Good Laboratory Practice Regulations Research Articles

Study on the Single Dose Toxicity of ShinEumHur Pharmacopuncture Injected into the Muscles of Rats.

Objectives:This study was carried out to analyze the single dose toxicity of ShinEumHur (SEH) pharmacopuncture injected into the muscles of Sprague-Dawley rats.Methods:The SEH pharmacopuncture was made in a clean room at the Korean Pharmacopuncture Institute (K-GMP). After the mixing process with sterile distilled water had been completed, the pH was controlled to between 7.0 and 7.5. All experiments were conducted at Biotoxtech, an institution authorized to perform non-clinical studies under the Good Laboratory Practice (GLP) regulations. Sprague-Dawley rats were chosen for the pilot study. Doses of SEH pharmacopuncture, 0.25, 0.5 and 1.0 mL, were administered to the experimental groups, and a dose of normal saline solution, 1.0 mL, was administered to the control group. We examined the survival rate, weights, clinical signs, mean hematology parameters, mean clinical chemistry, necropsy and histopathological findings.This study was conducted under the approval of the Institutional Animal Ethics Committee.Results:No deaths or abnormalities occurred in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To check for abnormalities in organs and tissues, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues.Conclusion:The above findings suggest that treatment with SEH pharmacopuncture is relatively safe. Further studies on this subject are needed to yield more concrete evidence.

Safety evaluation of cricket(Gryllus bimaculatus) extract in Sprague-Dawley rats

Recently, research investment in the improvement of food safety as a food source and specializing of nutritional source of edible insects is being actively conducted. Cricket especially has been attracting considerable interest in entomophagy; however, research on the safety assessment of cricket is limited. This study investigated the effects of cricket ethanol extract when orally administrated in Sprague-Dawley rats. Here, we performed a 4 wk repeated oral dose toxicity test in Sprague-Dawley rats following the Organization for Economic Cooperation and Development test guidelines 407 under Good Laboratory Practice regulation. Rats were randomly allocated 4 groups: vehicle control, 250, 500, 1,000 mg/kg test groups and administrated based on body weight for 28 d. The animals were observed for mortalities and clinical signs, body weight changes, food and water consumption. At the end of treatment period, blood and urine were collected and analyzed. Subsequently, the animals were sacrificed and subjected to gross pathological examination and organ weight measurement. The organs were preserved for histopathological examination. The results showed that there were no systemic toxicological effects related with the cricket ethanol extract in the 4 wk oral repeated dose toxicity study. It is considered that NOAEL of cricket ethanol extract is greater than 1,000 mg/kg/d and there was no target organ detected.

A Study on Single Dose Toxicity of Intravenous Injection of Mecasin Herbal Acupuncture

Objectives :This study was conducted to analyze the single dose toxicity of Mecasin (Gami-Jakyak Gamcho buja Decoction) herbal acupuncture administered in the vein of Sprague-Dawley rats. Methods :All experiments were performed at the Medvill, an institution licensed to conduct nonclinical studies, under the Good Laboratory Practice (GLP) regulations. Sprague-Dawley rats were chosen in this pilot study. In the experiment, Sprague-Dawley rats were divided into four groups of five male and five female animals per group. Doses of Mecasin herbal acupuncture, at 0, 500, 1,000, and 2,000 mg/kg, were given to the experimental groups, and a dose of normal saline solution, at 2 ml/kg, was administered to the control group. Mecasin herb acupuncture and normal saline were injected into the vein at once, and we observed mortality, clinical signs, weights, and gross findings for 14 days after injection. This study was conducted under the approval of the Institutional Animal Ethics Committee. Results : There is no death or abnormality in any of the four groups. All groups put on weights favorably. There are no significant gross findings in necropsy examinations. Conclusions :The above results showed that intravenous injection of 500-2,000 mg/kg of Mecasin herb acupuncture did not cause any changes in weight or, in the results of necropsy examinations, in mortalities. Therefore, the toxicity of Mecasin herb acupuncture was not confirmed, and the presumptive lethal dose of Mecasin herb acupuncture was higher than 2,000 mg/kg. The outcomes suggest that treatment with Mecasin herbal acupuncture is relatively safe. Further evaluations on this subject are needed to yield more concrete evidence.

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

A Study on the Single-dose Oral Toxicity of Super Key in Sprague-Dawley Rats.

