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Human equivalent dose calculation based on body surface area*

Human equivalent dose calculation based on body surface area*

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Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers, when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differenc...

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... In step 2, the NOAELs value is converted to HED on the basis of the body surface area correction factor (i.e., W 0.67 , which depends on the animal weight), using appropriate scaling factors from animal species. [11] Table 1 summarizes the factors for converting doses. The next step is selection of most appropriate species to use in calculation of MRSD. ...

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... We provided hesperetin in the mice's food (100 mg/kg/day) in order to treat naturally aged mice during old age. The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day based on an equation developed for interspecies dose conversion from animal to human studies [42]. After 6 months of treatment of the old WT mice (aged from 20-to 26-month old), serum biochemical analyses revealed that hesperetin has no detectable toxicity compared with a sex-matched and age-matched control group treated with Veh. ...
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Background The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Methods Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. Results Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. Conclusions Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.
... The therapeutic efficacy of ceAF on myocardial ischemia using swine models of IR was assessed at Shanghai Mincal Medical Research Co. Ltd. We used 1.0 ml/kg of ceAF for the swine model studies, which was roughly equivalent to 5.0 ml/kg in mice as calculated according to previously described guidelines for dosage conversion between experimental animals ( Fig. 3a and Fig. S4) (Nair and Jacob 2016). Echocardiographic evaluation on week 0, 1, 2, 4, and 8 indicated that ceAF treatment considerably preserved LVEF and LVFS after IR ( Fig. 3b-e). ...
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Myocardial regeneration has been considered a promising option for the treatment of adult myocardial injuries. Previously, a chick early amniotic fluid (ceAF) preparation was shown to contain growth-related factors that promoted embryonic growth and cellular proliferation, though the nature of the components within ceAF were not fully defined. Here we tested whether this ceAF preparation is similarly effective in the promotion of myocardial regeneration, which could provide an alternative therapeutic for intervening myocardial injury. In this study, a myocardial ischemic injury model was established in adult mice and pigs by multiple research entities, and we were able to show that ceAF can efficiently rescue damaged cardiac tissues and markedly improve cardiac function in both experimental models through intravenous administration. ceAF administration increased cell proliferation and improved angiogenesis, likely via down-regulation of Hippo-YAP signaling. Our data suggest that ceAF administration can effectively rescue ischemic heart injury, providing the key functional information for the further development of ceAF for use in attenuating myocardial injury.
... To simulate early intervention, AGNHW dissolved in saline (257 mg/kg) was administered orally 2 h after MCAO. By converting the body surface area of humans to rats, this dosage is equivalent to a daily dosage in human subjects (3 g/ pill per day) [32]. Saline was used as a vehicle control. ...
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Background Hemorrhagic transformation (HT) is a common complication of delayed tissue plasminogen activator (t-PA) treatment for ischemic stroke. Peroxynitrite plays an important role in the breakdown of blood–brain barrier (BBB) and the development of HT. We tested the hypothesis that Angong Niuhuang Wan (AGNHW), a traditional Chinese medicinal formula, could be used in conjunction with t-PA to protect the BBB, minimize HT, and improve neurological function by suppressing peroxynitrite-mediated matrix metalloproteinase-9 (MMP-9) activation. Methods We first performed quality control study and chemical identification of AGNHW by using UPLC. In animal experiments, male Sprague–Dawley rats were subjected to 5 h of middle cerebral artery occlusion (MCAO) followed by 19 h of reperfusion plus t-PA infusion (10 mg/kg) at 5 h of cerebral ischemia. AGNHW (257 mg/kg) was given orally at 2 h after MCAO. Hemorrhagic transformation was measured using hemorrhagic scores and hemoglobin levels in ischemic brains. Evans blue leakage was utilized to assess the severity of the blood–brain barrier (BBB) damage. The modified neurologic severity score (mNSS) test was used to assess neurological functions. Peroxynitrite and superoxide was detected by using fluorescent probes. MMP-9 activity and expression were examined by gelatin zymography and immunostaining. The antioxidant effects were also studied by using brain microvascular endothelial b.End3 cells exposed to 5 h of oxygen and glucose deprivation (OGD) plus 5 h of reoxygenation with t-PA treatment (20 µg/ml). Results AGNHW significantly reduced the BBB damage, brain edema, reduced hemorrhagic transformation, enhanced neurological function, and reduced mortality rate in the ischemic stroke rats with t-PA treatment. AGNHW reduced peroxynitrite and superoxide in vivo and in vitro and six active chemical compounds were identified from AGNHW with peroxynitrite scavenging activity. Furthermore, AGNHW inhibited MMP-9 activity, and preserved tight junction protein claudin-5 and collagen IV in the ischemic brains. Conclusion AGNHW could be a potential adjuvant therapy with t-PA to protect the BBB integrity, reduce HT, and improve therapeutic outcome in ischemic stroke treatment via inhibiting peroxynitrite-mediated MMP-9 activation. Graphical Abstract
... Administered solution volumes were adjusted based on individual animal weight to deliver the assigned dose. Animal equivalent treatment dosages were based on allometric scaling (Nair and Jacob 2016) and chosen to encompass and exceed the recommended dosage (0.017-0.067 mg/kg) for a 60-kg human. Table 1 Incidence of adverse clinical signs in mice dosed with CBNT *Showed signs of rough coat 2 days prior to death. ...
