Short-term High Doses Research Articles

Evaluation of High Dosages of Oral Meloxicam in American Kestrels ( Falco sparverius ).

To evaluate the toxicity of short-term high doses of meloxicam in American kestrels ( Falco sparverius ), 32 male captive-born, 1- to 4-year-old American kestrels were randomly assigned to 4 groups: 3 groups treated with meloxicam (n = 9 per group) and a control group (n = 5). Meloxicam was administered orally via feeding tube in the proventriculus at 2, 10, and 20 mg/kg every 12 hours for 7 days for the treatment groups, while the control group received saline solution. The birds were evaluated for the presence of clinical signs, abnormalities in the complete blood cell count and in the plasma biochemical panel for the 20-mg/kg group, and gross and histopathologic lesions. No clinical signs or mortality were observed in any group. No significant differences of clinical relevance were found in results of the packed cell volume, total solids, and biochemical panel, and no evidence of renal toxicity was found in the treatment or control groups. A significant correlation was found between hepatic lipidosis and meloxicam dose (P = .02). Two of 9 birds in the 20-mg/kg group developed gastric ulcers, although this result was not significant. None of the birds in the 2- and 10-mg/kg groups had similar lesions. Finally, meloxicam dosages up to 20 mg/kg did not result in nephrotoxicity in American kestrels. Further toxicologic studies to evaluate hepatotoxicity and gastrotoxicity of meloxicam in avian species are needed.

Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and increased urinary 8-nitroguanine in arsenic-exposed newborns and children

Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p<0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p<0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10–100μM) and long-term low doses (0.5–1μM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p<0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life.

"Effects of recombinant human erythropoietin high mimicking abuse doses on oxidative stress processes in rats".

Although many studies highlight how long-term moderate dose of Recombinant Human Erythropoietin (rHuEPO) treatments result in beneficial and antioxidants effects, few studies take into account the effects that short-term high doses of rHuEPO (mimicking abuse conditions) might have on the oxidative stress processes. Thus, the aim of this study was to investigate the in vivo antioxidant activity of rHuEPO, administered for a short time and at high doses to mimic its sports abuse as doping. Male Wistar healthy rats (n=36) were recruited for the study and were treated with three different concentrations of rHuEPO: 7.5, 15, 30μg/kg. Plasma concentrations of erythropoietin, 8-epi Prostaglandin F2α, plasma and urinary concentrations of NOx were evaluated with specific assay kit, while hematocrit levels were analyzed with an automated cell counter. Antioxidant activity of rHuEPO was assessed analyzing the possible variation of the plasma scavenger capacity against hydroxylic and peroxylic radicals by TOSC (Total Oxyradical Scavenging Capacity) assay. Statistical analyses showed higher hematocrit values, confirmed by a statistically significant increase of plasmatic EPO concentration. An increase in plasma scavenging capacity against peroxyl and hydroxyl radicals, in 8-isoprostane plasmatic concentrations and in plasmatic and urinary levels of NOX were also found in all the treated animals, though not always statistically significant. Our results confirm the literature data regarding the antioxidant action of erythropoietin administered at low doses and for short times, whereas they showed an opposite incremental oxidative stress action when erythropoietin is administered at high doses.

Meta-analysis of short-term high versus low doses of atorvastatin preventing contrast-induced acute kidney injury in patients undergoing coronary angiography/percutaneous coronary intervention.

This study aimed to investigate the impact of different doses of atorvastatin on contrast-induced acute kidney injury (CI-AKI) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) requiring contrast media by performing a meta-analysis. We searched the PubMed, EMBASE, Cochrane Library, Wanfang database, China National Knowledge Infrastructure, and VIP database through April 2014. Only randomized controlled trials (RCTs) comparing short-term high-dose atorvastatin with low-dose atorvastatin on CI-AKI were selected. The main outcomes were the change of acute kidney injury markers and the incidence of contrast-induced nephropathy (CIN). We combined 14 RCTs consisting of 1,689 patients. Compared with the low-dose atorvastatin, high-dose atorvastatin treatment was associated with a reduction in serum creatinine levels (weighted mean differences [WMD]-0.1 mg/dL; 95%CI -0.14 to -0.05). In addition, high-dose atorvastatin treatment was also associated with a lower incidence of CIN (risk ratios 0.41; 95%CI 0.29-0.56). This meta-analysis suggests that short-term high-dose atorvastatin therapy appears to be superior to the low-dose atorvastatin in preventing CI-AKI among patients undergoing CAG/PCI requiring contrast media.

