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PubMed2000

Conditioned compensatory response to ethanol as indicated by locomotor activity in rats.

Spontaneous motor activity (SMA) was used to investigate conditioned tolerance to the depressant effect of ethanol, and conditioned responses to stimuli predicting ethanol injection. Rats were injected with saline or ethanol at 800 or 1600 mg/kg, on alternate days, in two distinctly different locations, over a period of 20 conditioning days. The two ethanol doses were administered to separate groups of rats, but conditioned effects were determined by within-subject comparisons. Conditioned SMA responses (rearing and ambulatory activity) were measured after injection of saline in the location previously paired with ethanol treatment, and conditioned tolerance was determined by observing ethanol effects in rats tested in the environment previously paired with saline treatment. Ethanol-paired stimuli increased SMA (both activity measures, both dose-groups) during the conditioned response test. Absence of these conditioned stimuli during the tolerance test resulted in greater behavioral depression with the 800 mg/kg ethanol dose for both the rearing and ambulation measures; however, this effect was seen with the 1600 mg/kg dose for the rearing measure only. These results provide further evidence that Pavlovian conditioning is involved in tolerance to the depressant action of ethanol on overt behavior, and demonstrate the presence of such conditioned compensatory responses in the absence of ethanol treatment.

Animals↗
PubMed1977

Evidence for parallel development of tolerance to the hyperactivating and discoordinating effects of ethanol.

Rats maintained on diets containing 6.5% ethanol or equicaloric sucrose solutions were challenged at weekly intervals with 1.5 or 2.0 g/kg ethanol or isotonic saline 14 h after withdrawal from the diet. Tolerance developed to both the hyperactivating (increased line crossings and time active) and discoordinating (disrupted rotarod performance) effects of the 1.5 g/kg dose of ethanol, but was less obvious with the 2.0 g/kg dose. Chlorpromazine (2.5 mg/kg) had a greater depressant effect in animals chronically treated with ethanol, suggesting that some alterations in the functioning of noradrenergic and/or dopaminergic systems may accompany chronic ethanol treatment. However, amphetamine and propranolol did not appear to affect ethanol- and sucrose-treated rats differently. The present studies have therefore shown a parallel development of tolerance to the discoordinating and hyperactivating effects of ethanol and have implicated an underlying noradrenergic and/or dopaminergic mechanism, although the precise nature of the mechanism has not been clarified.

Alcoholic Intoxication↗
PubMed1996

Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants.

OBJECTIVE: To test whether early postnatal (0 to 3 hours) intravenous administration of ibuprofen will prevent patent ductus arteriosus (PDA) in preterm neonates. DESIGN: Prospective sequential controlled trial with three treatment arms. SETTING: Level 3 perinatal-neonatal intensive care nursery. PATIENTS: Thirty-four premature newborn infants born from February to August 1993 with a mean birth weight of 913 g (range, 565 to 1460 g) and gestational age of 26.9 weeks (range, 22.4 to 31.0). INTERVENTION: Infants were consecutively assigned within 3 hours of age to treatment with either one dose of ibuprofen lysine (10 mg/kg intravenously) followed by 5 mg/kg per dose intravenously at 24 and 48 hours of age (n = 12), one dose of ibuprofen lysine (10 mg/kg intravenously; n = 11), or saline (n = 11). OUTCOME VARIABLES: Primary outcome variable was the presence of ductus arteriosus by echocardiography and clinical assessments at 3, 7, and 21 days of life. Secondary outcome variables included presence of intraventricular hemorrhage, renal function, ventilatory and oxygen needs, hematologic changes, gastrointestinal function, time to full enteral feeding, duration of hospitalization, and age at discharge. RESULTS: The three groups of patients were comparable in birth weight, gestational age, antenatal administration of betamethasone, and other perinatal characteristics. Ibuprofen treatment significantly reduced plasma levels of prostaglandins, and the levels remained low for 72 hours in newborns who received three doses of the drug. The incidence of PDA and other variables did not differ between patients who received a single dose of ibuprofen and those given saline. However, compared with the saline-treated newborns, babies who received three doses of ibuprofen had no PDA (0/12 vs 7/11 for saline; P < .02), had lower daily mean airway pressures (mean +/- SD, 5.2 +/- 1.1 cm H2O vs 8.3 +/- 2.8 cm H2O for saline; P < .02) and better oxygenation index (2.6 +/- 0.6 vs 4.7 +/- 1.8 for saline; P < .02) at the end of the first week of life, and required fewer days of ventilation (25 +/- 14 days vs 44 +/- 26 days for saline; P < .03). Babies given three doses of ibuprofen tended to tolerate full oral feedings earlier (35 +/- 19 days vs 56 +/- 34 days for saline; P = .09), had shorter duration of hospitalization (71.2 +/- 22.6 days vs 127.3 +/- 74.7 days for saline; P < .05), and were discharged to home at an earlier postconceptional age (37.8 +/- 2.0 weeks vs 44.8 +/- 9.8 weeks for saline; P < .05). ibuprofen treatment in this phase I trial was not associated with any apparent early neurological, intestinal, renal, hepatic, or hematologic complications. CONCLUSIONS: Administration of three doses of ibuprofen within 3 hours after birth in preterm neonates reduced the incidence of PDA without causing notable early adverse drug reactions in this phase I trial. Early closure of the ductus arteriosus was also associated with better respiratory outcome and earlier discharge from the hospital.

