The influence of serial 50 µL microsampling on rats administered azathioprine, the immunosuppressive drug.

According to the ICH S3A Q&A, microsampling is applicable to pharmaceutical drugs and toxicological analysis. Few studies have reported the effect of microsampling on the toxicity of immunotoxicological drugs. The aim of this multicenter study was to evaluate the toxicological effects of serial microsampling on rats treated with azathioprine as a model drug with immunotoxic effects. Fifty microliters of blood were collected from the jugular vein of Sprague-Dawley rats at six time points from day 1 to 2 and 7 time points from day 27 to 28. The study was performed at three organizations independently. The microsampling effect on clinical signs, body weights, food consumption, hematological parameters, biochemical parameters, urinary parameters, organ weights, and tissue pathology was evaluated. Azathioprine-induced changes were observed in certain hematological and biochemical parameters and thymus weight and pathology. Microsampling produced minimal or no effects on almost all parameters; however, at 2 organizations, azathioprine-induced changes were apparently masked for two leukocytic, one coagulation, and two biochemical parameters. In conclusion, azathioprine toxicity could be assessed appropriately as overall profiles even with blood microsampling. However, microsampling may influence azathioprine-induced changes in certain parameters, especially leukocytic parameters, and its usage should be carefully considered.

Single and repeated dose (28 days) intravenous toxicity assessment of bartogenic acid (an active pentacyclic triterpenoid) isolated from Barringtonia racemosa (L.) fruits in mice.

Bartogenic acid (BA), an active pentacyclic triterpenoid, has been reported for anti-diabetic, anti-inflammatory, anti-arthritic, anti-cancer, and anti-tumor activity. However, toxicity profiling of BA has not been reported till date. Hence, this study is designed to evaluate the single dose (12.5, 25, 50 and 100 mg/kg) and repeated dose (1.5, 6, and 24 mg/kg) intravenous toxicity of BA in BALB/c mice. Control group received vehicle. In single dose toxicity study, two mortalities were observed at 100 mg/kg of BA whereas lower doses were well tolerated. In repeated dose toxicity study, no mortality was observed. 1.5 mg/kg of BA was well tolerated in mice of both sexes. At 6 mg/kg of BA, female mice showed significant reduction in the body weight as compared to the control group however no significant change was observed in male mice. 24 mg/kg of BA showed significant reduction in the body weight in mice of both sexes. Further, these mice showed significant change in the relative organ weight. However, no toxicologically relevant changes were observed in hematology, biochemistry, and histopathology. Based on the findings, No-Observed-Adverse-Effect-Level (NOAEL) for BA were found to be<24 mg/kg for male mice and<6 mg/kg for female mice.

In vitro genotoxicity assessment and 28-day repeated dose oral toxicity study of steady-calcium formula in rats.

Steady-calcium formula (SCF), a functional food mixture with potential of joint care, contains five major ingredients. However, the uncertain cross-reactivity among these included ingredients cannot be excluded. Hence, it is important to ensure the safety of this mixture. In this study, the safety of SCF was evaluated through in vitro genotoxicity assessment and 28-day oral toxicity study in rats. The bacterial reverse mutation test and mammalian chromosome aberration test displayed that SCF did not induce mutagenicity and clastogenicity. The 28-day repeated dose assessment of SCF in rats revealed no mortality and adverse effects in clinical signs, body weight, urinalysis, hematology, organ weight, and histopathology at all treated groups. Although some significant changes were observed in food intake and parameters of serum biochemistry at the highest dose in males, they were not dose-related and considered to be within normal range. These findings indicate that SCF does not possess genotoxic potential and no obvious evidence of subacute toxicity. These results demonstrate for the first time that the genotoxicity and subacute toxicity for SCF are negative under our experimental conditions and the no observed adverse effect level (NOAEL) of SCF may be defined as at least 5470 mg/kg/day.

Acute and subchronic oral toxicity assessment of extract from Etlingera pavieana rhizomes.

