Flunitrazepam variably alters morphine, buprenorphine, and methadone                 lethality in the rat

Opiates and substitution products are frequently abused, alone and in association with benzodiazepines. While this combination may result in severe respiratory depression and death, the quantitative relationship remains uncertain. We performed randomized, blinded intravenous median lethal dose (MLD) studies in Sprague–Dawley rats of morphine, buprenorphine, and methadone, alone and in combination with intraperitoneal flunitrazepam pretreatment. We employed the up-and-down method, performed in quadruplicate, comparing time to death following opioid injection. Results are expressed as median of four series (extremes). The MLDs of morphine, buprenorphine, and methadone alone were 64.0 (33.6:79.5), 234.6 (168.6:284.4), and 22.5 (19.3:24.1) mg/kg, respectively, and 60.6 (35.2:88.2), 38.4 (30.6:54.0), and 13.0 (9.7:13.8) mg/kg, respectively, after pretreatment with 40 mg/kg flunitrazepam. Times to death for morphine, buprenorphine, and methadone alone were 2.5 (0.8:24), 0.02 (0.0:24), and 2.0 (0.0:24) hours, respectively, and 13.5 (0.0:144), 24.0 (0.0:120), and 0.0 (0.0:24) hours, respectively, after pretreatment with flunitrazepam 40 mg/kg, ip. Flunitrazepam significantly altered methadone (P=0.02) and buprenorphine (P=0.02) but not morphine lethality (P=0.77). Flunitrazepam significantly prolonged time to death only for buprenorphine (P<0.01). Flunitrazepam–opioid drug–drug interactions are more complex than is generally believed. Mechanistic studies of flunitrazepam–opioid lethal interactions are needed.

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Toxicological Profile of the Pain-Relieving Antioxidant Compound Thioctic Acid in Its Racemic and Enantiomeric Forms

Antioxidants ◽

10.3390/antiox9080749 ◽

2020 ◽

Vol 9 (8) ◽

pp. 749

Author(s):

Elena Lucarini ◽

Elena Trallori ◽

Daniele Tomassoni ◽

Francesco Amenta ◽

Carla Ghelardini ◽

...

Keyword(s):

Lethal Dose ◽

Body Weight Loss ◽

Thioctic Acid ◽

Sprague Dawley ◽

Positive Effects ◽

Organ Toxicity ◽

Antioxidant Compound ◽

Sprague Dawley Rats ◽

Toxicological Profile

Thioctic acid is a multipotent antioxidant compound existing as dextrorotatory (+), eutomer and naturally occurring and levorotatory (−). It has been proven to help fight many pathologies and is sold as racemate. In agreement with studies claiming a greater biopotency of the eutomer compared to the levorotatory compound, we recently preclinically and clinically showed that (+) thioctic acid is a pain-reliever as effective as double-dosed racemate. We investigated acute and subchronical toxicity of (+/−) thioctic acid, (−) thioctic acid, (+) thioctic acid and (+) salt thioctic acid on Sprague–Dawley rats. For acute toxicity, compounds were administered intraperitoneally (i.p.) with a single-injection at 125, 240, 360, 480 µmol/kg, then rodents were tested for motorial coordination and minimum lethal dose (LDmin). A subtoxic dose (360 µmol/kg) was administered i.p. for 15 days and we finally evaluated motorial impairment, glycemia, organ toxicity, and apoptosis state. Acutely administered, the highest doses of all thioctic acid compounds negatively affected motorial ability and (−) thioctic acid LDmin resulted higher than the others. Subchronic administrations caused overall body weight loss, motorial impairment, mass loss in some organs. (+/−) and (−) thioctic acid injections enhanced caspase-3 activity in some organs, (−) enantiomer-treated animals displayed more marked organ toxicity signs. Together with our previous study on the biologic role of enantiomers, these data suggest a therapeutic use of (+) enantiomer-based formulations, thus lowering dose and toxicity without affecting the positive effects brought by the drug.