Analysis of Variance↗
PubMed1999

Chimeric peptide of Met-enkephalin and FMRFa induces antinociception and attenuates development of tolerance to morphine antinociception.

A synthetic chimeric peptide of Met-enkephalin and FMRFamide (YGGFMKKKFMRFa), based on MERF was synthesized. This peptide was tested for possible antinociceptive effects using the tail flick test in mice. The effect of the chimeric peptide on morphine antinociception and development of tolerance to the antinociceptive action of morphine was also investigated. The chimeric peptide produced significant, dose-dependent antinociception (40, 60 and 90 mg/kg) in the tail flick test. Pretreatment with naloxone (5 mg/kg, IP) significantly attenuated the antinociceptive effect induced by the chimeric peptide (90 mg/kg, IP), indicating involvement of an opioidergic mechanism. In combination experiments with morphine, the antinociceptive dose of the chimeric peptide (60 mg/kg, IP) potentiated morphine (7 mg/kg, IP) antinociception. A low dose of the chimeric peptide (10 mg/kg, IP), that did not produce significant antinociception on its own, also potentiated morphine antinociception. In the tolerance studies, male albino mice received twice daily injections of morphine (20 mg/kg, IP) followed by either saline (0.1 ml) or chimeric peptide (80 mg/kg, IP) for a period of 4 days. A control group received twice daily injections of saline (0.1 ml) for the same period. When tested on Day 5, tolerance to antinociceptive action of morphine (15 mg/kg, IP) was evidenced by decreased response in chronic morphine plus saline treated mice compared to control group. Concurrent administration of chimeric peptide (80 mg/kg, IP) with morphine significantly attenuated the development of tolerance to the antinociceptive action of morphine. The preliminary results of this study demonstrate that peripherally administered chimeric peptide can produce dose dependent, naloxone reversible, antinociception; potentiate morphine antinociception and attenuate morphine tolerance, indicating a possible role of these type of amphiactive sequences in antinociception and its modulation. These chimeric peptides may also prove to be useful tools for further ascertaining the role of FMRFa family of peptides in mechanisms leading to opiate tolerance and dependence.

Analgesics↗
PubMed1971

Immune response to chemically modified flagellin. II. Evidence for a fundamental relationship between humoral and cell-mediated immunity.

Flagellin (mol.wt. 40,000) from S. adelaide organisms and a series of acetoacetyl derivatives of flagellin were tested for their ability to induce humoral and cell-mediated immunity in adult rats. It was found that unmodified flagellin was an excellent inducer of antibody formation but a poor inducer of delayed-type hypersensitivity. In contrast, increasing acetoacetylation steadily destroyed the ability of flagellin to initiate antibody formation but enhanced the capacity of the molecule to induce flagellin-specific cell-mediated immunity and antibody tolerance. In fact, it appeared that in adult rats antibody formation and cell-mediated immunity may well be opposing immunological processes. Furthermore, the affinity of the acetoacetyl flagellins for anti-flagellin antibodies appeared to determine the type of immune response which predominated. High affinity antigen produced antibody formation whereas low affinity antigen induced cell-mediated immunity and antibody tolerance. The importance of affinity was further evidenced by the fact that a CNBr digest of flagellin induced humoral and cellular immune responses identical to an acetoacetylated flagellin of comparable antigenic activity. From these studies it was proposed that both humoral and cell-mediated immunity can be directed against the same antigenic determinants but that the specificity requirements for delayed hypersensitivity (and antibody tolerance) are less than those required for antibody formation. Some remarkable immunological features of the flagellin system were revealed. Flagellin induced comparable delayed-type hypersensitivity when injected in either saline or FCA. Furthermore, FCA only slightly enhanced the delayed responses induced by the acetoacetyl flagellins and in fact these preparations produced antibody tolerance whether injected in saline or adjuvant. Finally, in contrast to the adult tolerance induced by the acetoacetylated flagellins, which existed only at the antibody level, tolerance in neonatal rats existed at the level of both humoral and cell-mediated immunity. This finding is the first indication of a fundamental difference between neonatal and adult tolerance. The significance of these findings is discussed in the light of current immunological concepts and a hypothesis proposed to explain these phenomena.