In Southeast Asia, the rhizome of Etlingera pavieana is commonly consumed and parts of the rhizomes have been used as a medicine for the treatment of several disorders. Its pharmacological effects have previously been reported. However, its potential toxicity has not been described. This study aimed to evaluate in vivo toxicity of E. pavieana rhizome extract (EPE) in Sprague Dawley rats. Acute toxicity testing of EPE at a single dose of 2,000 mg/kg produced no toxic effects in female rats after 14 days of treatment. Subchronic toxicity testing showed that all doses of EPE (500, 1,000, and 2,000 mg/kg/day) produced no sign of toxicity during 90 days of treatment. All biochemical and hematological values were within normal ranges. There were no significant histopathological differences in the internal organs among the tested groups. Therefore, the no-observed-adverse-effect level of EPE was 2,000 mg/kg/day in both male and female rats, thereby confirming the safety of EPE for use in traditional medicines.

Safety evaluation study of lincomycin and spectinomycin hydrochloride intramuscular injection in chickens.

This study aimed to investigate the nonclinical safety of lincomycin and spectinomycin hydrochloride (LC-SPH) intramuscular (i.m) doses on target animals (chickens) to provide guidelines for dose level design and side effect monitoring in clinical trials. A total of 80 healthy Arbor Acres plus broiler chicks were completely randomized and blindly divided into four treatment groups (control, one-time dose, three-time dose, and five-time dose) of 20 chicks each (20 chickens per group). At the age of day 15, all chickens (except the control group) were administered LC-SPH intramuscularly (chest muscles) at different doses of 20 mg/kg.bw, 60 mg/kg.bw, and 100 mg/kg.bw respectively for 9 consecutive days recommended by veterinary international cooperation on harmonization (VICH) guidelines. The chickens had ad libitum access to antibiotic-free feed and water. Feeding chickens were observed twice a day throughout the study. The drug safety was evaluated by complete blood count, biochemical parameters, histopathological, clinical signs, body weight gain, and feed conversion ratio (FCR). Hence, considering the minor toxicity of 60 mg/kg, our results reveal that intramuscular injection of at least 20 mg/kg body weight has no effects on growth performance, clinical blood parameters, organ coefficient, and histopathological parameters. Thus, a combination of LC-SPH 20 mg/kg body weight i.m injection investigated safe followed daily administration for nine consecutive days in healthy chickens. It is concluded that the experimental results support the safety of 20 mg/kg body weight in combination for the further clinical research study.

Atypical presentation of SLC30A10 gene mutation with hypermanganesemia, seizures and polycythemia.

Manganese is an essential element that is ubiquitously present in our diet and water supply. It is a cofactor for several critical physiological processes. Elevated blood levels of Manganese secondary to SLC30A10 gene mutation presents distinctly with dystonia, polycythemia, chronic liver disease and a characteristic high T1 signal in basal ganglia on brain MRI. The primary treatment for this condition is chelation along with iron therapy. We report a previously healthy boy with compound heterozygous SLC30A10 gene mutations who had a unique clinical presentation with prominent seizures, polycythemia, and characteristic T1 hyperintensity in basal ganglia. Seizures have not been previously reported to be associated with this specific mutation.

Visceral leishmaniasis associated with macrophage activation syndrome: Case report and literature review.