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Background Cannabinol (CBN) is one of the many cannabinoids present in Cannabis sativa and has been explored as a potential treatment for sleeplessness. The purpose of this study was to determine the physiological and behavioral effects of subacute exposure to therapeutic and low pharmacological levels of a mechanically formed, stabilized water-soluble cannabinol nano-emulsion (CBNight™). Methods Sixty-two male mice were randomly assigned to one of six treatment groups given CBNight™ at dosages designed to deliver 0mg (control) to 4 mg/kg of CBN daily via oral gavage for 14 days. In-cage behavior was observed at 30 minutes and at 2, 4, 8, and 16 hours after each dose. After 14 days, the mice were sacrificed and necropsied. Organs were weighed and inspected for gross abnormalities, and blood was collected via cardiac puncture for clinical chemistry. Results No dosage-dependent adverse effects on behavior, body mass, or blood chemistry were observed, except that the highest doses of CBNight™ were associated with significantly lower eosinophil counts. Conclusions The commercially available, water-soluble CBN compound employed in this study does not appear to cause adverse effects in mice; rather, it appears to be well tolerated at pharmacological levels. The findings of eosinopenia at higher doses of CBN and lack of hepatotoxicity at any dosage employed in this study have not been reported to date.
... The pharmacodynamic profile of EMPA, DAPA and ERTU is similar, presenting over 1000-fold SGLT-2 selectivity over the SGLT-1 [15,23,75]. We chose to administer EMPA at 10 mg/kg/day as indicated by our previous studies [5,65] which is clinically relevant to 25 mg/day in humans according to inter-species calculations [62] and has exhibited a cardioprotective effect. DAPA and ERTU were given at the stoichiometrically equivalent dose (SED) of EMPA. ...
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Major clinical trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) exhibit protective effects against heart failure events, whereas inconsistencies regarding the cardiovascular death outcomes are observed. Therefore, we aimed to compare the selective SGLT-2i empagliflozin (EMPA), dapagliflozin (DAPA) and ertugliflozin (ERTU) in terms of infarct size (IS) reduction and to reveal the cardioprotective mechanism in healthy non-diabetic mice. C57BL/6 mice randomly received vehicle, EMPA (10 mg/kg/day) and DAPA or ERTU orally at the stoichiometrically equivalent dose (SED) for 7 days. 24 h-glucose urinary excretion was determined to verify SGLT-2 inhibition. IS of the region at risk was measured after 30 min ischemia (I), and 120 min reperfusion (R). In a second series, the ischemic myocardium was collected (10th min of R) for shotgun proteomics and evaluation of the cardioprotective signaling. In a third series, we evaluated the oxidative phosphorylation capacity (OXPHOS) and the mitochondrial fatty acid oxidation capacity by measuring the respiratory rates. Finally, Stattic, the STAT-3 inhibitor and wortmannin were administered in both EMPA and DAPA groups to establish causal relationships in the mechanism of protection. EMPA, DAPA and ERTU at the SED led to similar SGLT-2 inhibition as inferred by the significant increase in glucose excretion. EMPA and DAPA but not ERTU reduced IS. EMPA preserved mitochondrial functionality in complex I&II linked oxidative phosphorylation. EMPA and DAPA treatment led to NF-kB, RISK, STAT-3 activation and the downstream apoptosis reduction coinciding with IS reduction. Stattic and wortmannin attenuated the cardioprotection afforded by EMPA and DAPA. Among several upstream mediators, fibroblast growth factor-2 (FGF-2) and caveolin-3 were increased by EMPA and DAPA treatment. ERTU reduced IS only when given at the double dose of the SED (20 mg/kg/day). Short-term EMPA and DAPA, but not ERTU administration at the SED reduce IS in healthy non-diabetic mice. Cardioprotection is not correlated to SGLT-2 inhibition, is STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression.
