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This study was designed to compare the efficacy of subarachnoid morphine alone or in combination with bupivacaine and fentanyl for combined spinal-epidural analgesia in colorectal surgery. This is a prospective, randomised, double-blind clinical trial. Sixty patients undergoing low anterior resection were assigned to one of three groups: subarachnoid morphine, bupivacaine and fentanyl, subarachnoid morphine and bupivacaine or subarachnoid morphine only. Epidural catheter placement and subarachnoid injection were done via a combined spinal-epidural Epistar needle at L2-3. The epidural catheter was used for scheduled intraoperative bupivacaine and intermittent postoperative bupivacaine and morphine administration. Intraoperative epidural bupivacaine, intraoperative intravenous fentanyl use, time to first analgesia request, postoperative visual analogue scale pain scores, tramadol requirements and side-effects were recorded for 72 hours. Postoperative analgesia was comparable in all groups. Intraoperative fentanyl and bupivacaine consumption was lowest in the morphine, bupivacaine and fentanyl group. Time to first analgesia request was longer in the morphine, bupivacaine and fentanyl compared to the morphine group (P = 0.009). Tramadol use was lower in the morphine and bupivacaine group compared to morphine, bupivacaine and fentanyl (P = 0.017) on postoperative day two. There were no significant adverse effects. All patients ambulated the morning after surgery. The addition of bupivacaine and fentanyl to subarachnoid morphine did not confer any advantage on postoperative visual analogue scale scores and tramadol use, but lowered the need for additional intraoperative intravenous fentanyl and epidural bupivacaine and prolonged the time to first analgesia request. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bladder carcinoma is the second most common carcinoma considering urological malignancy. This carcinoma is more frequent in male population. In past, apperiance of this malignancy was connected to the eldery population. Nowadays, yanger and yanger patients are affected even in the years of 40. The most common causes of bladder carcinoma are: smoking, exposition to organic solvents, calculosis etc. Urinary diversion following the cystectomy can be resolved through ureterocutaneostomy, ileal conduit and neobladder construction. Neobladder construction is the most confortable urinary derivation for patients, but this surgical procedure is the one of the most difficult in whole urological surgery and may be connected with numerous complications. After radical cystectomy, standard pouch (SP) is constructed using 40 to 60 cm of ileum providing good capacity and low pressure with satisfactory continence. During the time, increasing SP capacity leads to metabolic dissorders, voiding problems, excessive mucus production, urinary infection and calculosis. Nowadays, quality of life is on the top of priority in oncological patients. We present our original surgical technique with short ileal segment (< 35 cm) used for pouch creation- Belgrade pouch (BP) which can obtain excellent oncological outcome and high level of quality of live. METHODS: In this prospective clinical study we included male patients with pT2/pT3 stage of transitional cell carcinoma and ASA physical status 1 or 2, operated in Urology clinic of MMA during ten years period (2003- 2012). Exclusion criteria were chemotherapy, disease progression and inability to come for regular check ups. This procedure was allowed by Ethical commity of MMA. In order to situate ileum in the pelvis small incision was performed on the mesenteric trap. „U“ shaped pouch was constructed using up to 35 cm of terminal ileum. Direct uretero- neobladder anastomosis were used. Urethropouch anastomosis was created with 6 (5-7) sutures, and traction of 500 g was used. Pouch was flushed twice per day until hospital discharge. Patients were instructed to void every two to three hours in daytime, and in the nightime, to void twice. Surgery duration, daytime and nightime continence, post-void residual volume (PVR), acidosis, vitamin B12 deficit, neobladder calculosis and hydronephrosis as consequence of VUR or stenosis at the anastomotic level were recorded after six months, one, two and three years after surgery. RESULTS: Fifty four male patients 62(42-77) years old underwent surgery of average duration 208(150-330) min. Neobladder was constructed using 29(24-35) cm of terminal ileum. Average hospitalisation following the surgery was 16 (14-27) days. One pateint (1,8%) has vascular injury of iliac vessles, which is suttured during the operation. One patient has obstructive ileus (1,8%), which was resolved by reoperation and ileal conduit derivation, and tree more patents (5,5%) had paralytic ileus, managed conservatively. No rectum injuries were reported. Data recorded during study are presented in Table 1. CONCLUSION: Based on our data we concluded that BP resulted in adequate pouch capacity, small PVR, satisfactory daytime and nightime continence, lower incidence of acidosis, calculosis and vitamin B12 deficiency, without signifficant voiding frequancy and hydronephrosis during three years period. [ABSTRACT FROM AUTHOR]

