Drug-Drug Interactions and Their Association With Quality of Life in Patients With Hypertension.

Introduction This study aimed to evaluate drug-drug interactions (DDIs) and their association with the quality of life in patients with hypertension. Materials and methods This cross-sectional study included 123 patients with hypertension. DDIs were evaluated using the Medscape Drug Interaction Checker Database (Medscape, New York, NY). The EuroQol-5D (EQ-5D) Quality of Life Scale was used for each patient. Results The overall blood pressure control rate (systolic/diastolic blood pressure levels, <140/90 mmHg) was 43% (53/123). The age of the patients with uncontrolled hypertension was higher than the patients with controlled hypertension (63.67 ± 11.00 vs. 58.42 ± 10.07 years; p = 0.007). The number of DDIs showed significant correlations, positively with age (r = 0.303, p = 0.001), total number of drugs (r = 0.784, p < 0.001), number of antihypertensive drugs (r = 0.640, p < 0.001), and body mass index (BMI) (r = 0.321, p < 0.001) and inversely with EQ-5D index score (r = -0.247, p = 0.006). The EQ-5D index and visual analog score were inversely correlated with age and BMI. Additional significant linear correlations between age and the total number of drugs, age and number of the antihypertensive drugs, the number of antihypertensive drugs and BMI, and the number of total drugs and BMI were detected. Of a total of 511 identified DDIs, 14 interactions in 12 patients were considered serious, 402 interactions in 82 patients were considered significant, and 95 interactions in 39 patients were considered minor. Conclusions This study supports that DDIs have important associations with antihypertensive treatment and the quality of life of patients. Higher age and BMI values were associated with a higher risk of DDIs and lower quality of life in patients with hypertension.

How COVID-19 changed clinical research strategies: a global survey.

OBJECTIVE: Clinical research has faced new challenges during the COVID-19 pandemic, leading to excessive operational demands affecting all stakeholders. We evaluated the impact of COVID-19 on clinical research strategies and compared different adaptations by regulatory bodies and academic research institutions in a global context, exploring what can be learned for possible future pandemics. METHODS: We conducted a cross-sectional online survey and identified and assessed different COVID-19-specific adaptation strategies used by academic research institutions and regulatory bodies. RESULTS: All 19 participating academic research institutions developed and followed similar strategies, including preventive measures, manpower recruitment, and prioritisation of COVID-19 projects. In contrast, measures for centralised management or coordination of COVID-19 projects, project preselection, and funding were handled differently amongst institutions. Regulatory bodies responded similarly to the pandemic by implementing fast-track authorisation procedures for COVID-19 projects and developing guidance documents. Quality and consistency of the information and advice provided was rated differently amongst institutions. CONCLUSION: Both academic research institutions and regulatory bodies worldwide were able to cope with challenges during the COVID-19 pandemic by developing similar strategies. We identified some unique approaches to ensure fast and efficient responses to a pandemic. Ethical concerns should be addressed in any new decision-making process.

Turkish inappropriate medication use in the elderly (TIME) criteria to improve prescribing in older adults: TIME-to-STOP/TIME-to-START.

PURPOSE: To improve prescribing in older adults, criterion sets have been introduced from different countries. While current criterion sets are useful to some extent, they do not meet the need in some European countries. Turkish inappropriate medication use in the elderly (TIME) criteria was planned to meet this need. METHODS: In phase 1, the user friendly sets: STOPP/START version2 and CRIME criteria were combined. National experts composed of geriatricians and non-geriatricians were invited to review and comment. In phase 2, thorough literature review was performed and reference-based revisions, omissions, and additions were made. Explanatory additions were added to some criteria to improve application in practice. In phase 3, all working group members reviewed the criteria/explanations and agreed on the final content. RESULTS: Phase 1 was performed by 49 expert academicians between May and October 2016. Phase 2 was performed by 23 working group academicians between October 2016 and November 2018 and included face-to-face interviews between at least two geriatrician members and one criterion-related specialist. Phase 3 was completed between November 2018-March 2019 with review and approval of all criteria by working group academicians. As a result, 55 criteria were added, 17 criteria were removed, and 60 criteria were modified from the first draft. A total of 153 TIME criteria composed of 112 TIME-to-STOP and 41 TIME-to-START criteria were introduced. CONCLUSION: TIME criteria is an update screening tool that differs from the current useful tools by the interactive study of experts from geriatrics and non-geriatrics, inclusion of practical explanations for some criteria and by its eastern European origin. TIME study respectfully acknowledges its roots from STOPP/START and CRIME criteria. Studies are needed whether it would lead improvements in older adults' health.