... A single dose of COVITRAP™ (20 µg/kg) was intranasally applied to 10-week-old female Sprague-Dawley rats (n=13). This dose was calculated based on the intended single-use amount in humans (2 µg/kg) multiplied by a humanto-rat conversion factor of 10 15 . Three rats without any intervention were used as controls. ...
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    Successful COVID-19 prevention requires additional measures beyond vaccination, social distancing, and masking. A nasal spray solution containing human IgG1 antibodies against SARS-CoV-2 (COVITRAP™) was developed to strengthen other COVID-19 preventive arsenals. Here, we evaluated its pseudovirus neutralization potencies, preclinical and clinical safety profiles, and intranasal SARS-CoV-2 inhibitory effects in healthy volunteers ( NCT05358873 ). COVITRAP™ exhibited broadly potent neutralizing activities against SARS-CoV-2 with PVNT50 values ranging from 0.0035 to 3.1997 μg/ml for the following variants of concern (ranked from lowest to highest): Alpha, Beta, Gamma, Ancestral, Delta, Omicron BA.1, Omicron BA.2, Omicron BA.4/5, and Omicron BA.2.75. It demonstrated satisfactory preclinical safety profiles based on evaluations of in vitro cytotoxicity, skin sensitization, intracutaneous reactivity, and systemic toxicity. Its intranasal administration in rats did not yield any detected circulatory levels of the human IgG1 anti-SARS-CoV-2 antibodies at any time point during the 120 hours of follow-up. A double-blind, randomized, placebo-controlled trial (RCT) was conducted on 36 healthy volunteers who received either COVITRAP™ or a normal saline nasal spray at a 3:1 ratio. Safety of the thrice-daily intranasal administration for 7 days was assessed using nasal sinuscopy, adverse event recording, and self-reporting questionnaires. COVITRAP™ was well tolerated, with no significant adverse effects in healthy volunteers for the entire 14 days of the study. The intranasal SARS-CoV-2 inhibitory effects of COVITRAP™ were evaluated in nasal fluids taken from volunteers pre- and post-administration using a SARS-CoV-2 surrogate virus neutralization test. SARS-CoV-2 inhibitory effects in nasal fluids collected immediately or six hours after COVITRAP™ application were significantly increased from baseline for all three variants tested, including Ancestral, Delta, and Omicron BA.2. In conclusion, COVITRAP™ was safe for intranasal use in humans to provide SARS-CoV-2 inhibitory effects in nasal fluids that lasted at least six hours. Therefore, COVITRAP™ can be considered an integral instrument for COVID-19 prevention.
    ... Moreover, the NC and PC groups received olive oil (200 μl) intraperitoneal injections as vehicle for four weeks. As per the dose conversion formula between human and mice (36), the injected amounts of hormones were equal to the highest daily doses of E2 (2 mg/ day; 33.3 μg/kg/day) and P4 (10 mg/day; 166.7 μg/kg/day) recommended for postmenopausal women of 60 kg body weight (32). While the EP group were treated with both hormones concurrently for four weeks, the E/P group received E2 alone for two weeks followed by E2 and P combined therapy for another two weeks to mimic normal female reproductive endocrinology at childbearing age. ...