Iron deficiency (IDA) and chronic disease (ACD) anemia are complications of inflammatory bowel diseases (IBDs). Therapeutic modalities in remission and active IBD depend on the type of anemia. This study evaluated the link between hepcidin-25, proinflammatory cytokines, and platelet activation markers as biomarkers of anemia and inflammation in active IBD and remission. This prospective observational study included 62 patients with IBD (49 with ulcerative colitis and 13 with Crohn's) and anemia. Patients were divided into Group I (no or minimal endoscopic signs of disease activity and IDA), Group II (moderate and major endoscopic signs of disease activity and mild ACD), and Control group (10 patients with IBD in remission, without anemia). We assessed the difference among groups in the levels of CRP, hemoglobin (Hgb), serum iron, ferritin, hepcidin-25, interleukins, TNF-α, IFN-γ, soluble CD40 ligand, and sP-selectin. Hepcidin-25 levels were significantly higher in Group II versus Group I (11.93 vs. 4.48 ng/mL, p < 0.001). Ferritin and CRP values showed similar patterns in IBD patients: significantly higher levels were observed in Group II (47.5 ng/mL and 13.68 mg/L) than in Group I (11.0 ng/mL and 3.39 mg/L) ( p < 0.001). In Group II, hepcidin-25 was positively correlated with ferritin (ρ = 0.725, p < 0.001) and CRP (ρ = 0.502, p = 0.003). Ferritin was an independent variable influencing hepcidin-25 concentration in IBD patients, regardless of disease activity and severity of anemia. IBD hepcidin-25 best correlates with ferritin, and both parameters reflected inflammation extent and IBD activity.

Background: Generative artificial intelligence (AI) models offer potential assistance in pain research data acquisition, yet concerns persist regarding data accuracy and reliability. In a comparative study, we evaluated open generative AI models' capacity to acquire data on acute pain in rock climbers comparable to field research., Methods: Fifty-two rock climbers (33 m/19 f; age 29.0 [24.0-35.75] years) were asked to report pain location and intensity during a single climbing session. Five generative pretrained transformer models were tasked with responses to the same questions., Results: Climbers identified the back of the forearm (19.2%) and toes (17.3%) as primary pain sites, with reported median pain intensity at 4 [3-5] and median maximum pain intensity at 7 [5-8]. Conversely, AI models yielded divergent findings, indicating fingers, hands, shoulders, legs, and feet as primary pain localizations with average and maximum pain intensity ranging from 3 to 4.4 and 5 to 10, respectively. Only two AI models provided references that were untraceable in PubMed and Google searches., Conclusion: Our findings reveal that, currently, open generative AI models cannot match the quality of field-collected data on acute pain in rock climbers. Moreover, the models generated nonexistent references, raising concerns about their reliability., (© 2024 the author(s), published by De Gruyter.)

