Short-term Administration Of High Doses Research Articles

Silver nanoparticle-induced oxidative stress-dependent toxicity in Sprague-Dawley rats.

Due to the intensive commercial application of silver nanoparticles (Ag-NPs), their health risk assessment is of great importance. For acute toxicity evaluation of orally administered Ag-NPs, induction of reactive oxygen species (ROS), activity of liver function enzymes [(alanine (ALT/GPT), aspartate (AST/GOT), alkaline phosphatase (ALP)], concentration of lipid hydroperoxide (LHP), comet assay, and histopathology of liver in the rat model were performed. Four groups of five male rats were orally administered Ag-NPs, once a day for five days with doses of 5, 25, 50, 100mg/kg, body weight. A control group was also made of five rats. Blood and liver were collected 24h after the last treatment following standard protocols. Ag-NPs exposure increased the induction of ROS, activities of the liver enzymes (ALT, AST, ALP), concentration of lipid hydroperoxide (LHP), tail migration, and morphological alterations of the liver tissue in exposed groups compared to control. The highest two doses, 50 and 100mg/kg showed statistically significant (p<0.05) increases in ROS induction, ALT, AST, ALP activity, LHP concentration, DNA damage, and morphological alterations of liver compared to control. Based on these results, it is suggested that short-term administration of high doses of Ag-NP may cause organ toxicity and oxidative stress.

Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients

Background:Ticagrelor is a direct-acting, reversibly binding, oral P2Y12 platelet inhibitor that reduces thrombotic cardiovascular events in patients with acute coronary syndrome. Dyspnea is one of the most commonly reported adverse events associated with ticagrelor.Objective:To determine the effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease (COPD) patients.Methods:Two randomized, double-blind, placebo-controlled, two-way crossover, single-center studies were conducted: 1) healthy elderly volunteers (55–75 years; n = 12); 2) patients with mild asthma (n = 11) or mild-to-moderate COPD (n = 7). Subjects were randomized to receive ticagrelor (a single 450 mg dose, 180 mg 12 hours later, twice daily for 2 days, and once on day 4) or placebo, with a 7 day washout. Pulmonary function at rest and during exercise was monitored using similar schedules and assessments across the two studies.Results:Resting pulmonary function parameters, including respiratory rate, minute ventilation, or tidal volume, were similar between ticagrelor and placebo in any cohort. Furthermore, bronchospasm (as determined by spirometry and pulse oximetry), was not observed with either ticagrelor or placebo in any cohort. Perception of breathing was generally similar following ticagrelor or placebo. Exercise performance was not affected, and no clinically relevant differences were seen in pulmonary parameters during exercise for ticagrelor or placebo. There was no apparent relationship between plasma concentrations of ticagrelor and its main metabolite and pulmonary function. Ticagrelor was well tolerated in all cohorts. Study limitations include the use of relatively few subjects without documented coronary artery disease.Conclusions:Short-term administration of high doses of ticagrelor did not appear to alter pulmonary function at rest and during exercise in subjects at risk of (healthy elderly) or with respiratory impairment (mild asthma or mild-to-moderate COPD).

Tissue-specific upregulation of HSP72 in mice following short-term administration of alcohol

Oxidative stress and cellular injury have been implicated in induction of HSP72 by alcohol. We investigated the association between HSP72 induction and oxidative stress in mouse tissues following short-term administration of high doses of alcohol and caffeine alone or in combination. Adult male C57BL/6J mice were gavaged with vehicle, alcohol (∼1.7g/kg/day), caffeine (∼44mg/kg/day), or alcohol plus caffeine once daily for ten consecutive days. Upon completion of the treatments, tissues were collected for structural and biochemical analyses. Alcohol alone caused mild to moderate lesions in heart, liver, and gastrocnemius muscle. Similar structural changes were observed following administration of alcohol and caffeine combined. Alcohol administration also led to decreased glutathione levels in all three tissues and reduced plasma superoxide dismutase capacity. In contrast, alcohol and caffeine in combination reduced glutathione levels only in liver and gastrocnemius muscle and had no effect on plasma superoxide dismutase. Significant elevations in HSP72 protein and mRNA and in HSF1 protein levels were noted only in liver by alcohol alone or in combination with caffeine. No significant changes in morphology and HSP72 were detected in any tissues tested following administration of caffeine alone. These results suggest that a redox mechanism is involved in the structural impairment caused by short-term high-dose alcohol. Oxidative tissue injury by alcohol may not be associated with tissue HSP72 induction. Induction of HSP72 in liver by alcohol is mediated at both the transcriptional and translational levels.

