Repeat Dose Research Articles

Risks for animal and human health related to the presence of polychlorinated naphthalenes (PCNs) in feed and food.

EFSA was asked for a scientific opinion on the risks for animal and human health related to the presence of polychlorinated naphthalenes (PCNs) in feed and food. The assessment focused on hexaCNs due to very limited data on other PCN congeners. For hexaCNs in feed, 217 analytical results were used to estimate dietary exposures for food-producing and non-food-producing animals; however, a risk characterisation could not be performed because none of the toxicological studies allowed identification of reference points. The oral repeated dose toxicity studies performed in rats with a hexaCN mixture containing all 10 hexaCNs indicated that the critical target was the haematological system. A BMDL20 of 0.05 mg/kg body weight (bw) per day was identified for a considerable decrease in the platelet count. For hexaCNs in food, 2317 analytical results were used to estimate dietary exposures across dietary surveys and age groups. The highest exposure ranged from 0.91 to 29.8 pg/kg bw per day in general population and from 220 to 559 pg/kg bw per day for breast-fed infants with the highest consumption of breast milk. Applying a margin of exposure (MOE) approach, the estimated MOEs for the high dietary exposures ranged from 1,700,000 to 55,000,000 for the general population and from 90,000 to 230,000 for breast-fed infants with the highest consumption of breast milk. These MOEs are far above the minimum MOE of 2000 that does not raise a health concern. Taking account of the uncertainties affecting the assessment, the Panel concluded with at least 99% certainty that dietary exposure to hexaCNs does not raise a health concern for any of the population groups considered. Due to major limitations in the available data, no assessment was possible for genotoxic effects or for health risks of PCNs other than hexaCNs.

Safety study of cannabidiol products in healthy dogs.

The tolerability of different cannabinoids given orally to dogs was evaluated in a randomized, non-blinded, negative controlled, parallel design 90-day repeat dose study with a 14-day recovery period. Healthy beagles (16 males and 16 females) were randomized into four treatment groups and treated with either medium chain triglyceride oil as the control or one of the following: broad spectrum cannabidiol, broad spectrum cannabidiol with cannabigerol, or broad spectrum cannabidiol with cannabidiolic acid at 5 mg total cannabinoids/kg body weight/day. Animals were observed daily with detailed clinical examinations conducted weekly. Animals were monitored for an additional 2 weeks after dosing. Body weights, food consumption and clinical pathology evaluations were included in the study. Cannabinoids were well tolerated when healthy male and female beagles were dosed for 90 consecutive days. Annual post-market surveillance data for hemp-derived supplement products sold for use in dogs from 2010 to 2023 (partial year) shows that the rate per 1 million administrations sold is 2.10 for adverse events and 0.01 for serious adverse events. Based on the results of this study, other published studies, and data from extensive post-market surveillance, hemp-derived cannabinoids are well tolerated in healthy dogs at a dose of 5 mg/kg body weight/day.

Potential i-Nos/Arg-1 Switch with NLRP3 and Parasitic Load Down Regulation in Experimental Schistosoma mansoni Infection via Chloroquine Repurposing.