Objectives: The quality of postoperative pain management is often poor. A "bundle," a small set of evidence-based interventions, is associated with improved outcomes in different settings. We assessed whether staff caring for surgical patients could implement a "Perioperative Pain Management Bundle" and whether this would be associated with improved multidimensional pain-related patient-reported outcomes (PROs)., Methods: "PAIN OUT," a perioperative pain registry, offers tools for auditing pain-related PROs and obtaining information about perioperative pain management during the first 24 hours after surgery. Staff from 10 hospitals in Serbia used this methodology to collect data at baseline. They then implemented the "Perioperative Pain Management Bundle" into the clinical routine and collected another round of data. The bundle consists of 4 treatment elements: (1) a full daily dose of 1 to 2 nonopioid analgesics (eg, paracetamol and/or nonsteroidal anti-inflammatory drugs), (2) at least 1 type of local/regional anesthesia, (3) pain assessment by staff, and (4) offering patients information about pain management. The primary endpoint was a multidimensional pain composite score (PCS), evaluating pain intensity, interference, and side effects that was compared between patients who received the full bundle versus not., Results: Implementation of the complete bundle was associated with a significant reduction in the PCS ( P < 0.001, small-medium effect size [ES]). When each treatment element was evaluated independently, nonopioid analgesics were associated with a higher PCS (ie, poorer outcome, and negligible ES), and the other elements were associated with a lower PCS (all negligible small ES). Individual PROs were consistently better in patients receiving the full bundle compared with 0 to 3 elements. The PCS was not associated with the surgical discipline., Discussion: We report findings from using a bundle approach for perioperative pain management in patients undergoing mixed surgical procedures. Future work will seek strategies to improve the effect., Competing Interests: This work was supported by (1) PAIN OUT was developed with funding from the European Community’s Seventh Framework Program FP7/2007-2013, Brussels, Belgium under Grant Agreement No. 223590. (2) The European Pain Federation (EFIC), Brussels, Belgium provided funding to the Serbian Pain Society to cover the costs of the project in Serbia. Funding included: (1) the annual subscription to PAIN OUT for 10 hospitals over a 2-year period, (2) two half-day face-to-face meetings so that the principal investigator and one research surveyor from each participating hospital could review the findings collected, and (3) partial remuneration to hospitals for data sets collected. The funds were transferred to the Serbian Pain Association, which then contacted each of the participating hospitals. W.M. received grants (paid to the institution) and personal fees from Grünenthal, grants (paid to the institution) from Pfizer and Mundipharma. Personal fees from TAD, BioQPharm, Bionorica, Kyowa, Northern Swan, and Tilray. U.M.S. received fees (paid to the institution) and reimbursement for travel costs from Sintetica and Sanofi-Aventis Swiss. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The Perioperative Pain Management Bundle was introduced in 10 Serbian PAIN OUT network hospitals to improve the quality of postoperative pain management. The Bundle consists of 4 elements: informing patients about postoperative pain treatment options; administering a full daily dose of 1-2 non-opioid analgesics; administering regional blocks and/or surgical wound infiltration; and assessing pain after surgery. In this study, we aimed to assess the cost-effectiveness of the Bundle during the initial 24 h after surgery., Materials and Methods: The assessment of cost-effectiveness was carried out by comparing patients before and after Bundle implementation and by comparing patients who received all Bundle elements to those with no Bundle element. Costs of postoperative pain management included costs of the analgesic medications, costs of labor for administering these medications, and related disposable materials. A multidimensional Pain Composite Score (PCS), the effectiveness measurement, was obtained by averaging variables from the International Pain Outcomes questionnaire evaluating pain intensity, interference of pain with activities and emotions, and side effects of analgesic medications. The incremental cost-effectiveness ratio (ICER) was calculated as the incremental change in costs divided by the incremental change in PCS and plotted on the cost-effectiveness plane along with the economic preference analysis., Results: The ICER value calculated when comparing patients before and after Bundle implementation was 181.89 RSD (1.55 EUR) with plotted ICERs located in the northeast and southeast quadrants of the cost-effectiveness plane. However, when comparing patients with no Bundle elements and those with all four Bundle elements, the calculated ICER was -800.63 RSD (-6.82 EUR) with plotted ICERs located in the southeast quadrant of the cost-effectiveness plane. ICER values differ across surgical disciplines., Conclusion: The proposed perioperative pain management Bundle is cost-effective. The cost-effectiveness varies depending on the number of implemented Bundle elements and fluctuates across surgical disciplines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bojic, Ladjevic, Palibrk, Soldatovic, Likic-Ladjevic, Meissner, Zaslansky, Stamer, Baumbach and Stamenkovic.)

The human brain contributes 2% of the body weight yet receives 15% of cardiac output and demands a constant supply of oxygen (O 2 ) and nutrients to meet its metabolic needs. Cerebral autoregulation is responsible for maintaining a constant cerebral blood flow that provides the supply of oxygen and maintains the energy storage capacity. We selected oxygen administration-related studies published between 1975-2021 that included meta-analysis, original research, commentaries, editorial, and review articles. In the present narrative review, several important aspects of the oxygen effects on brain tissues and cerebral autoregulation are discussed, as well the role of exogenous O 2 administration in patients with chronic ischemic cerebrovascular disease: We aimed to revisit the utility of O 2 administration in pathophysiological situations whether or not being advantageous. Indeed, a compelling clinical and experimental body of evidence questions the utility of routine oxygen administration in acute and post-recovery brain ischemia, as evident by studies in neurophysiology imaging. While O 2 is still part of common clinical practice, it remains unclear whether its routine use is safe., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Gullapalli P et al.)

