LSIM Safety Institute provides contract services using various disease models for efficacy pharmacology studies of drugs. Using old and new disease models, we are entrusted with studies of a wide range of fields including central nervous system, pain, infection, circulatory system, respiratory system, renal and urinary system, immune system, hematological system, inflammation, allergy, gastrointestinal system, skin, glucose/lipid metabolism system, cancer, and in vitro efficacy studies, and there is a growing demand particularly for efficacy evaluation concerning inflammation, fibrosis, and autoimmune disease. Our area of expertise is efficacy evaluation studies requiring surgery and we have extensive experience in studies using conventional animals, genetically modified animals, and mutant animals.
In recent years, we receive increasingly more inquiries about efficacy evaluation of products for regenerative medicine, and have achieved satisfactory results from contract studies on hepatitis, cerebral infarction, myocardial infarction, lower leg ischemia, arthritis, or urinary system using bone marrow/fat-derived stem cells or iPS cell-derived cardiac myocytes. We are also working toward handling other types of studies in consulting with our clients.
LSIM Safety Institute, having achieved many satisfactory results in handling of immunocompromised animals mainly in antitumor studies, is carrying forward "development of efficacy evaluation systems of products for regenerative medicine using immunocompromised animals (myocardial infarction, hepatitis, cerebral infarction, etc.)". We will make every effort to meet the variable needs of clients who are examining new approaches in development of products for regenerative medicine to treat diseases that are intractable with conventional treatments. Please feel free to inquire about details.
-Bennett (Planter mechanical stimulation, Planter thermal stimulation, Sensation stimulation)
-Chung (Planter mechanical stimulation, Planter thermal stimulation)
-Selzter (Planter mechanical stimulation, Planter thermal stimulation)
Neuropathic pain is a chronic painful disorder that manifests following peripheral/central neuropathy caused by physical disorder or due to functional disorder. We have extensive experience with Bennet, Chung, and Selzter models and are capable of preparing stable models.
Diabetic neuropathy is a diabetic complication and manifests earliest among the 3 main complications. Type 1 diabetes is induced by administration of streptozocin (STZ) for assessment of hypernociception.
The adjuvant-induced model is a model targeting pain due to systemic inflammation. It is widely used for screening/assessment of pain or anti-inflammatory drugs.
The carrageenan-induced model is a model targeting pain due to edema. It is widely used for screening/assessment of pain or anti-inflammatory drugs.
Taxane preparations including paclitaxel, vinca alkaloid preparations including vincristine, and platinum complex preparations including cisplatin and oxaliplatin cause adverse reactions due to peripheral neuropathy (numbness, sensory disturbance, pain) at high incidence.
Cancer pain, markedly impairing the patient QOL (Quality of life), needs to be controlled adequately. Using the bone metastasis model prepared by transplantation of rat breast cancer cell line MRMT-1 into the tibia of the same strain rat, we evaluate cancer pain.
1.1.7Pain hypersensitivity of low temperature burns
-Capsaicin induced pain hypersensitivity (Planter mechanical stimulation)
-UVB induced pain hypersensitivity (Planter mechanical stimulation, Planter thermal stimulation)
1.1.8Postoperative pain hypersensitivity (Planter mechanical stimulation)
Osteoarthritis (OA) is a disease characterized by degeneration and loss of articular cartilages and a lifestyle disease of the highest incidence among bone/joint diseases. We have a model of OA induced by administration of sodium monoiodoacetate (MIA) into the knee joint cavity.
Fibromyalgia of which cardinal symptom is cryptogenic generalized pain (wide-spread pain) with subsidiary symptoms including neuropsychiatric symptoms such as insomnia and depression, and autonomic nervous system symptoms such as irritable bowel syndrome and overactive bladder. The cold stress model is widely used as a fibromyalgia model.
Animals are housed in an operant-conditioning chamber equipped with levers and allowed to learn obtaining reward (tablet-type feed) by pressing the lever. Using this behavior, the effect of a drug on short-term memory can be assessed.
1.2.2Lesions in the nucleus basalis of meynert model
1.2.34-vessel occlusion (4VO) model
The kainic acid-induced seizure model is a model presenting status epilepticus where epileptic seizure persists intermittently over several hours, prepared by intraperitoneal administration of kainic acid which strongly excites the glutamatergic neuron.
Using the rat cerebral ischemia model by transient middle cerebral artery (MCA) occlusion, the efficacy of the test substance is assessed based on the volume of cerebral infarct area, neurological symptoms, or the results of the rotarod test as the indices. We have extensive experience in this field and are capable of preparing stable models.