In previous studies, the inhibitory effect of chloroquine on NLRP3 inflammasome and heme production was documented. This may be employed as a double-bladed sword in schistosomiasis (anti-inflammatory and parasiticidal). In this study, chloroquine's impact on schistosomiasis mansoni was investigated. The parasitic load (worm/egg counts and reproductive capacity index [RCI]), i-Nos/Arg-1 expression, splenomegaly, hepatic insult and NLRP3-immunohistochemical expression were assessed in infected mice after receiving early and late repeated doses of chloroquine alone or dually with praziquantel. By early treatment, the least RCI was reported in dually treated mice (41.48 ± 28.58) with a significant reduction in worm/egg counts (3.50 ± 1.29/2550 ± 479.58), compared with either drug alone. A marked reduction in the splenic index was achieved by prolonged chloroquine administration (alone: 43.15 ± 5.67, dually: 36.03 ± 5.27), with significantly less fibrosis (15 ± 3.37, 14.25 ± 2.22) than after praziquantel alone (20.5 ± 2.65). Regarding inflammation, despite the praziquantel-induced significant decrease in NLRP3 expression, the inhibitory effect was marked after dual and chloroquine administration (liver: 3.13 ± 1.21/3.45 ± 1.23, spleen: 5.7 ± 1.6/4.63 ± 2.41). i-Nos RNA peaked with early/late chloroquine administration (liver: 68.53 ± 1.8/57.78 ± 7.14, spleen: 63.22 ± 2.06/62.5 ± 3.05). High i-Nos echoed with a parasiticidal and hepatoprotective effect and may indicate macrophage-1 polarisation. On the flip side, the chloroquine-induced low Arg-1 seemed to abate immune tolerance and probably macrophage-2 polarisation. Collectively, chloroquine synergised the praziquantel-schistosomicidal effect and minimised tissue inflammation, splenomegaly and hepatic fibrosis.

Effect of Strong CYP3A4 Inhibition, CYP3A4 Induction, and OATP1B1/3 Inhibition on the Pharmacokinetics of a Single Oral Dose of Sotorasib.

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200mg of itraconazole, a strong CYP3A4 inhibitor, on 360mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960mg of sotorasib PKs was interrogated after a single dose of 600mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf. CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.

‘It is the Dose That Makes the Poison’ – A Critical View on Dose Level Setting in Extended-One Generation Reproductive Toxicity (EOGRT) Studies

Adequate dose level setting is essential for the evaluation of the toxicity of a substance, meaning that the dose level should not be too low to miss the potential of a substance to exert any toxic effects; it should also not be too high to induce various effects related to systemic toxicity that would hamper a proper evaluation of specific toxicity endpoints such as reproduction and fetal development. This discussion paper is meant to highlight the challenges faced by industry as a result of ECHA’s advice to select high dose levels when conducting EOGRT studies. In our view, in its concern for finding all possible hazards, ECHA is focused on testing at dose levels that may be too high for repeat dose toxicity studies. Such high dose levels may lead to an unethical increase in animal use and animal suffering, an inability to correctly interpret results and unacceptable requests for the repetition of studies leading to an even higher demand for experimental animals.

Toxicological evaluation of a fish oil concentrate containing Very Long Chain Fatty Acids

Very long chain fatty acids (VLCFA) have a chain length ≥24 carbons. Fish contain low levels of these fatty acids. A commercial oil called EPAX® Evolve 05 with an up-concentration of VLCFAs of approximately 10 times, has been developed as a dietary supplement by Epax Norway AS. A series of toxicological studies were performed using mice and rats to determine the safety and toxicity of repeat dosing with a gavage administered VLCFA formulation. The results suggest transient lipid accumulation in kidneys and liver. Lipid accumulation was seen with the test item and with the soya control but was not dose related. Liver and kidney lipid accumulation, whilst present in 14- day repeat dose study, was absent in a 90-day rat study. No treatment-effect was seen in urine analysis in any of the studies. No treatment-related effects were seen with a functional observation battery, ophthalmological examination, haematology, urine analysis, oestrus cycle, thyroid hormones, organ weight, or histopathology. In the 90-day study the liver enzymes ALP, AST and ALT were statistically significantly increased with test item but within control values. There were no associated histological findings in the liver suggesting there was no toxic effect and the normalisation of values for all liver enzymes in the recovery groups suggests an adaptive response rather than a prevailing toxic response. The no-observed-adverse-effect level (NOAEL) was determined as 1200 mg VLCFA/kg b.w./day.

Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates.

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.

