However, stratification showed decreased Cl in those SGA versus AGA newborns 3–4 weeks old and in those newborns with a postconceptional age of 27–29 weeks. There was no difference in Vd, normalized for weight, between SGA and AGA babies. The half-life of vancomycin was similar across most groups but was prolonged in SGA newborns aged 3–4 weeks. Conclusions: Vancomycin Cl differs between SGA and AGA newborns. This difference is greatest early in life and normalizes between groups after the fourth week of life or after 29 weeks postconceptionally. Normalized Vd is similar between SGA and AGA newborns. The elimination of vancomycin is comparable between SGA and AGA infants, except before the fifth week of life, when SGA newborns may eliminate the drug more slowly. Specific vancomycin dose recommendations for SGA versus AGA neonates may therefore be justified during the first month of life.

Efficacy and safety of topical nimesulide in the treatment of knee osteoarthritis.

Background:Osteoarthritis (OA) affects mainly older people who are more sensitive to adverse effects of classic nonsteroidal anti-inflammatory drugs. Recent publications indicate that topically applied nonsteroidal anti-inflammatory drugs are effective and much safer than their oral analogues. Objectives:In this double-blind, randomized, placebo-controlled study design, we aimed to investigate whether topical nimesulide treatment has any beneficial effect in knee OA patients. Methods:Seventy-four adult knee OA outpatients were enrolled. We used Western Ontario and McMaster Universities OA Index (WOMAC), Nottingham Health Profile (NHP), and patient and physician global satisfaction scores. WOMAC and NHP scores were measured at the initial and final visit. Treatment group received topical nimesulide gel 1% on the knee skin 3 times a day whereas placebo group received an identical-appearing gel for 30 days. Results:There was a significant improvement in the nimesulide treatment group for all 3 parameters and overall score of WOMAC between pretreatment and posttreatment values. The overall WOMAC scores was significantly better than placebo (P = 0.03), but physical functioning, stiffness, and pain scales did not reach statistical significance. For the NHP scores there was an improvement at “energy level,” “pain,” “physical motion,” and “NHP distress” scores in the treatment group whereas no improvement was found in the placebo group. Between-group differences were not significant. Both patient and physician satisfaction scores were significantly better in the treatment group. Conclusion:This study shows that topical nimesulide gel can have beneficial effects and can improve quality of life in patients with knee OA.

Cost-Minimization Analysis Comparing Topiramate with Standard Treatments in Migraine Prophylaxis

Migraine is a common disorder with a relatively high burden of disease from the perspective of both society and the individual patient. Optimizing the use of prophylactic treatment may decrease the frequency and severity of attacks thus reducing the burden of disease. In this regard, topiramate has been found to be as effective as propranolol in the prevention of migraine attacks. In the present study, a cost-minimization analysis was performed. Monthly preventive medication cost and price per migraine attack reduced were used as measures. In comparison with propranolol and flunarizine, topiramate was identified as being the most costly option for migraine prophylaxis with a monthly drug cost of USD 24.97–45.04 as compared with propranolol (USD 1.72–6.87) and flunarizine (USD 6.09–12.18). Current treatment options would appear to offer better value for money in achieving effective migraine prophylaxis unless additional benefits can be identified for topiramate in this patient group.

Comparison of the effects of systemic sildenafil, tadalafil, and vardenafil treatments on skin flap survival in rats

Abstract Objective: The most important issue in flap surgery is flap viability. This study aimed to compare the effects of most commonly used phosphodiesterase type 5 (PDE5) inhibitors on flap survival. Methods: A 3 × 9 cm flap was elevated from the dorsum of 32 Wistar albino rats. In the control group, saline was administered 2 hours before the flap elevation and continued for 2 days after the surgery. In the sildenafil, tadalafil, and vardenafil groups, the related drug was administered. Blood flow in the flaps was monitored with laser Doppler flowmetry. On postoperative day 7, flaps were photographed and biopsies were obtained. Results: The ratios of flap necrosis area in the tadalafil, sildenafil, and vardenafil groups were lower than that in the control group, but without significant difference (p = 0.077). Histopathological evaluation revealed no significant difference among the groups. Conclusion: The ratio of flap necrosis area tended to be lower in the groups receiving oral PDE5 inhibitors than in the control group, although not statistically significant. The role of PDE5 inhibitors needs to be evaluated in larger studies before a conclusion can be made regarding their effects on flap viability.