Acetoacetates↗
PubMed1996

Inhibition of phosphatidylinositol-3'-kinase prevents induction of endotoxin tolerance in vitro.

Previous studies have shown an increase in the expression of phosphatidylinositol-3'-kinase (PI-3'-K) in macrophages from endotoxin tolerant (ET) rats. This implicates PI-3'-K cell signaling in attenuated macrophage responsiveness to lipopolysaccharide (LPS). These experiments examined the effects of selective pharmacologic inhibition of PI-3'-K in an in vitro model of ET. To induce ET, RAW 264.7 macrophages cultured in RPMI 1640 with 10% fetal calf serum were initially exposed to 10 ng/ml LPS (E. coli 0111:B4) for 19 hr. Non-tolerant cells received an equal volume of phosphate buffered saline. Some cultures were also incubated with the specific PI-3'-K inhibitor wortmannin (10 nM) during this tolerizing period. Cells were then washed and re-challenged with 100 ng/ml LPS for 24 hr. Next, macrophage tumor necrosis factor-alpha (TNF-alpha) and nitrite production were measured as indicators of ET induction. Macrophage TNF-alpha production decreased significantly while nitrite production increased significantly following ET induction. Specific inhibition of PI-3'-K prevented this decrease in TNF-alpha and increase in nitrite production in ET macrophages. Production of each mediator returned to levels not different than in non-tolerant macrophages. In this in vitro model of macrophage ET, pharmacologic inhibition of the PI-3'-K signaling pathway prevented the induction of LPS tolerance as measured by the production of two inflammatory mediators.

Androstadienes↗
PubMed1975

DDT: short term effects on osmoregulation in black surfperch (Embiotoca jacksoni).

DDT injected intraperitoneally into black surfperch caused substantial increases in plasma osmotic concentration only at doses much larger than are likely to be encountered in nature. Increased plasma concentrations were below those tolerated by fish adapted to high salinities. Death of marine teleosts from DDT poisoning probably involves factors other than simply osmoregulatory failure.

Animals↗
PubMed1982

Effects of chronic opiate administration of spontaneous activity of fetal rats.

No studies have been reported previously on fetal behavior after chronic morphine administration during the period of opiate receptor ontogenesis. In the present study, pregnant rats were injected with 20 mg/kg/day divided into either two or four daily doses. The injections were made from day 12 through the end of gestation. On days 18-20, the effect of morphine and naloxone on fetal activity in the pretreated animals was assessed by visual observation and quantification. Animals exposed twice daily to morphine showed a morphine-induced depression in spontaneous activity similar to animals pretreated with saline while animals injected four times daily developed tolerance to the depressant effect of the morphine. Animals injected with either morphine or levorphanol were hyperactive after challenge with naloxone. Animals injected with saline or dextrorphan or pair-fed were not hyperactive after exposure to naloxone. Even though behavioral changes were seen in utero after injection of morphine, 30-day neonates which had been treated identically prenatally did not show changes in the analgesic response to morphine.

Animals↗
PubMed2002

Prophylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from Phase II studies.

The first clinical studies evaluating the safety and efficacy of melagatran, a novel, direct thrombin inhibitor, given subcutaneously as prophylaxis for venous thromboembolism (VTE) following total hip (THR) or total knee replacement (TKR) are reported. In Study I, 66 patients received subcutaneous melagatran (1.5-6 mg bid) in a poloxamer depot formulation, and in Study II, 104 patients received subcutaneous melagatran (2-4 mg bid) in saline or as a depot formulation in cyclodextrin. Treatment was given for 8-11 days, with the first dose administered immediately before surgery. Deep vein thrombosis (DVT) was assessed using mandatory bilateral venography on the last day of treatment, and pulmonary scintigraphy was performed if required. Bleeding complications occurred in the only patient who received melagatran 6 mg, and this dose-arm was discontinued. The frequency of VTE was low (12/129=9%, 95% confidence interval [CI]: 5-16%). Eight patients (6%) had distal DVT, three (2%) had proximal DVT, and in one patient (1%) pulmonary embolism (PE) was verified. In conclusion, subcutaneous melagatran 1.5-4.5 mg bid in saline or depot formulation was well tolerated and resulted in a low frequency of VTE.