BACKGROUND: The combination of visceral leishmaniasis (VL) and macrophage activation syndrome (MAS) makes the diagnosis difficult due to their similar clinical presentation, with a poor prognosis especially since the treatment is still poorly codified.We report the case of a 17-month-old female patient from Berkane, presenting for a 3 months history of anarchic fever with anemic syndrome made up of pallor and hemorrhagic syndrome made up of epistaxis. Physical examination revealed a temperature of 39 ° C, lower limbsedema, paleness of skin and mucous membranes, gingival petechiae, bleached hair, and hepatosplenomegaly. CASE PRESENTATION: The complete blood count showed pancytopenia with deep aregenerative normochromic normocytic anemia at 3 g/dL, leukocytes were at 4860/mm 3 with neutropenia at 680/mm 3 and thrombocytopenia at 12.000/mm3, the blood smear was without abnormality. These anomalies were associated with a hypoalbunemia, hypertriglyceridemia, hyperferritinemia, lactate dehydrogenase (LDH) level was at 337 IU/L, low prothrombin time (PT) at 56 % and fibrinogen level at 1 g/L. The direct Coombs test was positive. Examination of the myelogram revealed the presence of leishmania bodies and figures of hemophagocytosis. A diagnosis of visceral leishmaniasis associated with MAS was made.The patient was put on liposomal amphotericin B and corticosteroid therapy with good clinical and biological evolution and good therapeutic tolerance. CONCLUSION: The association of VL and MAS remains rare and should be evoked even in non-endemic areas since late diagnosis worsens the prognosis and may even be responsible for the death of patients despite an aggressive treatment.

In vivo and in silico studies of Dennettia tripetala essential oil reveal the potential harmful effects of habitual consumption of the plant seed.

Dennettia tripetala G. Baker (Annonaceae), is a plant with nutritional, social economy, and medicinal values. Its rising medicinal profile makes this plant a prospect in drug discovery. However, the reported strong addictive potential among habitual consumers makes the need to establish its safety imperative. In this report, we evaluated the safety profile of the essential oil of the seed of D. tripetala (EODS) in nulliparous female Wistar rats using in vivo single and repeated dose toxicity profiling, as well as in silico toxicity profiling of its known seed oil derived phytoconstituents. Our results showed consistent significant dose-dependent alterations in relative body weights, organ-body and organ-brain weight ratios, haematological and biochemical indices, as well as liver and kidney histoarchitectures, following single and repeated oral administrations. Significant alterations in liver and kidney histoarchitectures were consistent with the observed significant increase in AST/ALT ratio, suggesting deleterious effects of EODS on the kidney and liver. However, the lack of alterations in the histoarchitectures of the hippocampus and hypothalamus suggests that the brain may not have been adversely affected. Also, the in silico analysis suggests that hepatotoxic effects of EODS may be linked to Benzylnitrile, Humulene, Linalool, (Z)-ß-Ocimene. In addition, the failure of ß-Phenylnitroethane, the most abundant phytoconstituent of EODS, to pass phases I and II in silico toxicity screening, and the presence of Caryophyllene oxide, a known toxic compound, coupled with the predicted binding of both to DNA and protein, low LD50 and high percent mortality at 250 mg/kg of repeated doses, further confirmed the potentially toxic nature of EODS. We concluded that based on our in vivo and in silico observations, there is an urgent need for public education to regulate the excessive consumption of the seeds of D. tripetala.

Nonclinical safety evaluation of pabinafusp alfa, an anti-human transferrin receptor antibody and iduronate-2-sulfatase fusion protein, for the treatment of neuronopathic mucopolysaccharidosis type II.

Pabinafusp alfa is a fusion protein comprising a humanized anti-human transferrin receptor (TfR) antibody and human iduronate-2-sulfatase. It was developed as a novel modality to target central nervous system-related symptoms observed in patients with mucopolysaccharidosis type II (MPS II, also known as Hunter syndrome). As the fusion protein contains an entire IgG1 molecule that binds TfR, there may be specific safety concerns, such as unexpected cellular toxicity due to its effector functions or its ability to inhibit iron metabolism, in addition to general safety concerns. Here, we present the comprehensive results of a nonclinical safety assessment of pabinafusp alfa. Pabinafusp alfa did not exhibit effector functions, as assessed by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity studies in TfR-expressing hematopoietic cells. Repeat-dose toxicity studies in cynomolgus monkeys showed that pabinafusp alfa did not induce any significant toxicological changes at doses up to 30 mg/kg/week upon intravenous administration for up to 26 weeks. Interaction of transferrin with TfR was not inhibited by pabinafusp alfa, suggesting that the effect of pabinafusp alfa on the physiological iron transport system is minimal, which was confirmed by toxicity studies in cynomolgus monkeys. These findings suggest that pabinafusp alfa is expected to be safe for long-term use in individuals with MPS II.