Legal and ethical framework for global health information and biospecimen exchange - an international perspective.

BACKGROUND: The progress of electronic health technologies and biobanks holds enormous promise for efficient research. Evidence shows that studies based on sharing and secondary use of data/samples have the potential to significantly advance medical knowledge. However, sharing of such resources for international collaboration is hampered by the lack of clarity about ethical and legal requirements for transfer of data and samples across international borders. MAIN TEXT: Here, the International Clinical Trial Center Network (ICN) reports the legal and ethical requirements governing data and sample exchange (DSE) across four continents. The most recurring requirement is ethical approval, whereas only in specific conditions approval of national health authorities is required. Informed consent is not required in all sharing situations. However, waiver of informed consent is only allowed in certain countries/regions and under certain circumstances. The current legal and ethical landscape appears to be very complex and under constant evolution. Regulations differ between countries/regions and are often incomplete, leading to uncertainty. CONCLUSION: With this work, ICN illuminates the unmet need for a single international collaborative framework to facilitate DSE. Harmonising requirements for global DSE will reduce inefficiency and waste in research. There are many challenges to realising this ambitious vision, including inconsistent terminology and definitions, and heterogeneous and dynamic legal constraints. Here, we identify areas of agreement and significant difference as a necessary first step towards facilitating international collaboration. We propose the establishment of a working group to continue the comparison across jurisdictions, create a standardised glossary and define a set of basic principles and fundamental requirements for DSE.

Evaluating the relationship of blood pressure, plasma angiotensin peptides and aldosterone with cognitive functions in patients with hypertension.

Renin Angiotensin Aldosterone System (RAAS) plays an important role in the development of hypertension. On the other hand, hypertension is a well-known and independent risk factor for cognitive impairment. The aim of the present study was to evaluate the relationship of blood pressure control, plasma angiotensin peptides and aldosterone with cognitive functions. Forty-one patients who were under treatment with the same antihypertensive medications for at least three months were included in the study. Plasma angiotensin II, angiotensin 1-7, angiotensin IV, and aldosterone concentrations were analyzed using an enzyme-linked immunosorbent assay (ELISA). Standardized Mini Mental State Examination (SMMSE) was used to evaluate cognitive functions. When the participants were grouped according to their SMMSE scores (cut-off value: 26 points), we determined significant differences between systolic blood pressure (SBP) levels, diastolic blood pressure levels, plasma angiotensin II and angiotensin 1-7 concentrations of the groups. When the participants were stratified according to their SBP levels (cut-off value: 140 mm Hg), we found significant differences in SMMSE scores and plasma angiotensin IV concentrations of the groups. A negative correlation between SBP and SMMSE scores and strong linear correlations among angiotensin peptides levels were determined. The relationship found between SBP and SMMSE in the present study was compatible with the literature. Our 33 patients were using at least one angiotensin II receptor blocker (ARB). Regarding AT1 receptor blockage, the significant association between higher SMMSE scores and increased angiotensin peptides may support a finding that ARBs prevent dementia and improve cognitive function. Further larger studies are needed to confirm and prove the relation of RAAS biochemical parameters with cognitive function.

Renin-angiotensin-aldosterone system blockers and cardiovascular outcomes: a meta-analysis of randomized clinical trials.