Population Pharmacokinetics of Fasinumab in Healthy Volunteers and Patients With Pain Due to Osteoarthritis of the Knee or Hip.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1mg/kg IV or 0.1-0.3mg/kg SC)/fixed dose (9-12mg IV or 1-12mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1mg SCdose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Baby-COMET: Safety of avalglucosidase alfa after repeat dosing in treatment-naïve participants with infantile-onset Pompe disease (IOPD)

Baby-COMET: Safety of avalglucosidase alfa after repeat dosing in treatment-naïve participants with infantile-onset Pompe disease (IOPD)

Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose

Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl). To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose. This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023. Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference). The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics. This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes. In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting. ClinicalTrials.gov Identifier: NCT04764630.

Rationale and design of the NODE-303 study: evaluating the safety of symptom-prompted, self-administered etripamil for paroxysmal supraventricular tachycardia episodes in real-world settings

Paroxysmal supraventricular tachycardia (PSVT) is a common episodic arrhythmia characterized by unpredictable onset and burdensome symptoms including palpitations, dizziness, chest pain, distress, and shortness of breath. Treatment of acute episodes of PSVT in the clinical setting consists of intravenous adenosine, beta-blockers, and calcium channel blockers (CCBs). Etripamil is an intranasally self-administered L-type CCB in development for acute treatment of AV-nodal dependent PSVT in a non-medical supervised setting. This paper summarizes the rationale and study design of NODE-303 that will assess the efficacy and safety of etripamil. In the randomized, double-blinded, placebo-controlled, Phase 3 RAPID trial, etripamil was superior to placebo in the conversion of single PSVT episodes by 30 minutes post initial dose when administered in the non-healthcare setting; this study required a mandatory and observed test dosing prior to randomization. The primary objective of NODE-303 is to evaluate the safety of symptom-prompted, self-administered etripamil for multiple PSVT episodes in real-world settings, without the need for test dosing prior to first use during PSVT. Secondary endpoints include efficacy and disease burden. Upon perceiving a PSVT episode, the patient applies an electrocardiographic monitor, performs a vagal maneuver, and, if the vagal maneuver is unsuccessful, self-administers etripamil 70 mg, with an optional repeat dose if symptoms do not resolve within 10 minutes after the first dose. A patient may treat up to four PSVT episodes during the study. Adverse events are recorded as treatment-emergent if they occur within 24 hours after the administration of etripamil. Efficacy endpoints include time to conversion to sinus rhythm within 30 and 60 mins after etripamil administration, and the proportion of patients who convert at 3, 5, 10, 20, 30, and 60 min. Patient-reported outcomes are captured by the Brief Illness Perception Questionnaire, the Cardiac Anxiety Questionnaire, the Short Form Health Survey 36, the Treatment Satisfaction Questionnaire for Medication and a PSVT survey. Overall, these data will support the development of a potentially paradigm-changing long-term management strategy for recurrent PSVT.

Results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody) in combo with pembrolizumab (Pembro) in patients (Pts) with metastatic microsatellite-stable (MSS) colorectal cancer (CRC).