At present, neither specific antiviral drugs, nor vaccine is recommended for coronavirus disease 2019 (COVID-19) treatment. In this review we discuss the drugs suggested as therapy for COVID-19 infection, with a focus on chloroquine and hydroxychloroquine. The list of drugs used for COVID-19 treatment includes a combination of lopinavir and ritonavir, remdesivir, favipiravir, alpha-interferon, ribavirin, atazanavir, umifenovir, and tocilizumab. As their efficacy and safety are under investigation, none of the regulatory agencies approved them for the treatment of COVID-19 infection. Although chloroquine and hydroxychloroquine possess antiviral and immunomodulatory effects, in practice benefit of their use for COVID-19 treatment is controversial. Several studies investigating hydroxychloroquine were stopped and the French national medicines regulator suspended its use in clinical trials because of safety concerns. The results from the double-blind, randomised clinical trials, including large number of participants, will add better insight into the role of these two drugs as already available and affordable, antimalarial therapy. The ethical issue on emergency use of chloroquine and hydroxychloroquine in the settings of COVID-19 should be carefully managed, with adherence to the "monitored emergency use of unregistered and experimental interventions" (MEURI) framework or be ethically approved as a trial, as stated by the WHO. Potential shortage of chloroquine/hydroxychloroquine on the market can be overbridged with regular prescriptions by medical doctors and national drug agency should ensure sufficient quantities of these drugs for standard indications., (© 2020 John Wiley & Sons Ltd.)

Introduction: The burden of untreated postoperative pain is high., Objective: This study assessed feasibility of using quality improvement (QI) tools to improve management of perioperative pain in hospitals in multiple developing countries., Methods: The International Pain Registry and Developing Countries working groups, from the International Association for the Study of Pain (IASP), sponsored the project and PAIN OUT, a QI and research network, coordinated it, and provided the research tools. The IASP published a call about the project on its website. Principal investigators (PIs) were responsible for implementing a preintervention and postintervention study in 1 to 2 surgical wards in their hospitals, and they were free to choose the QI intervention. Trained surveyors used standardized and validated web-based tools for collecting findings about perioperative pain management and patient reported outcomes (PROs). Four processes and PROs, independent of surgery type, assessed effectiveness of the interventions., Results: Forty-three providers responded to the call; 13 applications were selected; and PIs from 8 hospitals, in 14 wards, in 7 countries, completed the study. Interventions focused on teaching providers about pain management. Processes improved in 35% and PROs in 37.5% of wards., Conclusions: The project proved useful on multiple levels. It offered PIs a framework and tools to perform QI work and findings to present to colleagues and administration. Management practices and PROs improved on some wards. Interpretation of change proved complex, site-dependent, and related to multiple factors. PAIN OUT gained experience coordinating a multicentre, international QI project. The IASP promoted research, education, and QI work., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Background: Metamizole is a medication with analgesic, antipyretic, spasmolytic, and weak anti-inflammatory effects. The aim of our study was to evaluate a six-year trend in the utilization and expenditure of metamizole in comparison to other group of licensed non-opioid analgesics in Serbia and Croatia, in order to rationalize its use and prescribing in these countries. Methods: The data of metamizole vs. all other non-opioid analgesics utilization and expenditure in Serbia and Croatia was analyzed according to the WHO methodology and expressed as defined daily doses per 1,000 inhabitants per day (DDD/1,000 inhabitants/per day) and total costs, respectively, during the 6-year period from 2010 to 2015. Results: In the observed period, utilization of metamizole was 3.31 fold higher in Serbia than in Croatia (median in Serbia was 2.238 vs. 0.675 in Croatia DDD/1,000 inhabitants/per day/per year). Expenditure of metamizole in the same period was 5.29-fold higher in Serbia than in Croatia (median in Serbia was 1,738,192.51 €/per year vs. 328,355.03 €/per year in Croatia). Conclusion: Utilization and expenditure of non-opioid analgesics, including metamizole, in Serbia was significantly higher comparing with Croatia.Further research is needed to determine whether the current analgesic consumption in Serbia meets the needs of the patient. The benefits of metamizole should be weighed against the risk of metamizole-induced adverse effects. Until then, its prescribing should be based on indications and the appropriate duration of therapy.