Adolescent↗
PubMed2003

Advances in the assessment of the uterus and fallopian tube function.

Hysterosalpingo-contrast-sonography (HyCoSy) using saline and Echovist is a well tolerated outpatient technique that provides a significant amount of information of relevance to the infertile woman that is not obtainable at hysterosalpingogram (HSG) whilst avoiding exposure to X-ray irradiation. When performed by experienced operators, it serves as a valuable, first-line screening test for the more invasive procedures of laparoscopy and dye chromopertubation and hysteroscopy. If detailed diagnostic information is required in women in whom there is no clinical or ultrasound evidence of pelvic pathology, the surgical technique of fertiloscopy can be considered to be appropriate. This technique permits confirmation that the ovum pick-up mechanism is normal, the tubes are patent and the uterine cavity is normal, while salpingoscopy and microsalpingoscopy permit the assessment of the tubal lumen.

Diagnostic Techniques, Obstetrical and Gynecologic↗
PubMed2001

Effects of heat pretreatment on histopathology, cytokine production, and surfactant in endotoxin-induced acute lung injury.

To determine the effect of heat stress on histopathology of acute lung injury (ALI) caused by administration of lipopolysaccharide (LPS), and to determine the roles of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, IL-10 and surfactants in heat-induced tolerance to ALI, we administered either saline or LPS (3 mg/kg of body weight) intravenously to male Sprague-Dawley rats without and with heat pretreatment. Five hours after LPS or saline treatment (23 h after heat-pretreatment), samples were obtained. We found that the histopathologic features of LPS-induced ALI were attenuated by heat-pretreatment. Heat-pretreatment did not decrease the elevated plasma or BAL fluid levels of TNF-alpha, IL-1beta, and IFN-gamma by LPS. The plasma level of IL-10 in LPS-treated rats with heat-pretreatment, however, was increased compared to that of LPS-treated rats without heat-pretreatment (P = 0.001). There were no differences in the BAL fluid concentrations of light or heavy density pulmonary surfactant phospholipids depending on heat-pretreatment in LPS-treated rats. These observations suggest that IL-10 might play a role in decreasing LPS-induced acute lung injury after heat-pretreatment.

Acute Disease↗
PubMed2003

Pilot study of the safety and effect of intranasal delipidated acid-treated Mycobacterium vaccae in adult asthma.

OBJECTIVE: There is epidemiological and experimental evidence that exposure to mycobacteria has the potential to suppress the development of atopy and/or asthma. Delipidated, deglycolipidated and arabinogalactan-depleted autoclaved Mycobacterium vaccae (delipidated acid-treated M. vaccae) has been shown to suppress allergen-induced airway eosinophilia in mice. METHODOLOGY: Thirty-seven adults with stable moderately severe asthma who were skin prick test-positive to house dust mite were randomized to receive two doses 2 weeks apart of delipidated acid-treated M. vaccae (first dose 0.4 mg and second dose 0.8 mg) or phosphate buffered saline, given as drops intranasally. Safety, tolerability and markers of asthma severity (including peak flow, FEV1, major and minor exacerbations, symptom scores and beta-agonist use), and nasal symptom scores, blood eosinophil and IgE levels were monitored for 8 weeks. RESULTS: Delipidated acid-treated M. vaccae was safe and well tolerated although there was an occasional mild local reaction. There were no statistically significant differences between the treatment group and placebo for any of the outcome variables. CONCLUSIONS: There is a requirement to elucidate the reasons why mycobacterial-based vaccines have not shown equivalent efficacy in human trials compared with animal models. The role of factors such as duration of disease, route of administration and the active component of mycobacteria need to be addressed.

Administration, Intranasal↗
PubMed1999

Safety and immunogenicity of capsular polysaccharide-tetanus toxoid conjugate vaccines for group B streptococcal types Ia and Ib.