1.6.1Methamphetamine-induced hyperactivity (Schizophrenia)
1.6.2Alcohol-induced movement disorder
The anti-depression-like effect of a drug is assessed based on duration of immobility as the index when the animal is forced to swim in water (forced swim). The forced swim test is performed under the conditions designed to fit the experimental environment of our company while still following the original method and has been conducted and observed by our company extensively.
The anti-depression-like effect of a drug is assessed based on duration of immobility as the index when the animal is suspended with the tail fixed (tail suspension). We have extensive background data from the tail suspension test where varying mouse strains and their drug sensitivities resulting in depression-like behavior were investigated.
1.7.3Reserpine-induced hypothermia
1.7.4Lipopolysaccharide-induced depression
1.8.1Treadmill fatigue test
1.9.16-hydroxydopamine (6-OHDA)-induced Parkinson's disease (rat)
1.10.1Test using ALS model (rat)
*Prior consultation is needed for procurement of animals.
1.11Hypoxic-ischemic encephalopathy
There is a biosafety level (BSL) 2 animal-rearing area in our company where virus- or bacteria-infection experiments up to BSL2 can be performed. We are prepared to perform studies with influenza virus and Staphylococcus aureus (including MRSA). Clinical isolates that the clinical research center of our company possesses can be provided for use.
2.2Staphylococcus aureus
2.3Methicillin-resistant Staphylococcus aureus
2.4Malaria parasite
*It is possible to correspond If malaria parasites is provided.
3.1.2Hypertension induced by ligation of renal artery
Cardiac disease is evaluated by the acute phase assessment for consideration of the therapy at the time of onset of myocardial infarction similar to that in clinical practice and by the chronic phase assessment for investigation of prognosis for prevention of cardiac failure and for life prolonging effect. We also undertake tests in the field of regenerative medicine.
3.3.1Silicon piece-cauda equina nerve compression
Abdominal aortic aneurysm (AAA) is a highly lethal disease when left untreated and surgery is said to be the only treatment. We have a calcium chloride-induced AAA model. This model enables measurement of the abdominal aorta diameter using the ultrasonograph.
Peripheral arterial disease (PAD) is frequently found in diabetic patients and elderly people, and when the disease becomes severe, leg amputation is inevitable, which leads to marked decrease of QOL (Quality of Life). The hindlimb ischemia model is widely used as the PAD model and frequently employed in studies not only on drugs but also on the regenerative effect of cell components such as bone marrow mononuclear cells.
3.6.1Thoracic aortic constriction model
4.1.1Citric acid- or capsaicin-induced
4.2.1Alcohol-induced asthma
Acute respiratory distress syndrome (ARDS) is a type of respiratory insufficiency which occurs abruptly in clinically severe patients. The condition around the time of disease onset is specifically called acute lung injury. The acute pneumonia model is prepared by inhalation of lipopolysaccharide (LPS).
4.4.1Phenol red Secretion
Idiopathic pulmonary fibrosis is a lung disease consisting primarily in severe fibrosis of the lung. The lung disease has poor response to steroids or immunosuppressive agents and poor prognosis. We prepare the bleomycin-induced pulmonary fibrosis model.
5.1.1Spontaneous diabetes model
5.1.2STZ-induced type I diabetes nephropathy model
Systemic lupus erythematosus (SLE) is an autoimmune disease where inflammation of unknown origin occurs in organs in the body, being classified as a collagen disease. Both MRL/lpr mice and NZBWF1 mice are known to have SLE-like lupus nephritis spontaneously and the animals are widely used as SLE models.
5.1.45/6 Nephrectomy
5.1.5Adenine-induced renal failure
Dysuria models include the overactive bladder model (OAB: cerebral infarction-induced), the interstitial cystitis model (IC: hydrochloric acid, cyclophosphamide, or acetic acid-induced), the lower urinary tract symptoms model [LUTS: benign prostatic hyperplasia (BPH)], the stress urinary incontinence (SUI) model, and the spinal cord injury model. Methods of evaluation include the cystometry method for measurement of intravesical pressure and the uroflowmetry for measurement of urodynamics in spontaneous urination. Urodynamics in microurination can be measured at intervals using the voiding function-measuring system developed by our company.