127 Background: ADG126 is a fully human anti-CTLA-4 IgG1 SAFEbody that has a cleavable masking peptide that blocks the antigen binding site. ADG126 is preferentially activated in the tumor microenvironment to afford prolonged on-tumor drug exposure and limited off-tumor toxicity. Activated ADG126 binds to a unique CTLA-4 epitope to prime T cells via partial ligand blockade and deplete immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC)/phagocytosis (ADPC). Preclinical studies showed that ADG126/Pembro combination effectively increases Teff/Treg ratio. In Phase 1b/2 studies, ADG126 demonstrated a favorable safety profile and clinical efficacy as monotherapy and in combination with anti-PD-1 therapy. Here we present results of the entire dose escalation and ongoing dose expansion cohorts including a cohort of patients with MSS CRC free of liver metastasis (NCT05405595). Methods: This is a Phase 1b/2, open-label, multicenter dose escalation and expansion study of ADG126/Pembro. Pts received ADG126 [6 or 10 mg/kg (mpk), Q3W or Q6W, IV] plus Pembro (200 mg, Q3W, IV). Primary endpoints are safety and tolerability. Secondary endpoints are PK, ADA, ORR, DCR, DOR and PFS per RECIST 1.1. Results: As of Aug 29, 2023, a total of 47 Pts have been treated in dose escalation (N=11) and expansion cohorts (N=36). The median age is 60.5 yrs (26-78); 31.9% Pts had at least 3 prior therapies, 12.8% Pts received prior IO therapies. A majority of Pts (74.5%) have what are considered immunologically “cold” tumors. ADG126 was dosed at 6 mpk Q6W (1 Pt) and Q3W (5 Pts), 10 mpk Q6W (17 Pts) and Q3W (24 Pts), and Pembro was dosed at 200 mg Q3W. No DLT or Grade 4/5 TRAE was observed at any dose level. TRAEs more than 10% are pruritis (N=9, 19.1%) and diarrhea (N=5, 10.6%). Grade 3 TRAEs were observed in 5 subjects: 1 G3 diarrhea (6 mpk, 16.7%), 1 G3 adrenal insufficiency (10 mpk Q6W, 5.9%), 1 each G3 pancreatitis, blurred vision and lipase increase (10 mpk Q3W, 12.5%); all TRAEs occurred after repeat dosing. For the MSS CRC expansion cohort, 7 SDs at ADG126 10 mpk Q6W dose level (N=11) were observed, and 2 PRs (including 1 initial PR) and 4 SDs at 10 mpk Q3W (N=13) were observed. Conclusions: ADG126/Pembro combination is well-tolerated up to the maximally administered dose of 10 mpk Q3W, with limited G3 TRAEs comparable to Pembro monotherapy. The 10 mpk ADG126 Q3W repeat dosing regimen maintains a favorable safety profile and demonstrates anti-tumor activity. The MSS CRC cohort of 10 mpk ADG126 Q3W surpassed the threshold set for part 1 of the Simon’s 2-stage design, and the second stage of the cohort is now enrolling. In conclusion, ADG126/Pembro has a significantly improved therapeutic index over the same class agents in combination with anti-PD-1 therapy, and encouraging early outcomes in patients of MSS CRC without liver metastasis. Clinical trial information: NCT05405595 .

Safety assessment of a proprietary fermented soybean solution, Symbiota®, as an ingredient for use in foods and dietary supplements: Non-clinical studies and a randomized trial.

A safety evaluation was performed of Symbiota®, which is made by a proprietary anaerobic fermentation process of soybean with multistrains of probiotics and a yeast. The battery of genotoxicity studies showed that Symbiota® has no genotoxic effects. Safety and tolerability were further assessed by acute or repeated dose 28- and 90-day rodent studies, and no alterations in clinical observations, ophthalmological examination, blood chemistry, urinalysis, or hematology were observed between the control group and the different dosing groups (1.5, 5, and 15 mL/kg/day). There were no adverse effects on specific tissues or organs in terms of weight and histopathology. Importantly, the Symbiota® treatment did not perturb hormones and other endocrine-related endpoints. Of note, the No-Observed-Adverse-Effect-Level was determined to be 15 mL/kg/day in rats. Moreover, a randomized, double-blind, placebo-controlled clinical trial was recently conducted with healthy volunteers who consumed 8 mL/day of placebo or Symbiota® for 8 weeks. Only mild adverse events were reported in both groups, and the blood chemistry and blood cell profiles were also similar between the two groups. In summary, this study concluded that the oral consumption of Symbiota® at 8 mL/day by the general population does not pose any human health concerns.

Preclinical cardiovascular safety assessment of pharmacology-toxicology relationship for a set of novel kinase inhibitors.