Statins in prevention of contrast-induced nephropathy in patients with coronary heart disease and renal insufficiency undergoing percutaneous coronary intervention

Objective To explore the role of short-term, high-dose atorvastatin in the prevention of contrast-induced nephropathy ( CIN ) in patients with renal insufficiency after percutaneous coronary intervention ( PCI ).Methods 41 patients with coronary heart discease ( CHD ) and renal insufficiency underwent scheduled PCI.They received either 80 mg/d of atorvastatin ( study group,n =21 ),or 20 mg/d of atorvastatin ( control group,n =20 ) for 3 days before PCI.Serum creatinine ( SCr )levels were measured before and on days 1,2,and 3 after PCI.CIN was defined as an increase in SCr values of ≥ 25％ or ≥ 0.5 mg/dl from the baseline within 3 days after PCI.Results There were no significant differences in levels of SCr between the two groups at different time points ( P ＞ 0.05 ).The incidence rate of CIN did not differ significantly between the two groups ( one in each group,P＞ 0.05 ).There was no significant difference in the peak level of SCr between the study group and the control group after intervention ( 232.4 μmol/L vs.227.6 μmol/L,P＞ 0.05 ).Conclusions On the basis of standard intravenous hydration,a short-term administration of high doses of atorvastatin before and after contrast exposure fails to decrease CIN occurrence in CHD patients with pre-existing renal insufficiency. Key words: Statins; Contrast-induced nephropathy; Prevention

Usefulness of Atorvastatin (80 mg) in Prevention of Contrast-Induced Nephropathy in Patients With Chronic Renal Disease

We investigated the efficacy of short-term high-dose atorvastatin in decreasing the risk of contrast-induced nephropathy (CIN) in patients with chronic kidney disease (CKD) subjected to coronary angiography and/or angioplasty. CIN occurs in up to 15% of patients with pre-existing CKD and affects clinical outcome. The protective effect of statin therapy against CIN is still controversial. A prospective, single-center study of 304 patients with baseline estimated creatinine clearance <60 ml/min were randomized to receive atorvastatin 80 mg/day or placebo for 48 hours before and 48 hours after contrast medium administration. All patients received intravenous saline hydration and oral N-acetylcysteine 1,200 mg 2 times/day. Iso-osmolar contrast medium was used. CIN was defined as an absolute increase of serum creatinine > or = 0.5 mg/dl within 5 days after the procedure. CIN occurred in 31 patients (10%), 16 (11%) in the placebo group and 15 (10%) in the atorvastatin group (p = 0.86). Mean increase in creatinine was not significantly different in the 2 groups (0.59 + or - 0.17 in placebo group vs 0.72 + or - 0.26 mg/dl in atorvastatin group, p = 0.31). Persistent kidney injury, defined as 1-month increase from baseline creatinine value > or = 25%, was observed in 30% in the placebo group and in 31% in the atorvastatin group (p = 0.58). In conclusion, a short-term administration of high doses of atorvastatin before and after contrast exposure, in addition to standard intravenous hydration and oral N-acetylcysteine, does not decrease CIN occurrence in patients with pre-existing CKD.

Long-term testosterone supplementation augments overnight growth hormone secretion in healthy older men

Circulating testosterone (T) and GH/IGF-I are diminished in healthy aging men. Short-term administration of high doses of T augments GH secretion in older men. However, effects of long-term, low-dose T supplementation on GH secretion are unknown. Our objective was to evaluate effects of long-term, low-dose T administration on nocturnal GH secretory dynamics and AM concentrations of IGF-I and IGFBP-3 in healthy older men (65-88 yr, n = 34) with low-normal T and IGF-I. In a double-masked, placebo-controlled, randomized study we assessed effects of low-dose T supplementation (100 mg im every 2 wk) for 26 wk on nocturnal GH secretory dynamics [8 PM to 8 AM, Q(20) min sampling, analyzed by multiparameter deconvolution and approximate entropy (ApEn) algorithms]. The results were that T administration increased serum total T by 33% (P = 0.004) and E(2) by 31% (P = 0.009) and decreased SHBG by 17% (P = 0.002) vs. placebo. T supplementation increased nocturnal integrated GH concentrations by 60% (P = 0.02) and pulsatile GH secretion by 79% (P = 0.05), primarily due to a twofold increase in GH secretory burst mass (P = 0.02) and a 1.9-fold increase in basal GH secretion rate (P = 0.05) vs. placebo. There were no significant changes in GH burst frequency or orderliness of GH release (ApEn). IGF-I levels increased by 22% (P = 0.02), with no significant change in IGFBP-3 levels after T vs. placebo. We conclude that low-dose T supplementation for 26 wk increases spontaneous nocturnal GH secretion and morning serum IGF-I concentrations in healthy older men.

High doses of interleukin-12 inhibit the development of joint disease in DBA/1 mice immunized with type II collagen in complete Freund's adjuvant.

