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Due to more comorbidities, polypharmacy is common in elderly patients and drug interactions are inevitable. It is also challenging to treat an elderly patient with a diagnosis of cancer. Prevalence and clinical impacts of drug interactions and using potentially inappropriate medications (PIMs) have been studied in geriatric patients. However, these are not well defined in oncology practice. The purpose of this study is to define the prevalence of PIMs and severe drug interactions (SDIs) in elderly cancer patients and investigate the factors associated with them. Patients more than 65 years of age in both inpatient and outpatient clinics were evaluated. Patient, disease characteristics, and medications used were collected by self reports and medical records. Drug interactions were checked with Lexicomp® and PIM was defined with 2012 update of Beers criteria. Severe drug interactions are defined with category D or X DIs. Logistic regression was used to compute odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between SDIs, PIMs, and clinical parameters. Four hundered and forty-five elderly patients (286 outpatient, 159 inpatient), with a median age of 70 (65–89) were evaluated. SDIs were present in 156 (35.1 %) of patients, 81 (28.3 %), and 75 (47.2 %) for outpatient and inpatients, respectively (p

Guvenc, Tolga/0000-0003-1468-3415; Engin-Ustun, Yaprak/0000-0002-1011-3848; ERGUN, HAKAN/0000-0002-7839-966X; Tapisiz, Omer/0000-0002-7128-8086 WOS: 000304097600056 PubMed: 21848411 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.

OBJECTIVE Metamizol, probably with its vascular smooth muscle relaxant effect, enhances rest myocardial perfusion with the use of technetium-99m-methoxyisobutylisonitrile. We aimed to investigate whether metamizol induction is also able to increase the detectability of the ischemic/jeopardized myocardium during thallium-201 myocardial perfusion scintigraphy (MPS). METHODS Twenty patients who had partially reversible/irreversible perfusion defects on their routine stress-redistribution-reinjection thallium-201 MPS were enrolled and metamizol-induced thallium-201 MPS (111 MBq thallium-201 was injected 45 min after 1 g oral metamizol) was acquired (10 min, 1 and 3 h later). Routine MPS and metamizol-induced MPS images were interpreted on the model of 17 segments using a visual uptake score (VUS; 0=normal, 1=mild, 2=moderate, 3=significant decreases, 4=no uptake). Thallium-201 uptake ratios (mean counts in the region of the perfusion defect/mean counts in the region of the normal-perfused wall) were calculated for each MPS. Blood pressure was monitored at 15-min intervals. MPS were compared with coronary angiography results. RESULTS Visual uptake score and thallium-201 uptake ratio results indicated that in the first and third hour metamizol-induced thallium-201 uptake was significantly higher (P

This study aims to investigate whether induction with metamizol, an analgesic-antipyretic drug having spasmolitic activity, could be used to increase the detectability of ischemic/jeopardized myocardium during MPS (myocardial perfusion scintigraphy).Metamizol-enhanced rest MPS (45 min after administration of 1 g metamizol orally, 740 MBq (99m)Tc sestamibi was injected, MPS was acquired 45 min later) was performed in 21 patients who had perfusion defects on their previous stress-rest (99m)Tc sestamibi MPS. Blood pressure was monitored at 15-min intervals. Stress, rest, metamizol-rest MPS images were interpreted on the model of 20 segments using a visual uptake score (VUS; 0 = normal, 1 = mild, 2 = moderate, 3 = significant decreases, 4 = no uptake). (99m)Tc sestamibi uptake ratios (MIBI-UR; mean counts in the region of the perfusion defect/mean counts in the region of the normal-perfused wall) were obtained on each MPS and compared with each other. Average MIBI-UR in each scintigraphic examination was calculated. MPS were compared with coronary angiography results.VUS and MIBI-UR results showed that metamizol-rest MPS displayed the defect reversibility better than rest MPS. Of the 14 segments with fixed perfusion defects on stress-rest MPS, 8 showed improvement of perfusion after metamizol induction. In 33 segments, lesion reversibility was better delineated on metamizol-rest MPS. Metamizol-induced sestamibi uptake was significantly higher (p0.001) than stress/baseline rest examinations as calculated by the MIBI-UR. Blood pressure remained unaltered. Coronary angiography results were in concordance with metamizol induced MPS.Metamizol-enhanced rest MPS increases detectability of ischemic/viable myocardium during MPS. Metamizol should be discontinued like nitrates before stress MPS since it may mask the visualization of ischemic perfusion defects.

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.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.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.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.This study shows that topical nimesulide gel can have beneficial effects and can improve quality of life in patients with knee OA.