Cardiovascular toxicity is one of the more common causes of attrition in preclinical and clinical drug development. Preclinical cardiovascular safety assessment involves numerous in vitro and in vivo endpoints which are being continually reviewed and improved to lower the incidence of cardiovascular toxicity that manifests only after the initiation of clinical trials. An example of notable preclinical toxicity is necrosis in the papillary muscle of the left ventricle in dogs that is induced by exaggerated pharmacological effects of vasodilators or positive inotropic/vasodilating off-target drug effects. Two distinct, small-molecule inhibitors that target an intracellular kinase, Compound A and Compound B, were profiled in 2-week dose-range finding and 4-week toxicity studies. Serum cardiac troponin (cTnI) was evaluated after a single dose and after 2-week and 4-week repeat dose studies with each kinase inhibitor. Acute effects on hemodynamic (heart rate, blood pressures, left ventricular contractility) and electrocardiographic (QTcV, PR, QRS intervals) endpoints by each inhibitor were assessed in an anesthetized dog cardiovascular model. Cardiovascular degeneration/necrosis with and without fibrosis was observed in dogs and correlated to increases in serum cTnI in repeat-dose toxicity studies. At the same doses used in toxicologic assessments, both kinase inhibitors produced sustained increases in heart rate, left ventricular contractility, and cardiac output, and decreases in mean arterial pressure. Cardiac pathology findings associated with these 2 kinase inhibitors were accompanied not only by cardiac troponin elevations but also associated with hemodynamic changes, highlighting the importance of the link of the physiologic-toxicologic interplay in cardiovascular safety assessment.

N-Nitrosodimethylamine investigations in Muta™Mouse define point-of-departure values and demonstrate less-than-additive somatic mutant frequency accumulations.

The N-nitrosamine, N-nitrosodimethylamine (NDMA), is an environmental mutagen and rodent carcinogen. Small levels of NDMA have been identified as an impurity in some commonly used drugs, resulting in several product recalls. In this study, NDMA was evaluated in an OECD TG-488 compliant Muta™Mouse gene mutation assay (28-day oral dosing across seven daily doses of 0.02-4 mg/kg/day) using an integrated design that assessed mutation at the transgenic lacZ locus in various tissues and at the endogenous Pig-a gene-locus, along with micronucleus frequencies in peripheral blood. Liver pathology was determined together with NDMA exposure in blood and liver. The additivity of mutation induction was assessed by including two acute single-dose treatment groups (i.e. 5 and 10 mg/kg dose on Day 1), which represented the same total dose as two of the repeat dose treatment groups. NDMA did not induce statistically significant increases in mean lacZ mutant frequency (MF) in bone marrow, spleen, bladder, or stomach, nor in peripheral blood (Pig-a mutation or micronucleus induction) when tested up to 4 mg/kg/day. There were dose-dependent increases in mean lacZ MF in the liver, lung, and kidney following 28-day repeat dosing or in the liver and kidney after a single dose (10 mg/kg). No observed genotoxic effect levels (NOGEL) were determined for the positive repeat dose-response relationships. Mutagenicity did not exhibit simple additivity in the liver since there was a reduction in MF following NDMA repeat dosing compared with acute dosing for the same total dose. Benchmark dose modelling was used to estimate point of departure doses for NDMA mutagenicity in Muta™Mouse and rank order target organ tissue sensitivity (liver > kidney or lung). The BMD50 value for liver was 0.32 mg/kg/day following repeat dosing (confidence interval 0.21-0.46 mg/kg/day). In addition, liver toxicity was observed at doses of ≥ 1.1 mg/kg/day NDMA and correlated with systemic and target organ exposure. The integration of these results and their implications for risk assessment are discussed.