Objectives:This study was performed to analyze the single-dose oral toxicity of the super key (processed sulfur).Methods:All experiments were conducted at Medvill, an institution authorized to perform non-clinical studies, under the Good Laboratory Practice (GLP) regulations. In order to investigate the oral toxicity of super keyWe administered it orally to Sprague-Dawley (SD) rats. The SD rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of super key 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg were administered to the experimental groups, and a dose of normal saline solution, 10 mL/kg, was administered to the control group. We examined the survival rates, weights, clinical signs, gross findings and necropsy findings. This study was conducted under the approval of the Institutional Animal Ethics Committee. (Approval number: A01-14018).Results:No deaths or abnormalities occurred in any of the four groups. Although slight decreases in the weights of some female rats were noted, no significant changes in weights or differences in the gross findings between the control group and the experimental groups were observed. To check for abnormalities in organs, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs.Conclusion:The results of this research showed that administration of 500 ─ 2,000 mg/kg of super key did not cause any changes in the weights or in the results of necropsy examinations. Neither did it result in any mortalities. The above findings suggest that treatment with super key is relatively safe. Further studies on this subject are needed to yield more concrete evidence.

Single-dose Intramuscular-injection Toxicology Test of Water-soluble Carthami-flos and Cervi cornu parvum Pharmacopuncture in a Rat Model.

Objectives:The aim of the study is to investigate both the single-dose intramuscular injection toxicity and the approximate lethal dose of water-soluble Carthami-flos and Cervi cornu parvum pharmacopuncture (WCFC) in male and female Sprague-Dawley (SD) rats.Methods:The study was conducted at Biotoxtech Co. according to the Good Laboratory Practice (GLP) regulation and the toxicity test guidelines of the Ministry of Food and Drug Safety (MFDS) after approval of the Institutional Animal Care and Use Committee. Dosages for the control, high dose, middle dose and low dose groups were 0.5 mL/animal of saline and 0.5, 0.25 and 0.125 mL/animal of WCFC, respectively. WCFC was injected into the muscle of the left femoral region by using a disposable syringe (1 mL, 26 gauge). The general symptoms and mortality were observed 30 minutes, 1, 2, 4, and 6 hours after the first injection and then daily for 14 days after the injection. The body weights of the SD rats were measured on the day of the injection (before injection) and on the third, seventh, and fourteenth days after the injection. Serum biochemical and hematologic tests, necropsy examinations, and histopathologic examinations at the injection site were performed after the observation period.Results:No deaths, abnormal clinical symptoms, or significant weight changes were observed in either male or female SD rats in the control or the test (0.125, 0.25, and 0.5 mL/animal) groups during the observation period. No significant differences in hematology and serum biochemistry and no macroscopic abnormalities at necropsy were found. No abnormal reactions at injection sites were noted on the topical tolerance tests.Conclusion:The results of this single-dose toxicity study show that WCFC is safe, its lethal doses in male and female SD rats being estimated to be higher than 0.5 mL/animal.

A Study on Single Dose Toxicity of Mecasin Pharmacopuncture Injection in Muscle

Objectives: This study was carried out to analyze the single dose toxicity of Mecasin(Gami-Jakyak Gamcho buja Decoction) pharmacopuncture in muscle of Sprague-Dawley rats. Methods: All experiments were performed at the Medvill, an institution acknowledged to conduct non-clinical studies, under the Good Laboratory Practice (GLP) regulations. Sprague-Dawley rats were chosen in this pilot study. The reason Sprague-Dawley rats were chosen is that they have been widely used in safety test in the field of medicine, so the results can be easily compared with many other databases. Doses of Mecasin pharmacopuncture, 0, 500, 1,000, and 2,000mg/kg, were registered to the experimental groups, and a dose of normal saline solution, 10 ml/kg, was registered to the control group. Mecasin pharmacopuncture and normal saline were injected into the thigh of the rats by disposable syringes at intervals of six hours twice a day. This study was performed under the approval of the Institutional Animal Ethic Committee. Results: There is no death or abnormality in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To inspect abnormalities in organs and tissues, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues. Conclusion: The above outcomes suggest that treatment with Mecasin pharmacopuncture is relatively safe. Further evaluations and studies on this subject are needed to prove more concrete evidence.