Background: Intrauterine growth retardation (IUGR) results in substantial decrease in nephron number and renal and liepatic 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 newboms. 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 (V d ) and half-life (t 1/2 ) for each subject. Pharmacokinetic profiles were compared between groups. Results: Overall, Cl, V d and t 1/2 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 newboms with a postconceptional age of 27-29 weeks. There was no difference in V d , normalized for weight, between SGA and AGA babies. The half-life of vancomycin was similar across most groups but was prolonged in SGA newboms aged 3-4 weeks. Conclusions: Vancomycin Cl differs between SGA and AGA newboms. This difference is greatest early in life and normalizes between groups after the fourth week of life or after 29 weeks postconceptionally. Normalized V d is similar between SGA and AGA newboms. The elimination of vancomycin is comparable between SGA and AGA infants, except before the fifth week of life, when SGA newboms 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.

Candida albicans is an opportunistic pathogen that causes life-threatening systemic infection in immunocompromised host. However, little is known about the effects of yeast on the cardiovascular functions. This study examined the effects of C. albicans septicemia on the heart and vessel functions and nitric oxide (NO) production in infected rabbits. Anaesthetized animals were challenged with intravenous C. albicans (6 x 10(8)/kg) or saline and the blood pressure of rabbits were measured over 5 h. After that response of the isolated thoracic aorta, right atrium and left papillary muscle were recorded. Blood pressure significantly decreased in the infected rabbits during the septicemia but in the control animals it was stable. The blood nitrite levels and NO-synthases (eNOS, iNOS) expression and tissue nitrite levels in the heart and aorta were similar in the both groups. In the aorta isolated from C. albicans-infected rabbits, acetylcholine-induced endothelium-dependent relaxation was decreased, but contractions induced by phenylephrine were potentiated. The NOS inhibitor, L-N(G)-nitro-arginine methyl ester (L-NAME)-induced contraction increase in the right atrium was depressed by the yeast-infection. In the heart and aorta, microscopic examination revealed no tissue invasion of C. albicans. These results indicate the ability of C. albicans-induced septicemia to destroy NO-related responses of the heart and aorta and may have important implications for functional damage to endothelium and the regulation of cardiovascular functions. In addition, NOS induction and NO over-production are not stimulated by systemic C. albicans infection, which would alter the host immune reaction and homeostasis.

WOS: 000167601000004, PubMed ID: 11291345, 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 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.

The risk of fistula formation is a major concern after incision and drainage of an anorectal abscess.Our objective was to the test the effects of antibiotic treatment on fistula formation after incision and drainage of anorectal abscesses.Randomized, placebo-controlled, double-blind study.Multicenter trial at 3 teaching hospitals in Turkey.Patients who underwent abscess drainage between September 2005 and January 2008 were evaluated for eligibility. Exclusion criteria included penicillin allergy, antimicrobial agent usage before enrolment, other infection, previous anorectal surgery, inflammatory bowel disease, suspicion of Fournier gangrene, secondary and recurrent anorectal abscesses, anal fistula at time of the surgery, immune compromised states, and pregnancy.Patients were randomly assigned to receive placebo or amoxicillin-clavulanic acid combination treatment for 10 days after abscess drainage.The primary end point was rate of anorectal fistula formation at 1-year follow-up.: Of 334 patients assessed for eligibility, 183 entered the study (placebo, 92; antibiotics, 91). Data were available for per-protocol analysis from 151 patients (placebo, 76; antibiotics, 75) with a mean age of 37.6 years; 118 patients (78.1%) were men. Overall, 45 patients (29.8%) developed anal fistulas during 1-year follow-up. Fistula formation occurred in 17 patients (22.4%) in the placebo group and in 28 patients (37.3%) in the antibiotic group (P = .044). Risk of fistula formation was increased in patients with ischiorectal abscess (odds ratio, 7.82) or intersphincteric abscess (odds ratio, 3.35) compared with perianal abscess.Antibiotic treatment following the drainage of an anorectal abscess has no protective effect regarding risk of fistula formation.