Subchronic safety evaluation of hot-water extract from thinned immature mangos (Mangifera indica 'Irwin'): 90-days oral toxicity study in rats.

Thinned immature fruit of the mango tree (Mangifera indica 'Irwin') are handled as waste. In this study, we conducted a 90-days toxicity study in male and female Sprague Dawley rats to evaluate the safety of a hot-water extract of thinned immature mango fruits (TIMEx) administered by oral gavage at doses of 500, 1000 and 2500 mg/kg body weight/day. Treatment did not result in death or changes in the behavior or external appearance of the animals. No alterations were observed in hematological or serum chemical parameters, urinalysis, food consumption, body weight gain or organ weights at the end of the treatment period, with the exception of higher mean corpuscular volume in male rats that received high doses and lower serum creatine phosphokinase levels in female rats that received medium doses. Under the conditions of this study and based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for TIMEx was 2500 mg/kg/day. The findings indicate that TIMEx is safe for consumption and should be investigated as a candidate food.

Toxicity and bioaccumulation of manganese and chromium in different organs of common carp (Cyprinus carpio) fish.

The present research work was carried out to determine the bioaccumulation of manganese and chromium in the gills, intestine, muscles, skin and bones, as well as its acute toxicity and effects on hematological and biochemical parameters in Common carp (Cyprinus carpio). Adult carps were exposed for 96 h to manganese sulphate and chromium chloride solution, a sub lethal concentration was used in the experiment. Bioaccumulation was highest in the gills followed by intestine > muscles > skin > bones. The concentration of hematocrit (HCT) (37.3 ± 0.36), hemoglobin (HGB) (9.0 ± 0.04), Red Blood Cells (RBCs) (3.7 ± 0.025), mean corpuscular volume (MCV) (121.2 ± 0.36), mean corpuscular hemoglobin (MCH) (41.3 ± 0.3) and mean corpuscular hemoglobin concentration (MCHC) (41.06 ± 0.072) was significantly higher at 96 h (P < 0.01) after exposure to manganese and chromium, while the concentration of platelets (PLT) (16.8 ± 0.12) and white blood cells (WBCs) (62.7 ± 0.11) was lower at 96 h of exposure. Serum glutamic pyruvic transaminase (SGPT) (40.6 ± 0.4), Blood Urea (13 ± 0.1), serum triglycerides (231.21 ± 0.04), high-density lipoprotein (HDL) (39 ± 0.07), serum Alkaline PO4 (242 ± 0.2), lactate dehydrogenase (LDH) (1239 ± 13.21), and serum Uric Acid (4.81 ± 0.33) were significantly higher (P < 0.01) at 96 h of exposure. The highest concentration of serum cholesterol (339 ± 0.09), serum reatinine (0.9 ± 0.01), low density lipid (240 ± 0.2) was observed at 24 h. Serum glutamic-oxaloacetic transaminase (SGOT) (19 ± 0.13), and serum albumin were at the highest level at 72 h (3.19 ± 0.07) (P < 0.01) post exposure.

Role of TMPRSS6 rs855791 (T > C) polymorphism in reproductive age women with iron deficiency anemia from Lahore, Pakistan.