About 40% of invasive group B streptococcal (GBS) isolates are capsular polysaccharide (CPS) types Ia or Ib. Because infant and maternal GBS infections may be preventable by maternal vaccination, individual GBS CPS have been coupled to tetanus toxoid (TT) to prepare vaccines with enhanced immunogenicity. Immunogenicity in rabbits and protective capacity in mice of a series of type Ia- and Ib-TT conjugates increased with the degree of polysaccharide-to-protein cross-linking. In total, 190 healthy, nonpregnant women aged 18-40 years were randomized in four trials to receive Ia- or Ib-TT conjugate (dose range, 3.75-63 microg of CPS component), uncoupled Ia or Ib CPS, or saline. All vaccines were well-tolerated. CPS-specific IgG serum concentrations peaked 4-8 weeks after vaccination and were significantly higher in recipients of conjugated than of uncoupled CPS. Immune responses to the conjugates were dose-dependent and correlated in vitro with opsonophagocytosis. These results support inclusion of Ia- and Ib-TT conjugates when formulating a multivalent GBS vaccine.

Adolescent↗
PubMed2001

A fertile amphiploid between durum wheat (Triticum turgidum) and the x Agroticum amphiploid (Agropyron cristatum x T. tauschii).

Agropyron (Gaertn) is a genus of Triticeae which includes the crested wheatgrass complex, i.e. A. cristatum (L.) as representative species containing the P genome. This species is an important source for increase the genetic variability of both durum and bread wheat. Among the possible interesting features to be introgressed into wheat are resistance to wheat streak mosaic virus, rust diseases, and tolerance to drought, cold and moderate salinity. By crossing tetraploid wheat (Triticum turgidum conv durum, 2n = 4x = 28; AABB) with a fertile allotetraploid (2n = 4x = 28; DDPP) between diploid wheat (T. tauschii) and crested wheatgrass (A. cristatum L.), amphiploid plants were obtained. Fluorescence in situ hybridization (FISH) using both genomic DNA from A. cristatum and the repetitive probe pAs1, proved that the plants were true amphiploids with a chromosome number 2n = 8x = 56 and genomic constitution AABBDDPP. Using total genomic in situ hybridization (GISH) to study meiotic metaphase I, data on allosyndetic and autosyndetic chromosome pairing were obtained. The amphiploids were perennial like the male parent but their morphology was close to that of the wheat parent. They were resistant to wheat leaf rust and powdery mildew under field conditions.

Chimera↗
PubMed1990

Paracellular intestinal absorption of glucose, creatinine, and mannitol in normal animals: relation to body size.

Mice, rats, or rabbits were provided with a liquid diet of 10-12% glucose (Glc), 0.5-1% creatinine, 1-2% mannitol, and mannitol labeled with 3H on a terminal carbon. Average rates of ingestion of Glc were greater than maximum rates of active, carrier-mediated Glc transport reported for the intestines of these species. The discrepancy was small in mice but increased exponentially with body weight (BW). Ingestion-absorption of Glc increased exponentially with the 0.73 power of BW as expected from metabolic rate, whereas active transport, estimated from the literature, varied exponentially with the 0.50 power of BW. It is estimated that in humans the ingestion-absorption rate of Glc may be 10-20 times greater than active transport. In the presence of Glc, 50-65% of the ingested creatinine was recovered in urine compared with 75-85% recovered after intraperitoneal or subcutaneous injections. The amount of creatinine recovered in urine depended on the amount of ingested Glc, as predicted from the effects of Glc on width and permeability of absorptive cell junctions. Eighty percent or more of the 3H label on mannitol was recovered in urine or other body fluids, although most of the [3H]mannitol was oxidized to [3H]water after being absorbed intact from the intestine. It is concluded that in the presence of Glc, creatinine and mannitol (together with Glc, amino acids, and other small nutrients) are absorbed passively by solvent drag between absorptive cells, as found previously in anesthetized rats (J. R. Pappenheimer and K. Z. Reiss. J. Membr. Biol. 100: 123-136, 1987). The ratio of solvent drag to carrier-mediated transport increases exponentially with BW and may account for the capacity of human intestines to absorb large amounts of Glc during prolonged exercise, Glc tolerance tests, or oral Glc-saline therapy for dehydration.

Animals↗
PubMed2005

Dose-response effect of elevated plasma free fatty acid on insulin signaling.

