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Comparative toxicity study on classical and modified version of Jawarish Jalinoos (a traditional Unani formulation) in rats

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      Abstract

      Background

      Jawarish Jalinoos (JJ) is a classical semisolid traditional Unani formulation clinically used for the treatment of weakness of vital organs, liver, and stomach. Although JJ has been widely used clinically for several decades, no scientific report is available for its safety.

      Methods

      JJ and its sugar-free tablet version (SFJJ; formulated to target diabetic population) were assessed for safety in rats. Ninety-day repeated dose oral toxicity study was performed as per the Organisation for Economic Co-operation and Development Guideline 408. JJ was orally administered at the dose of 2000 mg/kg bw/d, whereas SFJJ was orally administered at the doses of 506 mg/kg body weight (bw)/d, 1012 mg/kg bw/d, and 2024 mg/kg bw/d for 90 days. The animals were periodically observed for clinical signs of toxicity, mortality, morbidity, body weight changes, and feed consumption. At the end of the study, hematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight, and histological examination were performed.

      Results

      Treatment with SFJJ and JJ showed no significant differences in body weight gain, feed consumption, hematology, clinical biochemistry, and serum electrolytes. No gross pathological findings and differences in relative organ weights were observed between control and drug treated rats. Histological examination revealed no toxicologically significant abnormalities related with SFJJ or JJ treatment.

      Conclusion

      The 90-day repeated dose oral toxicity study demonstrates that the no observed adverse effect level of SFJJ and JJ is greater than 2024 mg/kg bw/d and 2000 mg/kg bw/d (p.o.) in rats, respectively. Both formulations were found to be safe up to the tested dose levels and experimental conditions, and therefore safe for clinical use as specified in the literature.

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      Most cited references 19

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      Dose translation from animal to human studies revisited.

      As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.
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        The current state of serum biomarkers of hepatotoxicity.

        The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione-S-transferase alpha (GSTalpha) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in early clinical trials.
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          Measuring Motor Coordination in Mice

          Mice are increasingly being used in behavioral neuroscience, largely replacing rats as the behaviorist's animal of choice. Before aspects of behavior such as emotionality or cognition can be assessed, however, it is vital to determine whether the motor capabilities of e.g. a mutant or lesioned mouse allow such an assessment. Performance on a maze task requiring strength and coordination, such as the Morris water maze, might well be impaired in a mouse by motor, rather than cognitive, impairments, so it is essential to selectively dissect the latter from the former. For example, sensorimotor impairments caused by NMDA antagonists have been shown to impair water maze performance2. Motor coordination has traditionally been assessed in mice and rats by the rotarod test, in which the animal is placed on a horizontal rod that rotates about its long axis; the animal must walk forwards to remain upright and not fall off. Both set speed and accelerating versions of the rotarod are available. The other three tests described in this article (horizontal bar, static rods and parallel bars) all measure coordination on static apparatus. The horizontal bar also requires strength for adequate performance, particularly of the forelimbs as the mouse initially grips the bar just with the front paws. Adult rats do not perform well on tests such as the static rods and parallel bars (personal observations); they appear less well coordinated than mice. I have only tested male rats, however, and male mice seem generally less well coordinated than females. Mice appear to have a higher strength:weight ratio than rats; the Latin name, Mus musculus, seems entirely appropriate. The rotarod, the variations of the foot fault test12 or the Catwalk (Noldus)15 apparatus are generally used to assess motor coordination in rats.
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            Author and article information

            Affiliations
            [a ]Central Research Institute of Unani Medicine, Hyderabad, India
            [b ]Central Council for Research in Unani Medicine (CCRUM), Ministry of AYUSH, Government of India, New Delhi, India
            Author notes
            [* ] Corresponding author. Department of Pharmacology, Central Research Institute of Unani Medicine, Opposite ESI Hospital, AG’s Colony Road, Erragadda, Hyderabad, Telangana 500 038, India.Central Research Institute of Unani MedicineHyderabadIndia gmhusain@ 123456gmail.com
            Contributors
            Journal
            Integr Med Res
            Integr Med Res
            Integrative Medicine Research
            Elsevier
            2213-4220
            2213-4239
            18 January 2017
            March 2017
            18 January 2017
            : 6
            : 1
            : 66-78
            5395683 S2213-4220(16)30151-2 10.1016/j.imr.2017.01.001
            © 2017 Korea Institute of Oriental Medicine. Published by Elsevier.

            This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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