Single-dose Intravenous Toxicology Testing of Daebohwalryeok Pharmcopuncture in Sprague-Dawley Rats

Objectives:The aims of the study were to test the single-dose intravenous toxicity of Daebohwalryeok pharmacopuncture (DHRP) in Sprague-Dawley (SD) rats and to estimate the crude lethal dose.Methods:The experiments were conducted at Biotoxtech Co., a Good Laboratory Practice (GLP) laboratory, according to the GLP regulation and were approved by the Institutional Animal Care and Use Committee of Biotoxtech Co. (Approval no: 110156). The rats were divided into three groups: DHRP was injected into the rats in the two test groups at doses of 10 mL/kg and 20 mL/kg, respectively, and normal saline solution was injected into the rats in the control group. Single doses of DHRP were injected intravenously into 6 week old SD rats (5 male and 5 female rats per group). General symptoms were observed and weights were measured during the 14 day observation period after the injection. After the observation period, necropsies were done. Then, histopathological tests were performed. Weight data were analyzed with a one-way analysis of variance (ANOVA) by using statistical analysis system (SAS, version 9.2).Results:No deaths and no statistical significant weight changes were observed for either male or female SD rats in either the control or the test groups during the observation period. In addition, no treatment related general symptoms or necropsy abnormalities were observed. Histopathological results showed no DHRP related effects in the 20 mL/kg DHRP group for either male or female rats.Conclusion:Under the conditions of this study, the results from single-dose intravenous injections of DHRP showed that estimated lethal doses for both male and female rats were above 20 mL/kg.

Toxicity of Eun-bi San Pharmacopuncture Injection in the Muscle of Rats.

Objectives:This study was carried out to analyze the single-dose toxicity of Eun-Bi San pharmacopuncture injected into the muscle of Sprague-Dawley (SD) rats.Methods:All experiments were performed at Biotoxtech, an institution certified to conduct non-clinical studies under the Good Laboratory Practice (GLP) regulations. Six week old SD rats reared by ORIENTBIO were chosen for this pilot study. The reason SD rats were chosen is that they have been widely used in safety tests in the field of medicine, so the results can be easily compared with many other databases. The Eun-Bi San pharmacopuncture was made in a clean room at the Korean Pharmacopuncture Institute (KPI, K-GMP). The constituents of the Eun-Bi San pharmacopuncture are Angelicae gigantis radix, Strychni semen and Glycyrrhizae radix. These were extracted at low temperature and low pressure in an aseptic room at the KPI. Doses of Eun- Bi San pharmacopuncture, 0.25, 0.5 and 1.0 mL, were administered to the experimental groups, and a dose of normal saline solution, 1.0 mL, was administered to the control group. This study was performed under the approval of the Institutional Animal Ethics Committee of Biotoxtech Co., Ltd.Results:No deaths or abnormalities occurred in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To determine if abnormalities existed in any organs and tissues, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues.Conclusion:The results of this study suggest that treatment with Eun-Bi San pharmacopuncture is relatively safe and that its clinical use may be beneficial. Further evaluations and studies on this subject will be needed to provide more concrete evidence in support of these conclusions.

Single-dose Intramuscular Injection Toxicology of Danggui Pharmacopuncture (DGP) in Sprague-Dawley Rats.

Objectives:The purpose of the study is to assess both the approximate lethal dose and the single dose intramuscular injection toxicity of Danggui (Angelica gigantis radix) pharmacopuncture (DGP) in Sprague-Dawley (SD) rats.Methods:The experiments were conducted at the good laboratory practice (GLP) laboratory, Biotoxtech Co., which is a laboratory approved by the ministry of food and drug safety (MFDS). The study was performed according to the GLP regulation and the toxicity test guidelines of the MFDS (2009) after approval of the institutional animal care and use committee of Biotoxtech. Single doses of DGP were injected intramuscularly into the rats in three test groups of 6 week old SD rats (5 male and 5 female rats per groups) in the amounts of 0.1, 0.5, and 1.0 mL/animal for groups 2, 3, and 4, respectively, and normal saline solution in the amount of 1.0 mL/animal was injected intramuscularly into the rats (5 male and 5 female rats) in the control group. Observations of the general symptoms and weight measurements were performed during the 14 day observation period after the injection. Hematologic and serum biochemical examination, necropsy, and a local tolerance test at the injection site were done after the observation period.Results:No death was observed in three test groups (0.1, 0.5 and 1.0 mL/animal group). In addition, the injection of DGP had no effect on general symptoms, weights, hematologic and serum biochemical examination, and necropsy. The results from the local tolerance tests at injection site showed no treatment related effects in the SD rats.Conclusion:The results of single dose intramuscular injection of DGP suggest that the approximate lethal dose is above 1.0 mL/animal for both male and female SD rats and that intramuscular injection of DGP may be safe.