Estrogen has neuroprotective effects in neurodegenerative disorders and models of neuronal damage. The effectiveness of estradiol (EST) (1 mg/kg and 10 mg/kg doses) in cold-induced brain injury (CIB) model was evaluated and compared with standard dexamethasone treatment. Forty-eight male Wistar rats (250-300 g) were randomly divided into 6 groups: sham operated, CIB + no treatment, CIB + 1 mg/kg dexamethasone, CIB + 1 mg/kg EST, CIB + 10 mg/kg EST, CIB + vehicle (ethanol). Rats were placed on stereotaxic frame and a craniotomy of 5 mm diameter was performed on the parietal lob under general anesthesia (ketamine+xylazine). A metal probe of 5 mm diameter was cooled (2 min) in liquid nitrogen (-190 degrees C) and was applied on the craniotomy area for 3 min. The treatment was started immediately after the CIB. Twenty-four hours later the whole brain was isolated and study parameters were assessed. The parameters were tissue wet/dry weight ratio, lipid peroxidation, and histopathological examination of the depth of injury. Both 1 mg/kg dexamethasone and 1mg/kg EST treatment significantly reduced all the measured injury parameters, whereas 10 mg/kg EST had no effect on any of the parameters. This study shows that EST at lower concentrations is beneficial in this model of cold-induced brain injury. However, the effect of EST is dual and higher concentrations, in contrast, do not affect or even may be detrimental in brain injury.

Background Nimesulide is available in gel formulation and applied mainly for topical pain management. However, its passage to the synovial fluid is not yet clear. The aim of this study was to evaluate if topical administered nimesulide passes into the synovial fluid and to compare its concentration with the oral nimesulide administration regimen. Methods Synovia and plasma nimesulide concentrations were investigated in patients after topical (Sulidin gel 1%) and oral (Mesulid tablet) drug administration. 34 adult outpatients who were scheduled to have an arthroscopic knee examination for mainly meniscal tears repair and who had knee pain during this period were enrolled in the first part of the study. One group received topical nimesulide gel to the skin of the knee whereas the second group received oral 2 x 100 mg nimesulide tablets, 4-7 days before the planned arthroscopy. Synovial fluid and plasma samples were taken simultaneously during the arthroscopy and analyzed using HPLC. In addition, an open-label pilot study was performed to investigate the efficacy and safety of 1-week administration of nimesulide gel. 63 knee osteoarthritis patients were asked to complete the WOMAC Osteoarthritis Index questionnaire before and 1 week after use of Sulidin gel applied 3 times daily. Results Synovia and plasma nimesulide concentrations were 19.7 +/- 8.6, 11.8 +/- 3.0 and 1958.8 +/- 397.5, 3631.9 +/- 799.3 ng/ ml for topical and oral administration groups, respectively. There was a significant (paired Student's t-test) improvement after 1 week nimesulide treatment in all WOMAC Osteoarthritis Index parameters measured. Conclusion Nimesulide passes into the synovial fluid after topical administration and may have potential benefits in knee osteoarthritis treatment. The actual efficacy and safety of topical nimesulide gel administration should be investigated in a long-term, randomized, placebo-controlled clinical trial.

Dipyrone, an effective analgesic drug, is widely used in the management of headache. However, few studies have evaluated its efficacy and safety in migraine. We aimed to assess the efficacy and safety of 1 g dipyrone (Novalgin, two 500 mg tablets) on pain and related symptoms in acute migraine attacks with or without aura in a double-blind, cross-over, randomized, placebo-controlled, multi-center study design. Seventy-three migraine with or without aura patients, diagnosed according to the IHS criteria, were randomized to receive dipyrone (for 2 attacks) and placebo (for 1 attack). Pain intensity was measured on a four-point verbal pain scale before and 1, 2, 4 and 24 hours after drug intake. Significant improvement of pain was achieved with dipyrone compared to placebo at all time points measured. Both patient and physician evaluations were significantly in favor of dipyrone. Side effects were few and trivial in both groups. We conclude that dipyrone is an effective, safe and cost-effective option in acute migraine management.

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.

Background Despite the well known inflammatory effects of tumour necrosis factor α (TNF), the mechanism of TNF-mediated lung injury following ischaemia–reperfusion (I/R) is still unclear. In this study, the role of TNF in the development of acute lung injury following intestinal I/R was investigated. Methods Male Wistar rats underwent either sham operation (n = 10), 1 h of superior mesenteric artery occlusion and 2 h of reperfusion (I/R, n = 10), or pretreatment with anti-TNF polyclonal antibody 2 mg/kg and I/R (n = 6). Lung injury was evaluated by Evans blue dye concentration, immunohistochemical staining and morphometric analysis. Intestinal injury was assessed by Evans blue dye concentration and histological examination. Results Intestinal I/R resulted in lung injury characterized by an increase in Evans blue dye concentration, neutrophil sequestration, and obvious staining for expression of pulmonary CD11b and CD18. Pretreatment of animals with anti-TNF antibody led to a reduction in the sequestration of neutrophils, and a decrease in expression of pulmonary intracellular adhesion molecule 1 and CD18. Anti-TNF antibody pretreatment also reduced the intestinal microvascular injury but not histological grade after intestinal I/R. Conclusion Treatment with an anti-TNF antibody resulted in a significant attenuation of lung injury following intestinal I/R. The data indicate that TNF is an important trigger for upregulation of pulmonary endothelial and neutrophil adhesion molecules after intestinal I/R.