Evaluating Risk Factors for Developing Hypoglycemia During Treatment of Hyperkalemia With Intravenous Regular Insulin

Background: The conventional dose of 10 units of intravenous (IV) regular insulin to treat hyperkalemia has been associated with hypoglycemia. There have been retrospective studies evaluating weight-based dose vs conventional dose of IV regular insulin but the comparative efficacy and safety is not well established. Objective: Evaluate the difference in weight-based dosing of IV regular insulin between patients who experienced hypoglycemia vs. patients who did not experience hypoglycemia after the administration of IV regular insulin. Methods: This was a retrospective, electronic chart review at a single academic medical center which included patients ≥18 years of age with an emergency department or inpatient encounter who were administered IV regular insulin within 6 hours of a pre-treatment potassium of ≥5 mmol/L. Results: There was no significant difference in the weight-based insulin dose between patients who experienced a hypoglycemic event and patients who did not experience a hypoglycemic event (.14 vs .22 units/kg; P = .44). The potassium-lowering effect was similar between the two groups (1.02 vs .96 mmol/L; P = .56). A regression analysis revealed that female sex, low baseline blood glucose (glucose <140 mg/dL), and those who received a repeat dose of IV regular insulin were independent risk factors for development of hypoglycemia. Conclusion: This study found no difference in hypoglycemic events and potassium lowering based on IV weight-based regular insulin dosing, however other risk factors may predict hypoglycemia.

Safety Evaluation of Vatari Guggulu through Acute and 90-day Repeated Dose Toxicity Study in Experimental Animals

Abstract Background: Vatari Guggulu is an Ayurvedic Medicine used in the treatment of Vata disorders. It contains Vatari taila (Castor oil), Shuddha gandhaka (purified Sulphur), Haritaki (Terminalia chebula Retz.), Vibhitaki (Terminalia bellirica [Gaertn.] Roxb.), Amla (Emblica officinalis Gaertn) and guggul (Purified Commiphora mukul Hook). As per the Ayurvedic texts, it is widely used clinically in the treatment of rheumatoid arthritis, hip pain, sciatica, gout, joint pain, and burning sensation. However, there are no systematic toxicity studies were performed to scientifically evaluate the safety of Vatari Guggulu. Objectives: The present study was designed to investigate the safety of Vatari Guggulu in acute and 90-days repeated dose oral toxicity as per Organization for Economic Cooperation and Development guidelines 423 and 408. Materials and Methods: During the acute toxicity, Vatari Guggulu was orally administered at a single limit dose of 2000 mg/kg. The mortality and clinical signs were observed for 14 days. Similarly, the 90-days repeated dose toxicity was studied by administering the Vatari Guggulu at a limit dose of 1000 mg/kg. Results: In the acute toxicity, there were no signs of toxicity, and the LD50 was calculated as &gt;2000 mg/kg. During the 90 days of repeated dose toxicity, the Vatari Guggulu at the dose of 1000 mg/kg did not show any signs of toxicity as compared to the control. The hematological, serum biochemical, and urine analysis profile of the Vatari Guggulu at the dose of 1000 mg/kg did not show any significant difference as compared to the control (P &gt; 0.05). Further, the histopathological data of control and Vatari Guggulu-treated rats were found to be normal. Conclusions: It was concluded that the test drug Vatari Guggulu is found to be safe upto 2000 mg/kg in acute toxicity and 1000 mg/kg in 90-days repeated dose oral toxicity study. The NOAEL of Vatari Guggulu is established as 1000 mg/kg/day.

Effects of letrozole on rat placental development.

We examined the morphological effects of letrozole on placental development in pregnant rats. Letrozole was orally administered at a repeat dose to pregnant rats at 0 mg/kg (control group) and 0.04 mg/kg (letrozole group) from gestation day (GD) 6 to GD 20. In the letrozole group, fetal mortality and placental weight increased from GD 15 onwards and GD 13 onwards, respectively. Fetal weights increased on GDs 15 and 17 but decreased on GD 21. Histopathologically, letrozole treatment induced multiple cysts lined with undifferentiated syncytiotrophoblasts in the trophoblastic septa on GD 13. These cysts then develop into dilated maternal sinusoids with congestive hyperemia, resulting in an enlarged placenta. In the metrial gland, there was a dilated lumen of the spiral artery and interstitial edema throughout the experimental period, resulting in thickened metrial gland. These changes are considered to be due to maternal blood circulation stagnation in the metrial gland, which is associated with dilated maternal sinusoids in the labyrinth zone. Thus, although letrozole induces an enlarged placenta due to congestive hyperemia of the labyrinth zone and transient increases in fetal weight, these placentas are thought to decline in function as the pregnancy progresses, leading to intrauterine growth restriction at the end of pregnancy.