Toxicity studies of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide) as a colonoscopic imaging agent in rats

We are investigating an imaging agent that detects early-stage primary colorectal cancer on the mucosal surface in real time under colonoscopic observation. The imaging agent, which is named the nanobeacon, is fluorescent nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide). Its potential use as an imaging tool for colorectal cancer has been thoroughly validated in numerous studies. Here, toxicities of the nanobeacon were assessed in rats. The nanobeacon was prepared according to the synthetic manner which is being established as the Good Manufacturing Practice-guided production. The rat study was performed in accordance with Good Laboratory Practice regulations. No nanobeacon treatment-related toxicity was observed. The no observable adverse effect levels (NOAEL) of the nanobeacon in 7-day consecutive oral administration and single intrarectal administration were estimated to be more than 1000mg/kg/day and 50mg/kg/day, respectively. We concluded that the nanobeacon could be developed as a safe diagnostic agent for colonoscopy applications. From the Clinical EditorColon cancer remains a major cause of death. Early detection can result in early treatment and thus survival. In this article, the authors tested potential systemic toxicity of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin (PNA) and poly(N-vinylacetamide) (PNVA), which had been shown to bind specifically to colonic cancer cells and thus very promising in colonoscopic detection of cancer cells.

A Global GLP Approach to Formulation Analysis Method Validation and Sample Analysis

Nonclinical pharmacokinetic (PK) and toxicokinetic (TK) toxicology safety studies are performed using good laboratory practice (GLP) regulations to ensure the availability of safe medicines. International GLP regulations uniformly require that dose concentration, homogeneity/uniformity and stability be known prior to administration. However, the United States Food and Drug Administration (US FDA) and the Organisation for Economic Cooperation and Development (OECD) both confirmed that GLPs do not apply to validation of analytical methods used to determine the concentration of GLP test article in drug dosage forms. It is our assertion that the outcome of nonclinical toxicology safety studies is inherently dependent upon accurate and precise dose formulations. In this paper, we attempt to provide supporting evidence as to why formulation method validation and sample analysis for supporting nonclinical toxicology studies should be consistently conducted under the framework of GLP principles across the globe. GLP studies are planned, performed, monitored, recorded, reported and archived according to a protocol, study plan or standard operating procedure (SOP) which is authorized prior to performing the experiments. All applicable experimental parameters and associated acceptance criteria are pre-defined. The FDA asked for responses to the Advance Notice of Proposed Rulemaking for 21 CFR Part 58 GLPs for Nonclinical Laboratory Studies [Docket No. FDA–2010–N–0548] on December 21, 2010. Several comments were received stating that guidance regarding the validation of formulation analysis methods and subsequent use for supporting GLP toxicology study sample analysis is warranted at this time and should be conducted consistently. Adherence to GLP principles for method validation and sample analysis would inherently improve the quality of nonclinical safety studies. Furthermore, the recently published White Paper titled, “Nonclinical dose formulation analysis method validation and sample analysis” should be the keystone of this effort.

A study on the oral toxicity of mecasin in rats.

Objectives:In this study, we investigated the oral toxicity of Gami-Jakyak Gamcho buja Decoction (Mecasin) to develop safe treatmentsMethods:All experiments were conducted at the Medvill, an institution authorized to perform non-clinical studies, under the Good Laboratory Practice (GLP) regulations. In order to investigate the oral toxicity of Mecasin, we administered Mecasin orally to rats. Sprague-Dawley rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of Mecasin, 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg, were administered to the experimental groups, and a dose of normal saline solution, 10 mL/kg, was administered to the control group. We examined the survival rate, weight, clinical signs, and gross findings. This study was conducted under the approval of the Institutional Animal Ethics Committee.Results:No deaths or abnormalities occurred in any of the four groups. Although slight decreases in the weights of some female rats were noted on the third day, no significant changes in weights or gross findings between the control group and the experimental groups were observed. To check for abnormalities in organs, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs.Conclusion:The results showed that administration of 500 − 2,000 mg/kg of Mecasin did not cause any changes in weight or in the results of necropsy examinations. It also did not result in any mortalities. The above findings suggest that treatment with Mecasin is relatively safe. Further studies on this subject are needed to yield more concrete evidence.