OBJECTIVE: Hypertension is the most prevalent modifiable risk factor for cardiovascular (CV) and cerebrovascular morbidity and mortality. This study aimed to assess the effects of renin-angiotensin-aldosterone system (RAAS) blockade on CV outcomes. METHODS: This study was designed according to the Preferred Reporting Items for Systemic reviews and Meta-Analyses statement. Databases were searched for articles published as of December 2014. Two sets of studies were selected. One set included randomized clinical trials comparing RAAS blocker (angiotensin II receptor blocker [ARB] or angiotensin-converting enzyme inhibitor [ACEI]) with placebo or active treatment. Second set included head-to-head randomized clinical trials comparing an ARB with an ACEI. Studies in both sets had reported any CV outcome parameter or death, i.e., all-cause mortality, CV mortality, emergence of CV events, myocardial infarction, cerebrovascular event, stroke, heart failure, and hospitalization for heart failure. RESULTS: Fifty-four pairwise comparisons of 51 trials with 277,609 patients were included. Statistically significant differences in favor of RAAS blockers vs non-RAAS blockers (risk ratio [RR] ranging from 0.805 to 0.967) were observed in terms of most CV outcomes, including all-cause mortality, CV mortality, CV events, myocardial infarction, heart failure and stroke. ARBs and ACEIs were found to be completely comparable (RR ranging from 0.923 to 1.090, all non-significant). CONCLUSION: RAAS blockers are superior to medications other than RAAS blockers with respect to impact on CV outcomes in patients with hypertension. ARBs and ACEIs are comparable in terms of these outcomes.

Renin inhibitors in diabetes and hypertension: an update.

The coexistence of hypertension and diabetes increases the incidence of cardiovascular events and long-term morbidity and mortality. Blood pressure should be controlled with the most appropriate drugs as well as tight blood glucose control in patients with diabetes and hypertension. RAAS (Renin Angiotensin Aldosterone System) blockers have an important role in the treatment of these patients, in this sense, ACEi and ARB remained the major treatment option in hypertension guidelines. The most recent RAAS blocker to be approved by the FDA was aliskiren in 2007, a renin inhibitor. Studies showed that aliskiren is as effective as other antihypertensive drugs and has a safety profile similar to placebo. The potent renin inhibitor aliskiren directly inhibits the RAAS system at its rate limiting step and differently from other RAAS blockers; it decreases plasma renin activity (PRA). Although the relationship of increased PRA levels and cardiovascular risk has been shown, it is unclear if the PRA decrease provided by aliskiren has an impact on clinical outcomes and cardiovascular endpoints. On the other hand, large trials like ASPIRE, AVANT-GARDE, ALTITUDE, ASTRONAUT, which investigated the combination of aliskiren with other RAAS blockers, failed to show the expected outcomes or resulted with an increased incidence of adverse effects, which raised more questions. As a result of the ALTITUDE trial, combination of aliskiren with an ACEi or ARB is not recommended in patients with hypertension and diabetes, or at least moderate renal dysfunction. Trials designed to prove aliskiren's efficacy in new indications like diabetes, may face similar problems related to dual RAAS blockade because in the majority of cases, the optimal treatment is achieved with an ACEi or ARB. In this conjuncture, the increase in adverse events seen with aliskiren might be related to dual RAAS blockade rather than aliskiren directly. For instance, it is unclear whether the adverse event incidence would be the same, less, or higher if ALTITUDE was designed to investigate ACEi and ARB combination without aliskiren. In fact, every new molecular entity and mechanism of action faces the same barriers. For the time being, differentiating points like PRA lowering effects as an add-on therapy to calcium channel blockers or hydrochlorothiazide, and the populations that might have additional benefit, should be carefully investigated.

Aliskiren: review of efficacy and safety data with focus on past and recent clinical trials.

Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. Clinical data have substantiated that the antihypertensive effectiveness of aliskiren is similar to that of the other major antihypertensive agents. Furthermore, aliskiren has a similar safety profile to placebo. Combination treatment with aliskiren showed significant blood pressure and proteinuria reductions compared with monotherapy. Aliskiren decreases plasma renin activity in contrast to other renin-angiotensin-aldosterone related drugs. The efficacy of aliskiren in treating major cardiovascular events and the prevention of end-organ damage are being investigated in the ASPIRE HIGHER program. Although the first studies of the ASPIRE HIGHER program such as ALOFT, AVOID, AGELESS showed favorable findings, ASPIRE and AVANT-GARDE studies provided contradictory results. Subsequently, the ALTITUDE study was terminated early because of safety issues and lack of beneficial effects. Most recently, the ASTRONAUT trial showed no reduction in cardiovascular death or heart failure rehospitalization with the addition of aliskiren to standard therapy in patients who were hospitalized for heart failure and with reduced left-ventricular ejection fraction. The results of ongoing studies in other patient groups such as the ATMOSPHERE trial are awaited.