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Safety Assessment of Zigbir®: A Polyherbal Formulation in Sprague-Dawley Rats

Journal of Toxicology ◽

10.1155/2012/589520 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Joseph Joshua Allan ◽

Ranjit Madhukar Bhide ◽

Amit Agarwal

Keyword(s):

Body Weight Gain ◽

Lethal Dose ◽

Clinical Signs ◽

Food Supplement ◽

Toxicity Study ◽

Sprague Dawley ◽

Polyherbal Formulation ◽

Sprague Dawley Rats ◽

Repeated Dose Toxicity ◽

Effect Level

The safety of Zigbir®, a polyherbal formulation intended for use as food supplement, was evaluated in Sprague-Dawley rats treated orally at the dose of 2000 mg/kg in acute and at 250, 500, and 1000 mg/kg for 90 days in subchronic toxicity study. The median lethal dose of Zigbir® was found to be more than 2000 mg/kg, and fourteen-day repeated dose toxicity study revealed it to be safe up to 1000 mg/kg. The subchronic study did not show any mortality or treatment-related adverse clinical signs. The treated animals exhibited normal feed intake and comparable body weight gain except for a decrease in females of 500 and 1000 mg/kg groups. Ocular examination revealed no abnormalities. Further, Zigbir® administration in rats did not induce any major changes in urinalysis, hematological, and biochemical evaluations except for minor alterations in few parameters at different dose levels. Gross and histopathological findings did not show any lesions attributable to Zigbir® administration. The no observed effect level of Zigbir® was found to be 500 and 250 mg/kg in male and female Sprague-Dawley rats.

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Fluoropolymer-based Emulsions for the Intravenous Delivery of Sevoflurane

Anesthesiology ◽

10.1097/aln.0b013e31818630ff ◽

2008 ◽

Vol 109 (4) ◽

pp. 651-656 ◽

Cited By ~ 32

Author(s):

Jonathan P. Fast ◽

Mark G. Perkins ◽

Robert A. Pearce ◽

Sandro Mecozzi

Keyword(s):

Body Weight ◽

Jugular Vein ◽

Lethal Dose ◽

Therapeutic Index ◽

Volatile Anesthetics ◽

Maximum Amount ◽

Clinical Use ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Righting Reflex

Background The intravenous delivery of halogenated volatile anesthetics has been previously achieved using phospholipid-stabilized emulsions, e.g., Intralipid. However, fluorinated volatile anesthetics, such as sevoflurane, are partially fluorophilic and do not mix well with classic nonfluorinated lipids. This effect limits the maximum amount of sevoflurane that can be stably emulsified in Intralipid to 3.5% vol/vol. This is a significant limitation to the potential clinical use of Intralipid-based emulsions. Methods The authors prepared a 20% vol/vol sevoflurane emulsion using a novel fluorinated surfactant and tested its effectiveness and therapeutic index by administering it to male Sprague-Dawley rats via intravenous injection into the jugular vein. The median effective dose to induce anesthesia (ED50), the median lethal dose (LD50), and the therapeutic index (LD50/ED50) were determined. Anesthesia was measured by loss of the forepaw righting reflex. Results The ED50 and LD50 values were found to be 0.41 and 1.05 ml emulsion/kg body weight, respectively. These lead to a therapeutic index of 2.6, which compares favorably with previously determined values of emulsified isoflurane, as well as values for propofol and thiopental. Conclusions A novel semifluorinated surfactant was able to considerably increase the maximum amount of stably emulsified sevoflurane compared with Intralipid. These formulations can be used to rapidly induce anesthesia with bolus dosing from which recovery is smooth and rapid.