Efficacy, safety and tolerability of quetiapine: short-term high doses with long-term follow-up

IntroductionQuetiapine is effective and well tolerated in the treatment of schizophrenia at doses up to 800 mg/day, but data on its use at doses above this level are limited.MethodsIn this open-label study, 35 hospitalised patients with schizophrenia, schizoaffective disorder, bipolar disorder or alcohol-induced psychosis, who received quetiapine at doses up to 1600 mg/day in a 4-week acute phase, were followed for up to 14 months as outpatients. The primary efficacy measure was the Clinical Global Impression of Improvement (CGI-I) scale.ResultsAt the end of the 4-week hospitalisation period, overall 94.3% of patients had experienced improvements in symptoms, with 37.1% “very much improved”, 37.1% “much improved”, and 20% “minimally improved”, according to the CGI-I scale. No patient experienced a worsening of symptoms during quetiapine treatment and there was no change in two (5.7%) patients. Among the 12 patients receiving >800 mg/day, 10 (83.3%) were “very much” or “much improved”. Quetiapine was well tolerated: no increase in extrapyramidal symptoms or other adverse events was observed even at doses above 800 mg/day, with no changes in safety parameters.ConclusionResults indicate that short-term quetiapine therapy at doses up to 1600 mg/day, with maintenance doses up to 1000 mg/day, may be an effective and well-tolerated treatment for patients with psychoses who require high doses of antipsychotics for difficult-to-treat symptoms. However, large randomised, controlled trials are required to confirm these findings.

Tumour induction in rats following exposure to short-term high dose aristolochic acid I

The purpose of this study was to assess the carcinogenic activity of aristolochic acid I (AAI) in short-term high doses. Forty-four female Sprague-Dawley rats were randomly assigned to two groups. A dose of 50 mg/kg/day AAI was administrated to rats in the experimental group by gavage consecutively for 3 days, while the control group received only distilled water, after which renal function and pathological changes were assessed. At day 8 post-treatment AAI had induced elevations of both plasma urea and creatinine, coupled with increased urine production, urinary proteins, glucose and N-acetyl-beta-glucosaminidase. At 1, 3 and 6 months post-treatment renal function and urinary parameters for the experimental group approached baseline values. However, tumours and preneoplastic proliferation were both observed at 6 months for the experimental group. The rate of occurrence of preneoplastic proliferation in the kidneys was 100% (14/14); the rate of occurrence of renal tumours was 28.6% (4/14), which included three mesenchymal tumours and one case of renal oncocytoma; the rate of occurrence of extrarenal tumours was 7.1% (1/14), which was a case of mammary duct carcinoma. Renal preneoplastic proliferation and renal tumours, as well as extrarenal tumours, were not observed in control rats during the 6 months. These results differ from previous reports in that tumours originating from both epithelial and mesenchymal tissues were found, which may be attributed to the duration of treatment and the dosage of the drug. These data indicate that AAI administered in an acute manner at high doses does in fact have carcinogenic properties.

Weight-based rt-PA Thrombolysis Protocol for Acute Native Arterial and Bypass Graft Occlusions

To determine technical success and complications with weight-adjusted dosing of recombinant tissue plasminogen activator (rt-PA) for arterial and bypass graft occlusions. During an 8-month period, prospective data were collected on patients undergoing catheter-directed thrombolysis. Retrospective review of all medical charts and blood bank data were performed for confirmation. All patients underwent a standard weight-adjusted protocol for catheter-directed thrombolysis. Thrombolytic therapy with rt-PA (0.2 mg/mL) was defined as low-dose when 0.02 mg/kg/h rt-PA was used and high-dose when 0.04 mg/kg/h of rt-PA was used. Low-dose heparin therapy was used. Total infusion time, total dose, and hourly rate of dose were calculated. Technical success, defined as complete removal of all clot without surgical intervention, complications, and frequency of transfusions were tabulated. A total of 35 patients underwent catheter-directed thrombolysis with rt-PA, including a total of 21 bypass grafts (60%) and 14 native arteries (40%). Mean age was 57 years (+/- 22.5; range, 3 mo to 83 y). Average rate of heparin infusion was 472.8 U/h (+/- 227). Success rates for graft thrombolysis were 90% (18 of 21). Success rates for native vessels were 79% (11 of 14). In patients who underwent only a low-dose protocol, the transfusion rate was 15% and major complications were 10%. In patients with a combined low-dose/high-dose administration, the transfusion rate was 46% and major complications were 13%. Overall success rate and major complication rates were 86% (30 of 35) and 11% (four of 35), respectively. Frequency of transfusions was 37% (13 of 35; mean, 2.8 U). Although weight-adjusted dosing for rt-PA provides a high efficacy of relieving ischemia, the rate of complications, especially bleeding, seems excessive in comparison to historical experience with urokinase. Administration of short-term high doses of rt-PA did not appear to have any beneficial effect. Further investigation with lower dosing and concentration should be considered.

Risks and benefits of nicotine to aid smoking cessation in pregnancy.