The efficacy and safety of triple vs dual combination of angiotensin II receptor blocker and calcium channel blocker and diuretic: a systematic review and meta-analysis.

Many hypertensive patients require ≥2 drugs to achieve blood pressure targets. This study aims to review and analyze the clinical studies conducted with dual or triple combination of angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics. Medical literature between January 1990 and April 2012 was reviewed systematically and data from eligible studies were abstracted. Data were analyzed using random-effects models. Of the 224 studies screened, 7563 eligible patients from 11 studies were included. Triple combinations of ARBs (olmesartan or valsartan), CCBs (amlodipine), and diuretics (hydrochlorothiazide) at any dose provided more blood pressure reduction in office and 24-hour ambulatory measurements than any dual combination of these molecules (P<.0001 for both). Significantly more patients achieved blood pressure targets with triple combinations (odds ratio, 2.16; P<.0001). Triple combinations did not increase adverse event risk (odds ratio, 0.96; P=.426). Triple combinations at any dose seem to decrease blood pressure more effectively than dual combination of the same molecules without any remarkable risk elevation for adverse events. Further prospective studies evaluating the efficacy and safety of triple combinations, especially in the form of single pills, are required.

Potential adjuvant effects of Nigella sativa seeds to improve specific immunotherapy in allergic rhinitis patients.

OBJECTIVE: To investigate the effects of Nigella sativa seed supplementation on symptom levels, polymorphonuclear leukocyte (PMN) functions, lymphocyte subsets and hematological parameters of allergic rhinitis. SUBJECTS AND METHODS: Twenty-four patients randomly selected from an experimental group of 31 (mean age 34 years) sensitive to house dust mites with allergic rhinitis and a control group of 8 healthy volunteers (mean age 23 years) were treated with allergen-specific immunotherapy in conventional doses for 30 days. After a month of immunotherapy, 12 of the 24 patients and the 8 healthy volunteers were given N. sativa seed supplementation (2 g/day orally) for 30 days. The remaining 12 patients continued only on immunotherapy during the same period. The other 7 patients were given 0.1 ml saline solution subcutaneously once a week as a placebo. The symptom scores, PMN functions, lymphocyte subsets and other hematological parameters were evaluated before and after all treatment periods. RESULTS: There was a statistically significant increase in the phagocytic and intracellular killing activities of PMNs of patients receiving specific immunotherapy, especially after the addition of N. sativa seed. The CD8 counts of patients receiving specific immunotherapy plus N. sativa seed supplementation significantly increased compared to patients receiving only specific immunotherapy. PMN functions of healthy volunteers significantly increased after N. sativa seed supplementation compared to baseline. CONCLUSION: N. sativa seed supplementation during specific immunotherapy of allergic rhinitis may be considered a potential adjuvant therapy.

Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension.

OBJECTIVE: To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension. METHODS: In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed. RESULTS: At week 8, aliskiren, ramipril and aliskiren/ramipril lowered msDBP (mean+/-SEM) by 11.3+/-0.5, 10.7+/-0.5 and 12.8+/-0.5 mmHg, and msSBP by 14.7+/-0.9, 12.0+/-0.9 and 16.6+/-0.9 mmHg, respectively. Aliskiren/ramipril provided superior msDBP reductions to ramipril (p=0.004) or aliskiren (p=0.043) monotherapy; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg. Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction (p=0.0002) and superior for msSBP reduction (p=0.021). All treatments significantly lowered mean 24-hour ambulatory BP. Aliskiren significantly reduced PRA from baseline as monotherapy (by 66%, p<0.0001) or in combination with ramipril (by 48%, p<0.0001), despite large increases in PRC in all treatment groups. Aliskiren was well tolerated as monotherapy or in combination with ramipril. CONCLUSIONS: Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension.