BACKGROUND: Iron deficiency anemia (IDA) is the highest nutritional deficiency worldwide. It is a multifactorial disease, with a higher morbidity rate. TMPRSS6 polymorphisms importantly rs855791 is found to play an essential role in iron homeostasis in the human body. The rs855791 (T > C) polymorphism is highly associated with iron levels, and multiple blood parameters, leading to IDA. The role of TMPRSS6 rs855791 polymorphism and the significance of complete blood count (CBC) parameters in the pathogenesis of IDA is not yet studied in the Pakistani population. METHODS: We enrolled 113 cases and 136 controls to conduct a case control study. Complete blood count (CBC) and iron parameters were analyzed for association studies. PCR-RFLP based genotyping was performed. RESULTS: The TMPRSS6 rs855791 (T > C) polymorphism is significantly associated with IDA pathogenesis as observed in the codominant model and recessive models (P < 0.05, OR: 1.5 and 95% CI: 0.9, 2.6, P < 0.05, OR: 0.5 and 95% CI: 0.2, 0.9 respectively). Elderly women among cases (30-49 years) were found to be more susceptible to IDA (P < 0.05, AOR: 2.1 and 95% CI: 1.0, 4.2). The most significant parameters associated with IDA were red blood cell count (RBC) and hematocrit (Hct%) (P < 0.05, AOR: 16.5, 95% CI: 7.6, 35.9 and P < 0.05, AOR: 10.1, 95% CI: 2.5, 41.6, respectively). CONCLUSION: TMPRSS6 polymorphism at rs855791 (T > C) is significantly associated with IDA susceptibility in reproductive age women in Pakistan. Age, RBC count and Hct% are found to play an important role in IDA pathogenesis in our study population.

Sub-chronic dermal exposure to aircraft engine oils impacts the reproductive organ weights and alters hematological profiles of Sprague Dawley rats.

There is little data available for the toxicity of used aircraft engine oils relative to their unused (new) versions. This study was conducted to determine if grade 3 (G3) and 4 (G4) aircraft engine oils in their new states (G3-N and G4-N) and their used versions (G3-U and G4-U) have the potential to induce toxicity via dermal application. Male and female Sprague Dawley rats were dermally exposed to water (control), new and used versions of G3 and G4 oils to determine the oil sub-chronic toxicity potentials. A volume of 300 µL of undiluted oil was applied to the pad of the Hill Top Chamber System©. Then the chamber was attached to a fur-free test site located at the back of the rat for 6 h/day for 5 consecutive days/week for 21 days (15 total exposures). Recovery rats also received similar treatments and were kept for 14 days post-exposure to screen for reversibility, persistence, or delayed occurrence of toxic effects. Both G3 and G4 oils had a significant impact on the weight of male and female reproductive organs: testes weights for recovery rats exposed to G3-N significantly decreased (12%) relative to controls; G3-N and G3-U decreased uterus weights by 23% and 29%, respectively; G4-N decreased uterus weights by 32% but were resolved at the end of the recovery period; G4-N increased the weight of the adrenals and spleen for females by 34% and 27%, respectively, during the recovery period. G3 and G4 induced more changes in female blood indices than in those for males. Of all versions of oils, G4-N induced the most changes in profiles of female blood. G4-N significantly decreased the white blood cells, lymphocytes, neutrophils, eosinophils and increased the mean platelet volumes. Interestingly, males were not affected by exposure to G4-N oil. While G3-N decreased the white blood cells and lymphocytes for females it slightly increased those for males. In summary, G3 and G4 oils impacted the weights for male and reproductive organs. This study highlights the health risks that aircraft maintenance workers may be exposed to if precautions are not taken to minimize exposure to these oils.

Renoprotective effects of stevia (Stevia rebaudiana Bertoni), amlodipine, valsartan, and losartan in gentamycin-induced nephrotoxicity in the rat model: Biochemical, hematological and histological approaches.

The current study investigated the renoprotective effects of stevia, angiotensin-II type 1 receptor (AT1) blocker and calcium (Ca2+) channel blocker in gentamycin-induced nephrotoxicity in rat models. Six groups of male Sprague-Dawley rats of eight weeks old were taken for the experiment: sham control, nephrotoxicity, treatment with amlodipine (4 mg/kg/day); stevia (200 mg/kg/day); losartan (15 mg/kg/day) and valsartan (5 mg/kg/day), accordingly. The blood sample was taken for the assessment of renal and hepatic-functional variables like serum creatinine, blood urea, BUN and SGPT, SGOT, and total serum bilirubin. Hematological parameters were also examined. Histological examination has been done on kidneys and liver. Alterations of the body weight and the organ's weight were documented. Treatment with stevia and valsartan significantly decreased serum creatinine levels. A reduction of liver enzymes, and total serum bilirubin levels were observed in all the treatment groups. Treatment with valsartan and amlodipine, remarkably and stevia, mildly reduced the renal tissue damage, inflammation, and tubular necrosis. However, the present study demonstrated that losartan treatment aggravated kidney damage by increasing protein cast, calcification, tubular necrosis, and injury. This comparison indicated that both stevia and valsartan have beneficial renoprotective effect and valsartan offers a better treatment option in renal damage over losartan.