5.2.1Overactive bladder
5.2.2Dysuria in spinal cord
5.2.3Interstitial cystitis (hydrochloric acid, cyclophosphamide, or acetic acid-induced)
5.2.4Lower urinary tract symptoms (benign prostatic hyperplasia)
5.2.5Stress urinary incontinence
6.1Antigen sensitization -antibody production-
Systemic lupus erythematosus (SLE) is an autoimmune disease where inflammation of unknown origin occurs in organs in the body, being classified as a collagen disease. Both MRL/lpr mice and NZBWF1 mice are known to have SLE-like lupus nephritis spontaneously and the animals are widely used as SLE models.
6.3Psoriasis
6.4Chronic graft versus host disease (GVHD)
7.1Iron deficiency anemia (exsanguination)
Platelet aggregation is an important function for coagulation but may cause formation of thrombi which may lead to serious conditions such as encephalopathy and heart disease. Platelet aggregation test is widely used for evaluation of platelet coagulants etc.
The carrageenan-induced model is a model targeting pain due to edema. It is widely used for screening/assessment of pain or anti-inflammatory drugs.
8.1.2Brewer's yeast-induced pain
The adjuvant-induced model is a model targeting pain due to systemic inflammation. It is widely used for screening/assessment of pain or anti-inflammatory drugs.
Rheumatoid arthritis (RA) is a chronic inflammatory disease based on abnormal immune function, of which cardinal symptoms are polyarthritis and joint symptoms such as rapidly progressive joint destruction. This model prepared by immunization with type II collagen to induce arthritis is widely used as an arthritis model.
Osteoarthritis (OA) is a disease characterized by degeneration and loss of articular cartilages and a lifestyle disease of the highest incidence among bone/joint diseases. We have a model of OA induced by administration of sodium monoiodoacetate (MIA) into the knee joint cavity.
8.1.6UV-induced erythema
Pruritus observed in atopic dermatitis decreases quality of life (QOL) significantly. We have a conventional rearing environment and a disease model of spontaneous atopic dermatitis prepared by rearing NC mice in the conventional environment.
8.1.8Endometriosis
Experimental autoimmune encephalomyelitis (EAE) is an autoimmune model induced by immunization of protein antigens and peptides derived from the central nervous tissue, being used in researches of multiple sclerosis (MS) because the model has pathological symptoms similar to those of MS. We have models of two types, the relapse-remission type model (SJL mice) and the chronic type model (C57BL mice).
8.1.10X ray-induced oral mucositis model
Allergy is an important biological reaction based on immunoreaction. Type I allergy is IgE-mediated, type II allergy is cytotoxic or cytolytic, type III allergy is called immune complex type or Arthus type, and type IV allergy represents cell-mediated immunity. We possess the passive cutaneous anaphylaxis (PCA) model as the model of type I, and the delayed type hypersensitivity (DTH) as the model of type IV, all of which can be used for screening of anti-allergic agents.
8.2.1Passive cutaneous anaphylaxis (PCA) Type I
Pruritus is an unendurable impulse caused by various factors. We have scratching activity models induced by chemicals. These models enable objective evaluation of scratching activities caused by chemicals using the scratching measuring system.
In allergic conjunctivitis, itch, swelling of the conjunctiva, and eye discharge occur due to allergic reactions caused by antigens such as in pollinosis. We have various models prepared by antigen-antibody reactions caused by allergens including DNP-Ascaris, OVA, and ragweed.
8.3.1OVA-induced allergic conjunctivitis
8.3.2DNP-Ascaris-induced allergic conjunctivitis
8.3.3Ragweed pollen-induced allergic conjunctivitis
9.1.1Pylorus-ligated gastric ulcer
9.1.2Aspirin-induced gastric ulcer
9.1.3Indomethacin-induced gastric ulcer
Ulcerative colitis is a nonspecific inflammatory disease where ulcer and erosion are formed mainly on the colonic mucosa. The DSS-induced colitis model is widely used as the model of ulcerative colitis.
9.2.1Measurement by telemetry of gastrointestinal motility in unanesthetized and unrestrained conditions
9.3.1Enteral infusion high-speed injection load diarrhea
9.3.2Defecation (enema)
9.4.1Low-fiber diet
9.4.2Morphine (Dihydrocodeine)
9.5Small bowel obstruction model
9.6.1Ligature
9.7.1Thioacetamide-induced liver fibrosis
9.7.2D-galactosamine-induced hepatitis
9.7.3Concanavalin A (ConA) induced liver injury
Non-alcoholic steatohepatitis (NASH) is a pathological condition showing alcoholic steatohepatitis-like chronic hepatic disorder in spite of absence of drinking history. We have developed a unique NASH model accompanied with hepatic fibrogenesis and hyperlipidemia.