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Pharmacokinetics of a novel trioxane antimalarial drug 99/411: alterations upon rifampicin coadministration, single and multiple oral dose drug–drug interactions in Sprague-Dawley rats

International Journal of Pharmacokinetics ◽

10.4155/ipk-2017-0001 ◽

2017 ◽

Vol 2 (4) ◽

pp. 225-232

Author(s):

Mahendra Kumar Hidau ◽

Yeshwant Singh ◽

Shio Kumar Singh

Keyword(s):

Oral Dose ◽

Drug Interactions ◽

Antimalarial Drug ◽

Sprague Dawley ◽

Multiple Oral Dose ◽

Sprague Dawley Rats

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Efficacy of Levofloxacin Loaded Nonionic Surfactant Vesicles (Niosomes) in a Model of Pseudomonas aeruginosa Infected Sprague Dawley Rats

Advances in Pharmacological and Pharmaceutical Sciences ◽

10.1155/2020/8815969 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Satish Jankie ◽

Jenelle Johnson ◽

Amusa Sarafadeen Adebayo ◽

Gopal Krishna Pillai ◽

Lexley Maureen Pinto Pereira

Keyword(s):

Pseudomonas Aeruginosa ◽

Lethal Dose ◽

In Vitro Release ◽

Conventional Group ◽

Control Group ◽

Sprague Dawley ◽

Drug Release Profile ◽

Sustained Drug Release ◽

Bacterial Counts ◽

Sprague Dawley Rats

This study examined the effectiveness of niosomes loaded with levofloxacin in treating Pseudomonas aeruginosa (American Type Culture Collection—ATCC 27853) infections in Sprague Dawley rats since these infections are becoming more common and resistant to treatment. Levofloxacin entrapped in niosomes was prepared using the thin-film hydration method and was assessed for in vitro release and stability. Three groups of six (6) animals were infected with a lethal dose of Pseudomonas aeruginosa via the intraperitoneal (Ip) route. At six (6) hours postinfection, the animals were treated with either drug-free niosomes (control), free levofloxacin (conventional), or levofloxacin trapped in niosomes (Ip) at a dose of 7.5 mg/kg/once daily. Blood was collected via tail snips on days 0, 1, 3, 5, 7, and 10 for complete blood counts and viable bacterial counts (CFU/μl). At day 10, the animals were sacrificed, and the kidney, liver, and spleen were harvested for bacterial counts. The niosomes showed a sustained drug release profile and were most stable at 4°C. All animals in the control group succumbed to the infection; one animal from the conventional group died, and all niosome treated animals survived at day 10. The mean lymphocyte count (×109) was lower for the niosome (7.258 ± 1.773) versus conventional group (17.684 ± 10.008) ( p < 0.03 ) at day ten (10). Neutrophil counts (×109) were lower for the niosome (2.563 ± 1.609) versus conventional (6.2 ± 6.548) ( p < 0.02 ) groups. Though CFUs in the bloodstream were comparable for both treatment groups, the niosome treated group showed a significant reduction of CFUs in the liver, kidney, and spleen versus the conventional group (1.33 ± 2.074) vs (5.8 ± 3.74) ( p < 0.043 ), (1.5 ± 2.35) vs (9.6 ± 8.65) ( p < 0.038 ) and (3.8 4.71) vs (25.6 14.66) ( p < 0.007 ), respectively. These findings indicate that niosome is promising as a drug delivery system in treating systemic infections, but further work using niosomes with surface modification is recommended.

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Gastric and nongastric mechanisms for satiety action of cholecystokinin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1988.254.4.r628 ◽

1988 ◽

Vol 254 (4) ◽

pp. R628-R632 ◽

Cited By ~ 8

Author(s):

T. H. Moran ◽

P. R. McHugh

Keyword(s):

Gastric Emptying ◽

Linear Relationship ◽

Inhibitory Action ◽

Glucose Solution ◽

Dose Range ◽

Quantitative Relationship ◽

Dilution Method ◽

Sprague Dawley ◽

Testing Period ◽

Sprague Dawley Rats

The quantitative relationship between cholecystokinin's (CCK) inhibitory actions on gastric emptying and feeding was examined in rats. CCK (1, 2, 4, or 8 micrograms/kg) inhibited both the gastric emptying (determined by the dye dilution method) and ingestion of a 0.5-kcal/ml glucose solution in a 30-min testing period in 20-h deprived male Sprague-Dawley rats. Comparisons of the inhibitions of gastric emptying and feeding across the dose range of CCK revealed two components of CCK satiety: one defined by a linear relationship between the gastric inhibitory and feeding inhibitory actions of CCK through a dose range of 1-4 micrograms/kg, which accounted for 64% of the variability in the satiety action of CCK, and a second that appeared to be independent of the gastric inhibitory action of CCK.