28-day inhalation toxicity of 3-methoxybutyl chloroformate in rats.

The 28-day repeated inhalation study was applied for hazard assessment of 3-methoxybutyl chloroformate (3-MBCF) in Sprague Dawley rats. Groups of five rats per sex were exposed 6 h/day, 5 days per week for 4 weeks to test substance concentration (ranging from 3 to 12 ppm) using a whole-body exposure system. At the terminal sacrifice, following blood collection and gross pathological examination, organ weights were determined and fixed organs were examined. The micronucleus test was performed using bone marrow cells. Exposure of 3-MBCF induced mortality at concentrations above 6 ppm. Decreases in body weight and food intake, hematologic alterations, organ weight changes, and gross and microscopic findings were seen even at the lowest concentrations of 3 ppm. Histopathology revealed principal test substance exposure correlated with lesions in the respiratory tract in both male and female rats above 3 ppm. Groups of male rats exposed above 6 ppm show microscopic lesions in spleens, livers, testes and epididymides; however, the micronucleated polychromatic erythrocytes frequency in bone marrow cells was not changed. Based on histopathology of the respiratory tract and other organs, the no observed adverse effect level (NOAEL) of 3-MBCF in the present study was less than 3 ppm.

Bisphenol S impairs blood functions and induces cardiovascular risks in rats.

Bisphenol S (BPS) is an industrial chemical which is recently used to replace the potentially toxic Bisphenol A (BPA) in making polycarbonate plastics, epoxy resins and thermal receipt papers. The probable toxic effects of BPS on the functions of haemopoietic and cardiovascular systems have not been reported till to date. We report here that BPS depresses haematological functions and induces cardiovascular risks in rat. Adult male albino rats of Sprague-Dawley strain were given BPS at a dose level of 30, 60 and 120 mg/kg BW/day respectively for 30 days. Red blood cell (RBC) count, white blood cell (WBC) count, Hb concentration, and clotting time have been shown to be significantly (*P < 0.05) reduced in a dose dependent manner in all exposed groups of rats comparing to the control. It has also been shown that BPS increases total serum glucose and protein concentration in the exposed groups of rats. We have observed that BPS increases serum total cholesterol, triglyceride, glycerol free triglyceride, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) concentration, whereas high density lipoprotein (HDL) concentration has been found to be reduced in the exposed groups. BPS significantly increases serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities dose dependently. Moreover, serum calcium, bilirubin and urea concentration have been observed to be increased in all exposed groups. In conclusion, BPS probably impairs the functions of blood and promotes cardiovascular risks in rats.

Safety assesment of Bacillus clausii UBBC07, a spore forming probiotic.

Probiotics are vital bacteria that colonize the intestine and modify its microflora with benefits for the host. Very few members of the Bacillus group are recognized as safe for use and hence only a few strains are available as commercial preparations for application in humans and animals. Acute and subacute studies in rats were conducted to establish safety of Bacillus clausii (B. clausii) UBBC07. In the acute toxicity study, the oral LD50 for B. clausii UBBC07 was found to be >5000 mg/kg (630 billion cfu/kg) body weight. The NOAEL for B. clausii UBBC07 was found to be 1000 (126 billion cfu) mg/kg body weight/day by oral route in the subacute toxicity study. There were no significant differences between control and treated groups in any of the endpoints assessed using an OECD443 or OECD407 protocol. B. clausii UBBC07 was found to be resistant to three antibiotics -clindamycin, erythromycin and chloramphenicol. Analysis of the whole genome sequence of B. clausii UBBC07 revealed that the antibiotic resistance genes are present in chromosomal DNA which is intrinsic and not transferable. Toxin genes were also found to be absent. These results suggest consumption of B. clausii UBBC07 is safe for humans.