Carrageenan analysis. Part 3: Quantification in swine plasma

Development and validation of this method was conducted to support a 28-day piglet feeding study of swine-adapted infant formulations stabilised with carrageenan. The validation was performed in accordance with USFDA Good Laboratory Practice (GLP) Regulations and associated current bioanalytical guidelines. Separation of carrageenan from plasma protein was unsuccessful using saturated sodium chloride due to the extremely strong cross-linking interactions between carrageenan and protein. Poligeenan is the deliberately acid-hydrolysed low molecular weight polygalactan non-food product produced from carrageenan. Poligeenan molecules are nearly identical to carrageenan molecules with respect to molecular structure, the primary difference being molecular weight. These poligeenan molecules have similar molecular weight when compared with the lowest molecular weight fraction of carrageenan called the low molecular-weight tail (LMT). Poligeenan was separated from plasma protein using the salting procedure, this being due to the significantly weaker interaction with protein caused by its shorter molecular chain length. Thus, poligeenan was applied as a chemical analyte surrogate for the LMT of carrageenan solely for the development and validation of the method. This method was used to try to detect the LMT of the carrageenan test material during the 28-day piglet feeding study, and if such was absorbed into the bloodstream. Successful development and validation of the method was achieved using LC-MS/MS coupled with ESI in negative-ion mode. A standard curve of instrument response versus poligeenan concentration was developed using swine plasma spiked with a range of poligeenan concentrations. The lower level of quantification (LLOQ) of poligeenan was 10.0 µg ml–1, and the quantification range was 10.0–100.0 µg ml–1. No animals were fed poligeenan.

Strengthening the Peer Review Process for the International Journal of Toxicology

As scientists, we devote considerable time and effort in sharpening our skills to become better at our craft. It is disheartening, therefore, when we learn of another case of either scientific misconduct (eg, data falsification) or that the peer review process has failed our science. Recent instances of repurposing published data for new and sometimes multiple publications have been noted in submissions to International Journal of Toxicology (IJT). To get an idea of the scope of this problem, one should consult Retraction Watch, a Web site where the circumstances leading to manuscript retractions are discussed (http://retractionwatch.wordpress.com). At the last Society of Toxicology meeting (March 2014), there was a session on scientific misconduct. In that session, the speakers talked about research misconduct, plagiarism, authorship of manuscripts, and the legal requirements of scientific research (www.toxicology.org). Several key findings consistent with scientific misconduct were cited in that symposium including data falsification. Why do trained scientists engage in such behaviors? Is attempting to publish falsified data done to ensure more federal research funds or enhance the curriculum vitae for a promotion, tenure, or external recognition? Regardless of the motivation, when these instances are identified, the careers of the investigator are seriously jeopardized and can include civil or criminal penalties. Our colleagues in the industry will remember the incidents at Industrial Bio-Test Labs that ultimately led to institution of the Good Laboratory Practice regulations. The premise of this editorial is to point out that the peer review process is often not a high ‘‘hurdle or barrier’’ to publishing. When reviewers contemplate whether they should undertake the review of a manuscript, they should take into account their own time constraints (jobs and family commitments) as well as whether they have the knowledge base and absence of a conflict of interest that would make them appropriate reviewers for the manuscript. How much time should be devoted to a manuscript review? Having reviewed submitted manuscripts for many years for multiple toxicology journals, the devoted time is dependent on the quality and complexity of the submitted manuscript. Provenzale and Stanley address many of the issues of the peer review process and is highly recommended reading for new or even experienced reviewers. This publication is somewhat dated, but the content remains very pertinent. A second item that impacts the peer review process is the degree of scientific understanding of the submitted manuscript. This is more of an issue for journal editors and associate editors as they solicit reviewers. Do the editor and associate editor know the field or experts that can serve as reviewers? This issue is overcome by having a diversity of expertise within an editorial board and knowledge of potential reviewers beyond the editorial board. Furthermore, instructions to authors state that editors have the right to request original data for review. Overall, it is incumbent upon invited reviewers to decline an invited review if they do not have the expertise or experience to conduct a fair and knowledgeable review of the submitted manuscript. The repurposing of data for multiple publications is something that can be captured by the peer review process provided the reviewer spends the needed time with the submitted manuscript. Reviewers need to familiarize themselves with prior publications from the research group submitting a manuscript. Authors must be reminded that reuse of their own prior data is allowable, but the correct procedures for doing this must be followed. In this day of digital submissions and review, permission to reuse one’s own data can often be requested, and granted promptly, from the same portal from which a PDF or an HTML form of a published manuscript can be accessed. Arjo et al published a peer review of a study and cited poor experimental design, concerns with interpretation of the results, and the apparent lack of complete reporting of the data. The published study subject of the review by Arjo et al was published in a separate journal by Seralini et al. The fundamental issue expressed by Arjo et al was that the publication of Seralini et al clearly showed the failure of the peer review process, despite the high level of respect within the toxicology community for the journal (Food and Chemical Toxicology; FCT). Why the peer review process failed cannot be determined since members of the editorial board for that journal are wellknown and respected toxicologists. The article of Seralini et al