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Acute and Subchronic Oral Toxicity of Oil Palm Puree in Sprague–Dawley Rats

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17103404 ◽

2020 ◽

Vol 17 (10) ◽

pp. 3404

Author(s):

Zaida Zainal ◽

Augustine Ong ◽

Choo Yuen May ◽

Sui Kiat Chang ◽

Afiqah Abdul Rahim ◽

...

Keyword(s):

Lethal Dose ◽

Pharmaceutical Formulations ◽

Toxicity Study ◽

Sprague Dawley ◽

Oral Toxicity ◽

Subchronic Toxicity ◽

Organ Weights ◽

Sprague Dawley Rats ◽

Adverse Effect Level ◽

Effect Level

Palm puree is rich in antioxidants and is produced via blending various proportions of mesocarp fibre and crude palm oil. The aim of this study was to assess the acute and subchronic toxicity of palm puree in male and female Sprague–Dawley rats. For the acute toxicity study, animals administered single palm-puree doses (2000 mg kg−1) by gavage were observed daily for 14 d. For the subchronic toxicity study, the rats were administered 500, 1000, or 2000 mg kg−1 palm puree daily for 28 d. We evaluated body and organ weights; performed haematological, biochemical, and histopathological analyses of blood and organ samples during and after treatment; and calculated the oral no-observed-adverse-effect level (NOAEL). The toxicity studies showed no signs of toxicity or mortality. The haematological, biochemical, and histopathological analyses and body and organ weights indicated no evidence of substantial toxicity at any dose of palm puree. The oral lethal dose and NOAEL for the palm puree were greater than 2000 mg kg−1 d−1 over 28 d. To the best of our knowledge, the present study is the first to confirm the safety of palm puree as a novel functional food. These encouraging results warrant further studies to elucidate its potential for pharmaceutical formulations.

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Tk-deleted pseudorabies virus retains high pathogenicity in rats

Journal of Veterinary Research ◽

10.2478/jvetres-2021-0056 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Lirong Zhang ◽

Keyue Ruan ◽

Guoju Sang ◽

Zhaoyang Xu ◽

Wu Tong ◽

...

Keyword(s):

Spinal Cord ◽

Pseudorabies Virus ◽

Lethal Dose ◽

Trigeminal Ganglia ◽

Sprague Dawley ◽

Gene Encoding ◽

Intranasal Inoculation ◽

Sprague Dawley Rats ◽

Intramuscular Inoculation ◽

High Pathogenicity

Abstract Introduction The pseudorabies virus (PRV) gene encoding thymidine kinase (tk) is an important virulence-associated factor. Attenuation of PRV in susceptible animals is a frequent result of tk deletion. The aim of the study was to assess the pathogenicity of tk-deleted PRV in rats. Material and Methods Sprague Dawley rats were infected with the tk-deleted PRV strain SuHV-1 ΔTK:247via intranasal or intramuscular inoculation. PRV loads in ten tissues from dead and euthanised rats were determined using real-time PCR. Results Infection with SuHV-1 ΔTK:247 could cause death in rats. The 50% lethal dose (LD50) of SuHV-1 ΔTK:247 via intranasal inoculation was 103.16 TCID50 in rats. Intramuscular inoculation required a higher dose of SuHV-1 ΔTK:247 (105.0 TCID50). A high SuHV-1 ΔTK:247 titre was observed in the trigeminal ganglia or spinal cord of dead rats. Conclusion The results of this study show that rats are highly susceptible to PRV infection, and tk deletion did not completely diminish the pathogenicity of PRV in rats.

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