Background: Few studies analyzed the pattern of opioid analgesic utilization in hospital settings. The aim of this study was to determine the consumption pattern of parenteral morphine in patients hospitalized in the Serbian referral teaching hospital and to correlate it with utilization at the national and international level., Methods: In retrospective study, the required data were extracted from medical records of surgical patients who received parenteral morphine in the 5-year period, from 2011 to 2015. We used the Anatomical Therapeutic Chemical Classification/Defined Daily Doses (DDD) international system for consumption evaluation., Results: While the number of performed surgical procedures in our hospital steadily increased from 2011 to 2015, the number of inpatient bed-days decreased from 2012. However, the consumption of parenteral morphine varied and was not more than 0.867 DDD/100 bed-days in the observed period., Conclusion: Based on the available data, parenteral morphine consumption in our hospital was lower compared with international data. The low level of morphine use in the hospital was in accordance with national data, and compared with other countries, morphine consumption applied for medical indications in Serbia was low. Adequate legal provision to ensure the availability of opioids, better education and training of medical personnel, as well as multidisciplinary approach should enable more rational and individual pain management in the future, not only within the hospitals.

Introduction: This prospective, observational study evaluated transanal dearterialization (THD) efficacy and safety in grade 2-4 hemorrhoids (HD)., Methods: THD was performed under sedation-locoregional anesthesia in 402 outpatients. Patients had follow-up evaluation 3 days, 2 weeks, 1, 6 and 12 months postoperatively. Postoperative complications and recurrence of symptoms at 12 months were analyzed. The relationship between the learning curve and the number of postoperative complications was studied., Results: Mean patient age was 46.4 (range 20-85) years. A total of 268 patients (66.6%) were male. Sixteen patients (4.0%) had grade 2 HD, 210 (52.2%) had grade 3 and 176 (43.8%) had grade 4 HD. Surgery lasted 23 (17-34) min. A total of 67 patients had complications: bleeding in 10 patients (2.5%), hemorrhoidal thromboses in 10 (2.5%), perianal fistulas in 5 (1.2%), fissures in 14 (3.5%), urinary retention in 3 (0.8%), residual prolapse in 19 (4.7%), severe anal pain in 3 (0.8%), and perianal abscess in 3 patients (0.8%). Recurrent HD occurred in 6.3% (1/16) of grade 2 HD patients, 5.8% (12/210) of grade 3 patients and 9.7% (17/176) of grade 4 patients. Twelve months after THD, bleeding was controlled in 363 patients (90.5%), prolapse was controlled in 391 (97.3%) and pain markedly improved in 390 patients (97%)., Conclusion: THD appears safe and effective for grade 2-4 HD, and the number of complications decreased with increasing surgeon experience. THD advantages include mild pain, fast recovery, early return to daily activities and low incidence of complications., (Copyright © 2016 AEC. All rights reserved.)

Objective: Serum calcitonin (CT) is a sensitive but not specific marker for medullary thyroid carcinoma (MTC). There are a large number of conditions that may elevate CT levels., Case Report: Herein we present the case of a 47-year old woman with Hashimoto thyroiditis, goiter, cervical lymphadenopathy and high CT and CEA levels. After surgical extirpation of the lymph node neuroendocrine cancer metastasis was suspected. Computed tomography of the chest showed a tumor mass on the right lung. Bronchoscopy was performed and pathological and immunohistochemical analysis revealed large cell neuroendocrine lung cancer (LCNEC). After chemotherapy, significant reduction of tumor mass was achieved with a moderate decrease in CT levels in parallel., Conclusions: We present a female with LCNEC, a condition which is usually observed in older men (7(th) decade) and is not associated with CT secretion. Hashimoto thyroiditis is associated with increased incidence of different types of cancers (e.g. thyroid, colon). No reports at present exist on the incidence of lung cancers in patients with thyroid disease.