Violations of Good Laboratory Practice Regulations Can Potentially Lead to False Claims Act Liability

This article discusses potential liability under the False Claims Act if a device manufacturer has chronic, serious deficiencies in its quality assurance function and ongoing violations of laws and regulations designed to ensure the safety and efficacy of medical devices, including the Food, Drug,

The glucagon‐like peptide‐1‐based therapeutics exenatide and saxagliptin did not cause detrimental effects on the pancreas in mice, rats, dogs and monkeys

Recent reports in the literature have suggested that glucagon-like peptide-1 (GLP-1)-based therapies may lead to increased risk of pancreatic pathology leading to chronic pancreatic injury and pancreatic neoplasia. Extensive non-clinical and clinical safety testing was conducted to support the global development of exenatide twice daily, exenatide once weekly and saxagliptin. Our aim was to integrate these non-clinical data obtained with both mechanisms of GLP-1-based drugs to provide complementary data regarding the potential for drug-induced pancreatic safety signals. More than 70 regulated non-clinical toxicology studies in rodents and non-rodents were conducted in accordance with International Conference on Harmonisation and US Food and Drug Administration guidance documents, current industry standards, animal welfare regulations and in compliance with Good Laboratory Practice regulations. Treatment duration was up to 2 years in rodents and up to 12 months in non-rodents using high doses representing large multiples of human exposures (up to 130× for exenatide and 2200× for saxagliptin). Comprehensive pancreas assessments involved more than 2400 pancreata from animals exposed to exenatide and over 1700 pancreata from animals exposed to saxagliptin. Neither exenatide nor saxagliptin treatment resulted in drug-related microscopic changes indicative of acute or chronic adverse effects (including neoplasia) in the endocrine or exocrine pancreas, at doses far exceeding the maximum human systemic exposures. These data substantially add to the weight of evidence supporting the lack of non-clinical drug-induced pancreatic safety signals in animals exposed to GLP-1-based therapies.

Single Dose Toxicity of Chukyu (spine-healing) Pharmacopuncture Injection in the Muscle of Rats.

Objectives:This study was performed to analyze the single dose toxicity of Chukyu (spine-healing) pharmacopuncture.Methods:All experiments were conducted at the Biotoxtech, an institution authorized to perform non-clinical studies under the regulations of Good Laboratory Practice (GLP) regulations. Sprague-Dawley rats were chosen for the pilot study. Doses of Chukyu (spine-healing) pharmacopuncture, 0.1, 0.5 and 1.0 mL, were administered to the experimental groups, and a dose of normal saline solution, 1.0 mL, was administered to the control group. This study was conducted under the approval of the Institutional Animal Ethic Committee.Results:No deaths or abnormalities occurred in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To check for abnormalities in organs and tissues, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues except in one case, where interstitial infiltrating macrophages were found in one female rat in the 0.5-mL/animal experimental group.Conclusion:The above findings suggest that treatment with Chukyu (spine-healing) pharmacopuncture is relatively safe. Further studies on this subject are needed to yield more concrete evidence.

Role of the Study Pathologist

Toxicologic pathology relies on many disciplines of toxicology and basic sciences and often requires other fields and skills such as biostatistics, study design, guidelines, and knowledge of Good Laboratory Practices (GLP) regulations. Pathology is an integrative discipline where specific training and experience are required in order to integrate chemical or biological structures, molecular biology, physiology, and morphology for candidate selection and early development of a test article and to help in the design of appropriate preclinical/toxicology studies. Experience does matter and successful learning is determined by personal behavior; pathologists who not only read slides but research their topics and keep current with the literature are apt to be successful.

The Study Pathologist’s Role in GLP Studies

Results of early nonclinical "General Toxicology" studies are used to set a safe starting dose for first-in-human (FIH) clinical trials. In FIH trials, the research subjects are typically healthy volunteers who have little to gain but much to lose if a trial goes wrong. With that in mind, good laboratory practice regulations require that a standardized system be used for the conduct, documentation, and retention of study-related materials. The study pathologist, working within that system of standards, documentation, and oversight, is key to the identification of potential target organs of toxicity and other toxicologically significant findings.