The dose-response relationship between elevated plasma free fatty acid (FFA) levels and impaired insulin-mediated glucose disposal and insulin signaling was examined in 21 lean, healthy, normal glucose-tolerant subjects. Following a 4-h saline or Liposyn infusion at 30 (n = 9), 60 (n = 6), and 90 (n = 6) ml/h, subjects received a 2-h euglycemic insulin (40 mU . m(-2) . min(-1)) clamp. Basal plasma FFA concentration ( approximately 440 micromol/l) was increased to 695, 1,251, and 1,688 micromol/l after 4 h of Liposyn infusion and resulted in a dose-dependent reduction in insulin-stimulated glucose disposal (R(d)) by 22, 30, and 34%, respectively (all P < 0.05 vs. saline control). At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). The highest lipid infusion rate (90 ml/h) caused a further significant reduction in all insulin signaling events compared with the low-dose lipid infusion (P < 0.05-0.01) whereas the 60-ml/h lipid infusion caused an intermediate reduction in insulin signaling. However, about two-thirds of the maximal inhibition of insulin-stimulated glucose disposal already occurred at the rather modest increase in plasma FFA induced by the low-dose (30-ml/h) lipid infusion. Insulin-stimulated glucose disposal was inversely correlated with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.50, P = 0.001) and the plasma FFA level during the last 30 min of the insulin clamp (r = -0.54, P < 0.001). PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). In summary, in skeletal muscle of lean, healthy subjects, a progressive increase in plasma FFA causes a dose-dependent inhibition of insulin-stimulated glucose disposal and insulin signaling. The inhibitory effect of plasma FFA was already significant following a rather modest increase in plasma FFA and develops at concentrations that are well within the physiological range (i.e., at plasma FFA levels observed in obesity and type 2 diabetes).

Adult↗
PubMed2004

Sensing and adapting to environmental stress: the archaeal tactic.

Archaea occupy a considerable diversity of niches encompassing extreme environments with extreme of pH, salinity and temperature that cannot be tolerated by other forms of life. Survival and colonisation requires the capacity to sense, and adapt to environmental change. In this review we consider the issues of adaptation to environmental stresses, in particular the mechanisms that might be employed by different Archaea to respond to the specific challenges of their particular niche. We lay emphasis on the strategies adopted to respond to oxidative and chemical stress. In particular, this paper reviews major key points in the generation of reactive oxygen species in Archaea, defense mechanisms and genetic responses to oxidative stress. Finally, we discuss complex biological response mechanisms to chemical damage with particular attention to detoxification from metals and drugs.

Adaptation, Physiological↗
PubMed2003

Low-dose flunitrazepam for conscious sedation for EGD: a randomized double-blind placebo-controlled study.

BACKGROUND: EGD with conscious sedation is a safe procedure, but complications such as hypoxia can occur. The efficacy and safety of low-dose flunitrazepam (0.25 mg) was compared with a standard dose of flunitrazepam (0.5 mg) for moderate sedation during EGD. METHODS: In a randomized, double-blind, placebo-controlled trial, 75 outpatients (40 men, 35 women, mean age 45 [11] years) undergoing screening EGD were randomly assigned to one of 3 treatment arms: 0.25 mg of flunitrazepam (F0.25 group), 0.5 mg of flunitrazepam (F0.5 group), or placebo (normal saline solution), each administered intravenously. Patient tolerance was scored by using self-assessment questionnaires with visual analogue scales. Cardiopulmonary complications were assessed by monitoring blood pressure, heart rate, oxygen saturation, and the electrocardiogram during the procedure. RESULTS: The patient tolerance scores in the F0.25 and F0.5 groups, respectively 2.1 (2.1) and 2.3 (2.5), were significantly lower than that for the placebo group (6.5 [3.0]); there was no significant difference between F0.25 and F0.5. Cardiopulmonary complications in the F0.25 group were significantly lower than in the F0.5 group. Oxygen desaturation (oxygen saturation < 90%) was noted in two of 25 patients in the F0.5 group. Post-procedure drowsiness was observed in two of 24 (8.3%) patients in the F0.25 group and 3 of 21 (14.3%) in the F0.5 group (p = 0.2438). CONCLUSIONS: Patient tolerance of EGD with low-dose flunitrazepam (0.25 mg intravenously) was similar to that with a standard dose (0.5 mg intravenously) and significantly better than in the placebo group. Oxygen desaturation was observed only in the group that received the standard dose, suggesting that sedation with low-dose flunitrazepam is efficacious and safe for EGD.

Anti-Anxiety Agents↗