Effects of valsartan on stress-induced changes of serum vascular endothelial growth factor and nitric oxide in mice.

This study investigated the effects of renin-angiotensin system (RAS) blockade on stress-induced changes of serum vascular endothelial growth factor (VEGF) and nitric oxide (NO) in mice. Chronic stress increased the serum NO levels significantly compared to control group (p = .0172). Valsartan, an angiotensin II receptor antagonist, alone, did not make significant difference versus control group. In chronic stress + valsartan group, serum NO levels decreased nonsignificantly compared to chronic stress group. There was a nonsignificant increase in serum VEGF levels after chronic stress. Valsartan alone or with chronic stress did not significantly affect the serum VEGF levels. In conclusion, there was no correlation between NO and VEGF changes during the stress response. In this respect, there may be other mechanisms to explain the stress-induced NO increase.

Influence of polymerization method, curing process, and length of time of storage in water on the residual methyl methacrylate content in dental acrylic resins.

This study compared the influence of different polymerization methods (heat, auto-, and microwave energy), different curing processes (in the case of heat- and autopolymerized specimens), and length of storage of the polymerized specimens in distilled water at 37 degrees C on the residual methyl methacrylate (MMA) content in dental acrylic resin specimens. Residual MMA of 120 resin specimens were measured using high-performance liquid chromatography. For the heat-polymerized resins, the lowest residual MMA content was obtained when they were given a long-term terminal boil and then stored in the distilled water for at least 1 day. For the autopolymerized resins, the lowest residual MMA content was obtained when they were additionally cured in water at 60 degrees C and then stored in the distilled water at least 1 day. For the microwave-polymerized resins, the lowest residual MMA content was obtained when they were stored in the distilled water at least 1 month. The lowest overall residual MMA content was obtained from heat-polymerized specimens that were given a long-term terminal boil cure and then stored in the distilled water at least 1 day. Different polymerization methods and curing processes have different effects on residual MMA content. It is thus shown that storing a dental acrylic resin specimen in distilled water at 37 degrees C is a simple but effective method of reducing its residual MMA content.

Losartan may prevent the elevation of plasma glucose, corticosterone and catecholamine levels induced by chronic stress.

INTRODUCTION: Stress is a stimulus that activates the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Increased activity of the SNS causes to increment or impairment in blood pressure, heart rate, body temperature and plasma glucose and adreno- corticotrophic hormone (ACTH) levels. Angiotensin II (Ang II), which is a product of the renin-angiotensin system (RAS), is an important factor affecting the activity of the SNS and responses to stress. We suggest that the blockade of Ang II may be worthwhile in the prevention and treatment of diabetes mellitus and cardiovascular diseases affected by stress. Therefore, we investigated the effects of immobilisation stress on blood glucose, norepinephrine (NE), epinephrine (E) and corticosterone levels and the effects of an Ang II receptor antagonist, losartan, on these parameters. MATERIALS AND METHODS: The rats were kept in small cylindrical cages for 60 min/day for 10 consecutive days to perform chronic immobilisation stress. Losartan (10 mg/kg) was given daily by gavage to Losartan (L) and Losartan + Chronic Stress (L+CS) groups. Control (C) and Chronic Stress (CS) groups received an equal volume of saline daily by gavage for 10 days. After the last stress regimen, blood samples were collected for plasma glucose, NE, E and corticosteroid measurements. RESULTS: Plasma glucose, NE, E and corticosterone levels in the CS Group increased significantly compared with the C group. In Group L+CS, the plasma glucose, NE, E and corticosterone levels decreased significantly vs. Group CS. In Group L there was no significant difference vs. Group C. CONCLUSION: It can be speculated that chronic blockade of RAS may decrease the excess sympathetic responses to stress in cardiovascular diseases and prevent the likely development of Type II diabetes mellitus.

Alpha rhythm of the EEG modulates visual detection performance in humans.