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    Although ovarian sex steroids could have protective roles against colorectal cancer (CRC) in women, little is currently known about their potential anti-tumorigenic effects in men. Hence, this study measured the therapeutic effects of 17β-oestradiol (E2) and/or progesterone (P4) against azoxymethane-induced CRC in male mice that were divided into (n = 10 mice/group): negative (NC) and positive (PC) controls, E2 (580 µg/Kg/day; five times/week) and P4 (2.9 mg/Kg/day; five times/week) monotherapies, and concurrent (EP) and sequential (E/P) co-therapy groups. Both hormones were injected intraperitoneally to the designated groups for four consecutive weeks. Similar treatment protocols with E2 (10 nM) and/or P4 (20 nM) were also used in the SW480 and SW620 human male CRC cell lines. The PC group showed abundant colonic tumours alongside increased colonic tissue testosterone levels and androgen (AR) and oestrogen (ERα) receptors, whereas E2 and P4 levels with ERβ and progesterone receptor (PGR) decreased significantly compared with the NC group. E2 and P4 monotherapies equally increased ERβ/PGR with p21/Cytochrome-C/Caspase-3, reduced testosterone levels, inhibited ERα/AR and CCND1/survivin and promoted apoptosis relative to the PC group. Both co-therapy protocols also revealed better anti-cancer effects with enhanced modulation of colonic sex steroid hormones and their receptors, with E/P the most prominent protocol. In vitro, E/P regimen showed the highest increases in the numbers of SW480 (2.1-fold) and SW620 (3.5-fold) cells in Sub-G1 phase of cell cycle. The E/P co-therapy also disclosed the lowest percentages of viable SW480 cells (2.8-fold), whilst both co-therapy protocols equally showed the greatest SW620 apoptotic cell numbers (5.2-fold) relative to untreated cells. Moreover, both co-therapy regimens revealed maximal inhibitions of cell cycle inducers, cell survival markers, and AR/ERα alongside the highest expression of cell cycle suppressors, pro-apoptotic molecules, and ERβ/PGR in both cell lines. In conclusion, CRC was associated with abnormal levels of colonic sex steroid hormones alongside aberrant protein expression of their receptors. While the anti-cancer effects of E2 and P4 monotherapies were equal, their combination protocols showed boosted tumoricidal actions against CRC in males, possibly by promoting ERβ and PGR-mediated androgen deprivation together with inhibition of ERα-regulated oncogenic pathways.
    ... To optimise the outcome, the dose of TH was also increased into a higher dose (3.0g/kg), instead of 2.4g/kg as documented in those previous studies. 19 Additionally, the effects of TH supplementation when coupled with a diet change was also investigated, based on the current NASH management of nutritional counselling to reduce body weight and improve lipid profiles. ...
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    INTRODUCTION: Dyslipidaemia and obesity are two main features of non-alcoholic steatohepatitis (NASH). This study aimed to investigate the effects of Tualang honey (TH) supplementation on bodyweight, liver weight, and lipid profiles in high cholesterol diet (HCD) induced NASH animal model. MATERIALS AND METHODS: Sixteen Sprague-Dawley rats were given 12% HCD for 16 weeks to induce NASH. These animals were divided into 4 groups; Group 1 (continued HCD), Group 2 (changed to normal diet), Group 3 (normal diet and TH 1.2g/kg) and Group 4 (normal diet and TH 3.0g/kg) for the following 4 weeks. Bodyweight was measured daily. At the end of the study, blood was collected via retro-orbital bleeding and the rats were sacrificed to harvest their liver. RESULTS: The group 4 rats had significantly lower mean final bodyweight than rats in group 1, 2 and 3 (478.0±24.4 vs. 641.5±25.1, 593.8 ±29.3, 552.0±72.9 g, p<0.05). Animals in group 4 were also found to have a significantly lower mean liver weight compared to groups 1 and 2 (12.9±0.9 vs 20.1±2.2, 15.7±1.2 g, p<0.05). In comparison to controls, the mean concentration of total cholesterol was significantly lower in all the other groups and the lowest mean concentration of triglycerides was recorded in group 4 with significant difference when compared to the controls (0.9±0.4 vs 3.6±0.4 mmol/L, p<0.05). CONCLUSION: The change from HCD to a normal diet coupled with TH supplementation has been shown to reduce bodyweight, liver weight, total cholesterol and triglyceride levels in the 12% HCD NASH induced animal models.