Acute and sub-acute toxicity study of anti-obesity herbal granules in Sprague Dawley rats.

Toxicological studies are essential for developing novel medications in pharmaceutical industries including ayurvedic preparation. Hence, the present study is aimed to evaluate acute and 28-days repeated dose oral toxicity of anti-obesity polyherbal granules (PHG) in Sprague Dawley rats by OECD guidelines No 425 and 407, respectively. In an acute oral toxicity study, a single dose of 2 g/kg PHG was administered to rats and mortality, body weight, and clinical observations were noted for fourteen days. However, in the subacute oral toxicity study, the PHG was administered orally at doses of 0.3, 0.5 and 1 g/kg daily for 28 days to rats. Food intake and body weight were recorded weekly. On the 29th day, rats were sacrificed and subjected to haematological, biochemical, urine, necropsy, and histopathological analysis. In an acute oral toxicity study, no treatment-related, mortality, behavioral changes, and toxicity were found throughout fourteen days. Likewise, in the sub-acute toxicity study, no mortality and toxic effects were found in haematology, biochemical, urine, necropsy and histopathological analysis in rats for 28 days of treatment with PHG. Based on these results, the LD50 of PHG was found to be greater than 2 g/kg and the no-observed-adverse-effect level (NOAEL) of PHG for rats was found to be 0.5 g/kg/day. Thus, anti-obesity polyherbal granules showed a good safety profile in animal studies and can be considered an important agent for the clinical management of obesity.

The MISOPRED score: Development and validation of a clinical scoring system to predict the effectiveness of Misoprostol treatment for early pregnancy loss.

Misoprostol treatment for early pregnancy loss has varied success demonstrated in previous studies. Incorporating predictors in a single clinical scoring system would be highly beneficial in clinical practice. To develop and evaluate the accuracy of a scoring system to predict misoprostol treatment outcomes for managing early pregnancy loss. Retrospective cohort and validation study. Patients discharged from the gynecologic emergency department from 2013 to 2016, diagnosed with early pregnancy loss, who were treated with 800 mcg misoprostol, administrated vaginally were included. All were sonographically reevaluated within 48-72 hours. Patients in whom the gestational sac was not expelled or with endometrial lining >30 mm were offered a repeat dose and returned for reevaluation after seven days. A successful response was defined as complete expulsion. Clinical data were reviewed to identify predictors for successful responses. The scoring system was then retrospectively evaluated on a second cohort to evaluate its accuracy. Multivariate logistic regression was performed to identify factors most predictive of treatment response. The development cohort included 126 patients. Six factors were found to be most predictive of misoprostol treatment effectiveness: nulliparity, prior complete spontaneous abortion, gestational age, vaginal bleeding, abdominal pain, and mean sac diameter, yielding a score of 0-8 (the MISOPRED score), where 8 represents the highest-likelihood of success. The score was validated retrospectively with 119 participants. Successful response in the group with the lowest likelihood score (score 0-3) was 9%, compared with 82% in the highest likelihood score group (score 7-8). Using the MISOPRED score, approximately 15% of patients previously planned to receive misoprostol treatment can be referred for surgical management. MISOPRED score can be utilized as an adjunct tool for clinical decision-making in cases of Early pregnancy loss. To our knowledge, this is the first scoring system suggested to predict the success rate in these cases.