9.7.5Carbon tetrachloride-induced hepatitis (acute, chronic)
10.1.1Models of cut, skin defect, and decubitus - bedsore -
10.2.1Models of erythema - UV irradiation -, moisture retention, decreased collagen synthesis, and skin pigmentation
Diabetes causes complications including neuropathy, nephropathy, and cataract. It is very important to control blood glucose level for control of onset of complications. We have extensive experience with the streptozotocin (STZ)-induced type-1 diabetes model and models of type-2 diabetes typically in ZDF, GK rats, db/db, and KK-Ay mice; thus are able to deal with any strain.
Obesity represents abnormal energy metabolism characterized by the imbalance between energy taken and energy consumed, being a cause of many lifestyle diseases. We have the obesity model prepared by loading high-calorie diet (diet-induced obesity (DIO)).
Metabolic syndrome is a condition where hyperglycemia, dyslipidemia, and hypertension are caused with visceral fat accumulation as the common factor, possibly leading to life-threatening diseases when two or more such diseases occur concurrently. Prevention/improvement through diet modification and exercise is important and therapeutic agents for obesity are actively being developed. Respiratory quotient and energy consumption estimated by measurement of respiratory metabolism are important indices to assess the anti-obesity effect.
11.1.4Oral glucose tolerance test (OGTT), Insulin tolerance test (ITT)
11.2.1Spontaneous
11.2.2High-cholesterol diet loading
11.2.3Corn oil emulsion loading (inhibition of digestion-absorption of lipid)
Cancer-bearing mice and rats are prepared by implantation of various human, mouse, and rat tumor cell lines for evaluation of anti-tumor effect of drugs. Cell lines of biosafety level (BSL) 2 are available. Subcutaneous, intraperitoneal, and orthotopic (intracerebral, gastric, pancreatic, uterine, prostatic, etc.) implantation can be performed. We have experience with immunodeficient animals including nude mice, nude rats, SCID mice, NOD SCID mice, and NOG mice.Evaluation using PDX (Patient-Derived Xenograft) is also possible.
12.1Subcutaneous, intraperitoneal, and orthotopic implantations of human tumor cell line
12.2Subcutaneous, intraperitoneal, and orthotopic implantations of mouse tumor cell line
12.3Subcutaneous implantation of rat tumor cell line
We have achieved satisfactory results with the hematogenous lung metastasis model, the spontaneous lung metastasis model, and the splenic liver metastasis model. The splenic liver metastasis model prepared using human colon cancer cell line HT-29 is superior to the spontaneous metastasis model in reproducibility.
The rabbit VX2 cancer model is used mainly as a model of liver cancer. Intraarterial administration into the proper hepatic artery is employed according to angiography in human. This model enables evaluation based on the tumor size, pathological analysis, and observation by echography.
12.6Rabbit VX2 cancer metastasis - lung, liver, brain -
Using cancer cell lines obtained from various cell banks, anti-tumor effect of a drug is assessed. We have experience in using 60 or more different tumor cell lines. Assessment is based on the concentration of the drug where the cell viability becomes 50% (IC50). Detection methods using Cell Counting Kit-8 and Cell Titer-Glo (colorimetric method, fluorescence method, emission method) are available for assessment.
13.2Clot lysis test (blood of various animal species)
Using primary cultured cells, cytotoxicity of a compound is assessed based on enzymes released from the cells and cell viability. We have experience with liver parenchymal cells (rat, dog, monkey), adrenal cortex cells (rat, guinea pig, dog, monkey), neurons (rat), Schwann cells (rat), and Leydig cells (rat).
Many antibody drugs based on the antibody-dependent cellular cytotoxicity activities have been developed. Antibody-dependent cellular cytotoxicity (ADCC) activity measurement is known as a method of assessment of activities of such drugs. We have extensive experience in using monkey or human peripheral blood mononuclear cells (PBMC) as the effector cells.
Many antibody drugs based on the complement-dependent cytotoxicity activities have been developed. Complement-dependent cytotoxicity (CDC) measurement is known as a method of evaluation of activities of such drugs. We have extensive experience in using commercial human or rabbit complement.
13.7Gene Expression Profiling
Measurement: real-time PCR/RT-PCR analysis (various cell lines)
13.8Cell Surface Marker Profiling
Measurement: flow cytometry (various cell lines)
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