    ... To set the dose of omeprazole, the human equivalent dose was calculated and a dose 5-times higher (40 mg/Kg) was administered to ensure that embryos were exposed to the circulating drug levels [16,24]. To prepare the omeprazole and control solutions, pure dried Omeprazole (180 mg) (Fagron Iberica SAU, Zaragoza, Spain) was added to a dilution vehicle (1.3 mg) (SyrSpend SF Alka, 6.3 g, Fagron Iberica SAU, Zaragoza, Spain) and distilled water (20 mL). ...
    Article
    Conditions experienced in early life have long-lasting effects on offspring health. Despite this, little is known about how maternal exposure to drugs during pregnancy affects offspring teeth morphogenesis. In humans, omeprazole is a common drug used to mitigate Gastroesophageal Reflux Disease. Importantly, omeprazole is a non-specific proton-pump inhibitor, which may inhibit the proton pumps expressed in the developing tooth germ. To date, however, the effects of intrauterine life exposure to omeprazole on offspring tooth development remain unknown. In this study, we addressed this gap in a murine model. Pregnant female Swiss mice were exposed to daily doses of 40 mg/kg of omeprazole from the 5th to the 17th day of pregnancy and the effects of such exposure on offspring odontogenesis parameters such as morphological abnormalities, disruptions in the ameloblast and odontoblast layers and the presence of dentin matrix were measured. Omeprazole exposure significantly increased the prevalence (control: 21.6%; treatment: 60%; p = 0.001) and the risk (posterior mean and 95% credible interval; control: 0.230 [0.129; 0.347]; treatment: 0.593 [0.449; 0.730]) of offspring teeth morphological abnormalities, although there were no statistically significant effects of omeprazole exposure on other parameters of tooth development. These findings suggest that there are potential side-effects to offspring oral health of omeprazole use during pregnancy.
    ... For aim two, mice were randomly allocated to receive colchicine dissolved in distilled water at 0.2 mg/kg or vehicle (distilled water without colchicine) via daily gavage. The dose of colchicine was calculated using the formula ½animal equivalent dose ðmg/kgÞ = ðhuman dose = 2:5 mgÞ/ðK m ratio = 12:3Þ translated to 0.2 mg/kg for mice [13]. The body surface area (BSA) conversion index for a 20 g mouse was 0.0007 [13]. ...
    ... The dose of colchicine was calculated using the formula ½animal equivalent dose ðmg/kgÞ = ðhuman dose = 2:5 mgÞ/ðK m ratio = 12:3Þ translated to 0.2 mg/kg for mice [13]. The body surface area (BSA) conversion index for a 20 g mouse was 0.0007 [13]. The human dose of 2.5 mg translated in mice to 0.002 mg of colchicine per day using the BSA conversion index. ...
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    Background and Aims. The nacht domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is upregulated in human abdominal aortic aneurysm (AAA), but its pathogenic role is unclear. The aims of this study were firstly to examine whether the inflammasome was upregulated in a mouse model of AAA and secondly to test whether the inflammasome inhibitor colchicine limited AAA growth. Methods. AAA was induced in eight-week-old male C57BL6/J mice with topical application of elastase to the infrarenal aorta and oral 3-aminopropionitrile (E-BAPN). For aim one, inflammasome activation, abdominal aortic diameter, and rupture were compared between mice with AAA and sham controls. For aim two, 3 weeks after AAA induction, mice were randomly allocated to receive colchicine ( n = 28 , 0.2 mg/kg/d) or vehicle control ( n = 29 ). The primary outcome was the rate of maximum aortic diameter increase measured by ultrasound over 13 weeks. Results. There was upregulation of NLRP3 markers interleukin- (IL-) 1β (median, IQR; 15.67, 7.11-22.60 pg/mg protein versus 6.87, 4.54-11.60 pg/mg protein, p = .048 ) and caspase-1 (109, 83-155 relative luminosity units (RLU) versus 45, 38-65 RLU, p < .001 ) in AAA samples compared to controls. Aortic diameter increase over 80 days (mean difference, MD, 4.3 mm, 95% CI 3.3, 5.3, p < .001 ) was significantly greater in mice in which aneurysms were induced compared to sham controls. Colchicine did not significantly limit aortic diameter increase over 80 days (MD -0.1 mm, 95% CI -1.1, 0.86, p = .922 ). Conclusions. The inflammasome was activated in this mouse model of AAA; however, daily oral administration of colchicine did not limit AAA growth.