Cigarette smoking during pregnancy is the single largest modifiable risk for pregnancy-related morbidity and mortality in the US. Addiction to nicotine prevents many pregnant women who wish to quit smoking from doing so. The safety and efficacy of nicotine replacement therapy (NRT) for smoking cessation during pregnancy have not been well studied. Nicotine is classified by the US Food and Drug Administration as a Pregnancy Category D drug. Animal studies indicate that nicotine adversely affects the developing fetal CNS, and nicotine effects on the brain may be involved in the pathophysiology of sudden infant death syndrome (SIDS). It has been assumed that the cardiovascular effects of nicotine resulting in reduced blood flow to the placenta (uteroplacental insufficiency) is the predominant mechanism of the reproductive toxicity of cigarette smoking during pregnancy. Short term high doses of nicotine in pregnant animals do adversely affect the maternal and fetal cardiovascular systems. However, studies of the acute effects of NRT in pregnant humans indicate that nicotine alone has minimal effects upon the maternal and fetal cardiovascular systems. Cigarette smoking delivers thousands of chemicals, some of which are well documented reproductive toxins (e.g. carbon monoxide and lead). A myriad of cellular and molecular biological abnormalities have been documented in placentas, fetuses, and newborns of pregnant women who smoke. The cumulative abnormalities produced by the various toxins in cigarette smoke are probably responsible for the numerous adverse reproductive outcomes associated with smoking. It is doubtful that the reproductive toxicity of cigarette smoking is primarily related to nicotine. We recommend the following. Efficacy trials of NRT as adjunctive therapy for smoking cessation during pregnancy should be conducted. The initial dose of nicotine in NRT should be similar to the dose of nicotine that the pregnant woman received from smoking. Intermittent-use formulations of NRT (gum, spray, inhaler) are preferred because the total dose of nicotine delivered to the fetus will be less than with continuous-use formulations (transdermal patch). A national registry for NRT use during pregnancy should be created to prospectively collect obstetrical outcome data from NRT efficacy trials and from individual use. The goal of this registry would be to determine the safety of NRT use during pregnancy, especially with respect to uncommon outcomes such as placental abruption. Finally, our review of the data indicate that minimal amounts of nicotine are excreted into breast milk and that NRT can be safely used by breast-feeding mothers.

Effect of short-term high dose of steroids on the healing of microvascular anastomoses in a rabbit model: pilot study

Short-term high doses of steroids have been used in head and neck surgery to reduce swelling in free tissue transfers. This study was set up to assess the effect of this treatment on the healing of microvascular anastomoses in a rabbit model. Anastomoses were made in the common carotid artery and anterior facial vein in 40 animals, half of which were given high doses of methylprednisolone (2.5 mg/kg/day) intravenously for 48 h peri-operatively. The patency of the vessels was assessed and they were harvested for histological examination at 1, 3, 7, 14, and 90 days postoperatively. Steroids tended to reduce the swelling in the vessel walls during the early stages of healing (24 h and 3 days), and also to reduce the inflammatory cell count in the lumen of the vessels at 3 days. It seems likely from these initial observations that steroids are more likely to improve than jeopardize the healing of microvascular anastomoses.

Skin test responsiveness to four new tuberculins in patients with chronic obstructive airways disease receiving short term high doses of, or long term maintenance treatment with, prednisolone: clinical appearances and histometric studies.

The response to skin testing with tuberculins extracted from various species of mycobacteria was studied in 49 patients from Dundee with chronic obstructive airways disease. Seventeen had never been treated with steroids (group 1), 17 were receiving short term high doses of prednisolone (group 2) and did not have impaired Synacthen tests; 15 were receiving long term maintenance treatment and did have impaired Synacthen tests (group 3). Erythematous and indurated reactions were seen in a few patients, more commonly to antigens from Mycobacterium tuberculosis than to the other species: neither of the latter treatment groups showed appreciable reduction in reactivity compared with that of the group 1 patients. The number and microanatomical distribution of the T4 and T8 lymphocytes and the M3 bearing monocytes and macrophages was studied immunocytochemically in cryostat sections of biopsy specimens from the antigen injection sites. The density of these cells was significantly less in clinically negative reactions than in those with erythema or induration, but was unrelated to the presence or absence of a history of treatment with prednisolone. The T4:T8 ratio in the section as a whole was similar to that of the peripheral blood, but T8 cells were relatively more common in the perivascular and periappendicular foci, and T4 lymphocytes were predominant in the diffuse component of the infiltrate. I12 receptor bearing lymphocytes were uncommon: such cells were least common in the clinically negative reactions, but the number and distribution were apparently unrelated to the presence or absence of prednisolone treatment. It was concluded that currently accepted regimens of treatment with prednisolone did not reduce the effector arm of type IV (delayed type hypersensitivity) responses and so are unlikely to compromise this aspect of protective immunity.