Cerebral vasospasm is an important clinical phenomenon associated with a high mortality rate and therefore any promising findings in the laboratory deserve assessment in clinical practice. Dipyrone (Metamizol) has been in clinical use for its non-narcotic analgesic effect since 1922. In addition to its analgesic effect, dipyrone has been shown to possess spasmolitic activity in various smooth muscle organs. In our recent study, it was shown that dipyrone also has a relaxing effect in vascular smooth muscle preparations and that the smooth muscle relaxing effect on the rabbit thoracic aorta was produced by one of dipyrone's spontaneous degradation products. The present study was designed to examine the possible effects of dipyrone on the rabbit basilar artery in a model of cerebral vasospasm. Dipyrone was shown to have a clear spasmolitic effect in the rabbit basilar artery vasospasm produced by an intracisternal injection of autologous blood. This effect was apparent with either local or intravenous administration of dipyrone. These data suggest that dipyrone is potentially useful in the treatment of patients suffering from cerebral vasospasm in combination with other agents or alone.

To investigate the effects of intestinal ischemia and reperfusion (I/R) on the pulmonary vascular endothelium and smooth muscle.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.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.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.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.

This study examines the effects of Candida albicans on acethylcholineinduced, endothelium-dependent relaxation of thoracic aorta of rabbits, precontracted by phenylephrine (10−7M). Isolated vessel rings were incubated with C. Albicans, Saccharomyces cerevisiae, or their mannans, and endothelium-dependent relaxation was measured by the induction of acethylcholine. Endothelium-dependent relaxation remained unaffected after 3 hours by either C. albicans or S. cerevisiae, or their mannans. After 24 hours, however, incubation with C. albicans had completely abolished relaxation, whereas relaxation was decreased by mannan of C. albicans and continued unaffected by S. cerevisiae. In contrast, no change was registered with a 24 hours incubation of C. Albicans in a sodium nitroprusside-induced, endothelium-independent, vascular smooth muscle relaxation. Microscopical investigation of the morphological structure of vessel walls revealed penetration of C. albicans on the intimai surface after 3 hours incubation and infiltration of the yeast through the vessel wall after 24 hours. No changes in vessel morphology occurred after 3 or 24 hours with S. cerevisiae or the mannan of C. albicans. These results show the ability of C. albicans to inhibit endothelium-dependent, but not endothelium-independent, relaxation of vascular smooth muscle and may have important implications for functional damage to endothelial cells and the regulation of vessel tone and blood flow.

Phenprobamate (CAS 673-31-4) is a centrally acting skeletal-muscle relaxant agent. There are only two studies in the literature about the pharmacokinetics of phenoprobamate in man. The inconsistency between the results of these studies can be attributed partly to the different analytical methodologies used. A sensitive, specific and reproducible HPLC-assay, which may increase the reliability of the pharmacokinetic studies of phenprobamate in plasma, has been developed recently. The objective of this investigation was to assess the single-dose kinetics of phenprobamate in human and to determine the pharmacokinetic parameters of clinical and regulatory concern. The plasma pharmacokinetics of phenprobamate have been investigated following single oral administration at a dose of 800 mg in eleven healthy volunteers.

Findings have shown that dipyrone has a beneficial effect on skin flap survival. A pharmacologic explanation for this effect points to its vascular smooth muscle-relaxing effect. This study evaluated the effect of dipyrone on blood flow and thus survival of rat random dorsal skin flaps.For this study, 27 male Wistar albino rats were randomly assigned to control (treated with sterile saline) and treatment (treated with dipyrone 100 mg/kg) groups. A random dorsal skin flap measuring 4 x 10 cm was raised in each animal. The edges of the flap were sutured back into their original place. Dipyrone treatment continued at 100 mg/kg per day during the 7-day observation period. Blood flow was recorded by laser Doppler preoperatively (baseline), immediately after the flap was sutured back to its original position (acute), and on postoperative day 7. The degree of necrosis was evaluated by the grid method on day 7. Mean percentage necrosis and minimum laser Doppler readings were compared between the two groups.A significant increase in blood flow was observed in the dipyrone group at the acute phase but not on postoperative day 7. The percentage of the necrotic area was lower in the treatment group. However, it did not reach the significance level (p = 0.09).Dipyrone significantly increases [corrected] skin blood flow at the acute phase of flap elevation although the necrotic area does not reach the significance level.