Collagen-induced arthritis (CIA) is an (autoimmune) joint disease readily elicited in DBA/1 mice by immunization with type II collagen (CII) emulsified with complete Freund's adjuvant. It is a destructive arthritis involving about 50% of the limbs and occurs with an incidence of 70% to 100%. In this study we evaluated the effect of mouse recombinant interleukin-12 (mrIL-12) on CIA. Administration of mrIL-12 at high doses (1 micrograms/mouse, daily) for 2 or 3 weeks delayed the onset and reduced the incidence of CIA. Furthermore, the severity of CIA was much milder and in most cases restricted to single digits of the paws. Short-term administration of high doses of IL-12 exerted some, but less pronounced, disease-suppressing effect. In contrast, 10-fold lower doses of IL-12 given during the first 3 weeks, or high doses of IL-12 administered therapeutically proved to be ineffective. Only those regimens of IL-12 treatment that ameliorated CIA were associated with a down-regulation of the CII-specific antibody response. A strong inhibition of CII-specific IgG1 antibodies (10- to 20-fold) and a moderately (2- to 6-fold) suppressed IgG2b response was observed, whereas the level of CII-specific IgG2a antibodies remained high. Taken together, the results indicate that some initial events in the induction of CIA in DBA/1 mice injected with CII emulsified with CFA are suppressed by treatment with high doses of IL-12.

High dose titration of calcium channel blocking agents for primary pulmonary hypertension: Guidelines for short-term drug testing

Forty-seven patients with primary pulmonary hypertension were evaluated with a dose titration protocol utilizing nifedipine (20 mg orally) or diltiazem (60 mg orally) given every hour until maximal effectiveness was achieved. Of the patients tested, 15 (32%) had a >20% reduction in pulmonary artery pressure (mean 36.2 ± 8%, p < 0.01) and pulmonary vascular resistance (mean 50.2 ± 7%, p < 0.01) (pressure responders). Nineteen (40%) had 4.2 ± 20% reduction in pulmonary vascular resistance (mean 25.2 ± 12%, p < 0.01), with less than a 20% decrease in pulmonary artery pressure (resistance responders). Ten had no significant change in pulmonary artery pressure or pulmonary vascular resistance (nonresponders), and three were unable to tolerate the calcium channel blocking agents. No hemodynamic profile allowed prediction of the type of response to these agents. No mortality or serious morbidity was associated with the drug testing.These findings indicate that calcium channel blockers when titrated to maximally effective doses, may cause substantial reductions in pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension. Testing with hemodynamic monitoring is necessary to ascertain which patients will respond. Patients with primary pulmonary hypertension are able to tolerate short-term administration of high doses of calcium channel blockers.

Long-Lasting Effects on Rheology and Clearance of Bronchial Mucus after Short-Term Administration of High Doses of Carbocysteine-Lysine to Patients with Chronic Bronchitis

The rheological behavior and clearance of bronchial mucus samples collected by protected expectoration from 24 out-patients with simple chronic bronchitis were investigated before, at the end of a short period of treatment (4 days) with a single oral dose of 2.7 g (sachet) of carbocysteine-lysine (evening meal), and on the 4th and 8th days after the end of treatment versus placebo. In the group treated with carbocysteine-lysine, there were significant reductions in viscosity (-67, -48, -62%) and increases in mucociliary transport (+41, +31, +34%) at the three times mentioned. The most striking finding was that the improvements were still present 8 days after cessation of treatment. The elasticity parameter was not affected in any statistically significant way (-10, -24, +65%). These findings suggest the presence of some type of 'post-mucoactive' effect.

Effect of perhexiline maleate on lipid metabolism in the rat II. Liver and lung phospholipids after administration of high doses of perhexiline maleate

Short-term administration of high doses of the antianginal drug perhexiline maleate to rats produces an increase in liver and lung phospholipids. This increase is accompanied by alterations of phospholipid composition which tend to change in opposite directions in the two organs. After chronic treatment with the drug, the increase is still apparent in the liver but no longer in the lung, and the composition of phospholipids tends to become normal.

Serum lipid pattern in chickens of the obese strain.

SUMMARY Blood sugar, the serum concentration of total lipids, total glycerol, cholesterol and phosphatides were determined in chickens from the Obese strain (OS) of White Leghorns. Over 90% of these chickens are afflicted with a spontaneously occurring autoimmune thyroiditis and show clinical symptoms of hypothyroidism. Blood glucose levels were increased above normal limits in OS chickens up to 5 weeks of age. Significantly increased serum lipid concentrations were found in the OS chickens at the ages of 1, 5, 8 and 15 weeks, while 3-week-old OS chickens showed almost normal serum lipid levels. A single intravenous injection of heparin in a dose which prolonged bleeding time, had no 'clearing effect' on the serum of OS birds. Insulin given subcutaneously for 4 days had no effect on blood sugar but decreased the serum phosphatides and total lipid concentrations. The short-term administration of high doses of thyroxine significantly lowered the serum levels of total lipids, cholesterol, phosphatides and total glycerol.