Haematological evaluation of sodium fluoride toxicity in oryctolagus cunniculus.

Blood is promptly affected by environmental pollutants and toxicants that can cause many metabolic disorders. The high level of fluoride acts as a potential pollutant, insecticide and rodenticide with very high toxicity, associated with the hematological damage. This study aimed to determine the toxicity of Sodium Fluoride on hematological parameters in Oryctolagus cunniculus. Twenty rabbits were acclimatized and divided in to control group and three experimental groups.Experimental group-I, II and III were treated with 10, 30 and 50 mg/kg body weight doses of Sodium Fluoride orally. Various blood parameters such as TEC, Hb, HCT, MCV, MCH, MCHC, TLC and PLT count were investigated. Result findings showed that values of blood indices in experimental groups were significantly lower than the control group. Oneway ANOVA was applied for statistical analysis. The outcomes of the current studies indicated the reduction in RBC counts (anemia), leukocyte count (leukocytopenia), monocytosis, eosinopenia, neutrophilia and thrombocytosis on fluoride intoxication. Hematological disruptions like microcytic hypochromic anemia and decreased leukocyte count may be linked to the inflammatory effects of Sodium Fluoride on lymphatic organs.

Safety assessment of McB-E60 (extract of a Momordica sp.): Subchronic toxicity study in rats.

Momordica charantia plant is consumed as a foodstuff in some south Asian curries while its extract preparations have been traditionally used for lowering blood glucose levels in patients with diabetes mellitus. Nutritional Health Institute Laboratories (NHIL), LLC, Florida informed that it patented a new plant McB, as an interhybrid of three plants of Momordica genus. The objective of the present study was to investigate potential adverse effects, if any, of McB-E60 (extract of a Momordica sp.) in rats following subchronic administration. Sprague-Dawley rats (10/sex/group) were administered via oral gavage 0 (control), 250, 500 and 1000 mg/kg body weight (bw)/day of McB-E60 for 90 days. Additional 28-day recovery groups were maintained at control and high dose levels. No mortality or significant and adverse changes in clinical signs, neurological signs, body weight gain or feed intake were noted. No toxicologically significant changes in hematology, clinical chemistry, urinalysis and organ weights were noted. Gross and microscopic pathology examinations did not reveal treatment-related abnormalities. Any changes noted were incidental and within historical control ranges. Based on the results of this study, the No-Observed-Effect Level (NOEL) for McB-E60 (extract of a Momordica sp.) was determined as greater than 1000 mg/kg bw/day, the highest dose tested.

Ubiquitin is a versatile scaffold protein for the generation of molecules with de novo binding and advantageous drug-like properties.

In the search for effective therapeutic strategies, protein-based biologicals are under intense development. While monoclonal antibodies represent the majority of these drugs, other innovative approaches are exploring the use of scaffold proteins for the creation of binding molecules with tailor-made properties. Ubiquitin is especially suited for this strategy due to several key characteristics. Ubiquitin is a natural serum protein, 100% conserved across the mammalian class and possesses high thermal, structural and proteolytic stability. Because of its small size and lack of posttranslational modifications, it can be easily produced in Escherichia coli. In this work we provide evidence that ubiquitin is safe as tested experimentally in vivo. In contrast to previously published results, we show that, in our hands, ubiquitin does not act as a functional ligand of the chemokine receptor CXCR4. Cellular assays based on different signaling pathways of the receptor were conducted with the natural agonist SDF-1 as a benchmark. In none of the assays could a response to ubiquitin treatment be elicited. Furthermore, intravenous application to mice at high concentrations did not induce any detectable effect on cytokine levels or hematological parameters.