The effects of the changes in the frequency spectrum of the electroencephalogram (EEG) on the perception of near-threshold visual stimuli and on the event-related potentials (ERPs) produced by these stimuli were investigated on 12 healthy volunteers. The stimulus intensity, at which each subject could detect 50% of the presented stimuli, was defined as the sensory threshold for that subject. Single ERP trials were separated into two groups: trials with detected and undetected stimuli. The ERPs and the average power spectra of the 1 s prestimulus periods were computed for both conditions. P300 amplitudes of the ERPs, and total power and relative band powers of the delta (0.5-4 Hz), theta (4-7.5 Hz), alpha (7.5-13 Hz), beta (13-30 Hz), and gamma (30-70 Hz) frequency bands of the prestimulus power spectra were measured. Between the two conditions, a specific difference was observed in the relative power of the alpha band, which was significantly lower before detected stimuli (p < 0.01) in line with significantly higher amplitudes of the ERPs (p < 0.001). These results show that short-lasting changes in brain's excitability state are reflected the relative alpha power of the EEG, which may explain significant variability in perceptual processes and ERP generation especially at boundary conditions such as sensory threshold.

Effects of nitrendipine on reference and working memory of rats in three-panel runway.

This study was designed to investigate whether calcium-channel blocker, nitrendipine affects memory of rats in three-panel runway test. Nitrendipine (2-4 mg kg(-1), intra peritoneally (i.p.)) neither enhanced nor impaired reference and working memory performances of young adult rats. However, it improved impairment in reference memory induced by anticholinergic drug scopolamine (3 mg kg(-1), i.p.) while it had no effects on impairment in working memory induced by the same drug. The results suggest that nitrendipine may be of benefit in the treatment of memory disturbances resulted from cholinergic deficit.

Losartan may prevent the elevation of plasma glucose levels induced by chronic stress.

The effect of angiotensin II antagonist, losartan, on chronic stress-induced elevation of blood glucose levels was investigated in rats. Chronic immobilization stress caused an increase in blood glucose levels in rats. Administration of losartan (3 mg/kg, po) before stress exposure significantly prevented this increment. We suggest that losartan showed this effect by decreasing the excessive sympathetic response to stress. In conclusion, there is a relationship between stress, sympathetic nervous system, and renin-angiotensin system.

A model of pharmacology education: the experience of Istanbul Medical Faculty.

This article describes the pharmacology education program that has been applied since 1990 at the Istanbul Medical Faculty. In Turkey, medical education lasts 6 years after 11 years of general training. Each year, approximately 350 students join the Istanbul Medical Faculty. The education is mainly in conventional form: basic sciences and elementary clinical information are given mostly as didactic lectures accompanying practical courses for small groups, with each group consisting of about 50 students during the first 3 years. In the subsequent 2 years, students have several clinical clerkships, and the last year is an internship. Pharmacology, the bridge between basic and clinical sciences, has a special place in the medical training. Accordingly, the courses were expanded to 3, 4, and 5 years, the sum of all courses being approximately 140 hours. Pharmacology education took place along with basic sciences in the first years but with clinical sciences in the later years and is based on active learning methods.

Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia, tolerance and dependence in mice.

The effects of L-Canavanine, a selective inducible nitric oxide synthase (NOS) inhibitor and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, on pain threshold and morphine induced analgesia, tolerance and dependence in mice were investigated and compared. Morphine was administered by subcutaneous implantation of a pellet containing 40 mg free base and withdrawal was precipitated by intraperitoneal (i.p.) injection of naloxone (2 mg/kg). L-Canavanine (200 mg/kg, i.p.) did not affect the pain threshold, morphine-induced analgesia and the induction and expression phases of morphine tolerance and dependence. L-NAME (20 mg/kg, i.p.) significantly (p < 0.05) enhanced the pain threshold, potentiated morphine-induced analgesia and attenuated the expression phase of morphine dependence which has been characterized by withdrawal signs and body weight loss, but did not modify the induction phase of morphine tolerance and dependence. It is concluded that constitutive NOS isoforms which were inhibited by L-NAME may be involved specifically in the mechanisms of morphine induced analgesia, tolerance and dependence.