Background/aims: Early assessment of disease severity and vigilant patient monitoring are key factors for adequate treatment of acute pancreatitis (AP). The aim of this study was to determine the correlation of procalcitonin (PCT) serum concentrations and intra-abdominal pressure (IAP) as prognostic markers in early stages of AP., Methods: This prospective observational study included 51 patients, of which 29 had severe AP (SAP). Patients were evaluated with the Acute Physiology And Chronic Health Evaluation (APACHE II) score, C-reactive protein (CRP) and PCT serum concentrations and IAP at 24 h from admission. PCT was measured three times in the 1st week of disease and three times afterward, while IAP was measured daily. PCT and IAP values correlated with each other, and also compared with APACHE II score and CRP values., Results: PCT, IAP, CRP values and APACHE II score at 24 h after hospital admission were significantly elevated in patients with SAP. There was significant correlation between PCT and IAP values measured at 24 h of admission, and between maximal PCT and IAP values. Sensitivity/specificity for predicting AP severity at 24 h after admission was 89%/69% for APACHE II score, 75%/86% for CRP, 86%/63% for PCT and 75%/77% for IAP., Conclusions: Increased IAP was accompanied by increased PCT serum concentration in patients with AP. PCT and IAP can both be used as early markers of AP severity., (Copyright © 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to quantify the duration and severity of postoperative coagulopathy in order to establish the optimal time for epidural catheter removal., Methods: In a 2-year retrospective study, 140 consecutive patients underwent major liver resection., Results: Epidural catheters were present in 123 patients (87.9%). Resections were: 33 (26.8%) right hepatectomy (with or without left metastasectomy), 9 (7.3%) left hemihepatectomy (with or without right metastasectomy), 37 (30.1%) trisectionectomy (extended hemihepatectomy) and 44 (35.8%) non-anatomical metastasectomy. Surgery was quantified by segments resected (4 [range: 1-7]). Vascular inflow occlusion was used in 65.6%. Ischaemic time was 26.5 min (range: 0-104 min). Platelet count fell postoperatively and was lowest on day 2 (205±72 10(9) L(-1)). There was a significant increase in prothrombin time, activated partial thromboplastin time and International Normalised Ratio (INR) postoperatively, peaking on day 2 (21.5±5.6 s, 37.9±5.8 s and 1.9±0.5, respectively). Changes persisted beyond day 6. Epidural catheters were removed on day 5 (1-11), with a protocol criterion of INR <1.2. Actual INR on day 5 was 1.49±0.36., Conclusion: Despite this, no epidural or spinal haematoma was recorded.

The PROMO (preference for once monthly bisphosphonate) Study, conducted in seven hospital centres in Croatia between June 2007 and June 2008, was designed to analyse patient preference for weekly and monthly bisphosphonates in everyday clinical practice where the significant proportion of patients are not completely satisfied with the current osteoporosis treatment. Eligible participants were women with postmenopausal osteoporosis taking weekly bisphosphonates for the last 6 months. Those who agreed to be enrolled were transferred from weekly to monthly ibandronate for the next 6 months. There was no washout period between the two treatment regimens. At the baseline, patients expressed their satisfaction with the weekly treatment. At the end of the study, all patients were asked to complete the five-question survey specially designed for this study. Study population comprised 258 participants. Among 248 patients who completed the study, 244 (98.4%) declared their preference for one of the regimens or they had no preference. Once-monthly regimen was preferred by 231 patients (94.7%), whereas once-weekly regimen was preferred by five patients (2.0%). Eight patients (3.3%) indicated no preference. Furthermore, 93.0% of patients thought that monthly dosing was more convenient. Compared to weekly regimen, monthly dosing was associated with significantly higher satisfaction with the treatment and with significantly less adverse events. In line with these data, 85.9% of patients stated improved quality of life with monthly ibandronate. In summary, the PROMO Study demonstrated strong patient preference for monthly over weekly dosing which is expected to improve suboptimal adherence to weekly bisphosphonates.

Background: It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens., Methods and Results: To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg x kg(-1) x d(-1)) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced the activity and expression of vascular membrane-bound rac1, a GTPase required for the activation of the NAD(P)H oxidase. Finally, blood pressure levels were significantly decreased in spontaneously hypertensive rats treated with raloxifene. All SERM effects were also detected in healthy age-matched Wistar rats. In cultured rat aortic vascular smooth muscle cells, raloxifene inhibited angiotensin II-induced reactive oxygen species production dependent on estrogen receptor activation., Conclusions: Raloxifene treatment improves hypertension-induced endothelial dysfunction by increased bioavailability of NO. This is achieved by an increased activity of endothelial NO synthase and by an estrogen receptor-dependent reduction in release of reactive oxygen species from vascular cells. These vascular effects cause a profound blood pressure reduction and lead to decreased vascular damage in male spontaneously hypertensive rats.