Mediford Corporation 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. 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 addition, we have extensive experience in PCR, flow cytometry, and in vitro drug efficacy studies using various types of cells.

In recent years, we have been working on development of new modalities such as cell formulations (bone marrow, adipose-derived stem cells, etc.) and virus formulations. We have experience with cell formulations for hepatitis, cerebral infarction, myocardial infarction, hind limb ischemia, arthritis, and urinary system, etc. As for virus formulations, we have experience in cancer-related studies. In addition, we provide drug efficacy evaluation studies using various pathological models, such as a cancer transplantation model derived from Japanese cancer patients (PDX) and a hepatitis B virus infection model.

Service details

Central Nervous System

Pain (Infringement)

Neuropathic pain
  • 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.

Streptozotocin -induced (STZ) pain hypersensitivity (Planter mechanical stimulation)

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.

Adjuvant induced hyperalgesia (Randall-Selitto)

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.

Carrageenin induced hyperalgesia (Randall-Selitto)

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.

Anti-cancer agent-induced pain hypersensitivity (Planter mechanical stimulation, Sensation stimulation)

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 model (Metastatic bone tumor)

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.

Pain hypersensitivity of low temperature burns
Postoperative pain hypersensitivity (Planter mechanical stimulation)
Osteoarthritis (MIA-induced, weight distribution in hindlimb, mechanical stimulation of sole, heat 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.

Specific Alternation of Rhythm in Temperature (Fibromyalgia model, Planter mechanical stimulation)

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.

Learning and memory

Scopolamine-induced amnesia

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.

Lesions in the nucleus basalis of meynert model
4-vessel occlusion (4VO) model

Anxiety

Elevated plus maze test

The elevated plus-maze test (mice and rats), which was developed as an anxiety test method, can be used to evaluate the anxiolytic effects of test substances.

Social interaction test

Epilepsy

Kainic acid-induced seizure 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.

Pilocarpine-induced model

The pilocarpine-induced epilepsy model is a model of temporal lobe epilepsy induced by intraperitoneal administration of pilocarpine hydrochloride, a nonselective muscarinic receptor agonist.

Cerebral ischaemia

Transient middle cerebral artery occlusion

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.

Behavior and motor function

Methamphetamine-induced hyperactivity (Schizophrenia)
Alcohol-induced movement disorder

Depression model

Forced swimming test (Immobility time)

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.

Tail suspension test (Immobility time)

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.

Reserpine-induced hypothermia
Lipopolysaccharide-induced depression

Antidepressant-like effects of the drug are evaluated using a depression model (mouse) created by administering lipopolysaccharide (LPS) as an indicator of forced swimming and tail suspension immobility time.

Antifatigue

Treadmill fatigue test

Parkinson's disease

6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (rat)

Amyotrophic lateral sclerosis (ALS)

Test using ALS model (rat)

*Prior consultation is necessary for procurement of animals.

Hypoxic-ischemic encephalopathy (HIE)

Neonatal HIE model (rat)

Using the HIE model created, the efficacy of the drug is examined by the cylinder test, Morris water maze, etc. as indices.

Infection

Kumamoto Laboratories has a biosafety level (BSL) 2 animal-housing area 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 used. Also, using test strains provided by clients, we can perform infection experiments with various pathogens (up to BSL2).

Influenza virus

Staphylococcus aureus

Methicillin-resistant staphylococcus aureus

Malaria parasite

*Provision of malaria parasites is necessary.

Human hepatitis B virus

Mycobacterium respiratory tract infection (provision of test strain is necessary)

Aspergillus pneumonia model (provision of test strain is necessary)

Cardiovascular System

Hypertension

Spontaneous hypertention

Spontaneously hypertensive rats (SHR) can be used to study the antihypertensive or prophylactic effects of the test substance. Blood pressure measurements are performed using a non-heating/non-invasive blood pressure monitor for rats and mice.

Hypertension induced by ligation of renal artery
Salt-loaded hypertension (Dahl rats)

Dahl rats develop hypertension spontaneously when fed a high salt diet. The spontaneous hypertension model (Dahl rats) can be used to study the antihypertensive or prophylactic effects of drugs. Blood pressure is measured using a non-heating/non-invasive blood pressure monitor, but can also be measured using a catheter transducer.

Ischemia - induced cardiac disorder

Cardiac infraction (Permanent ligation / ishcemia-reperfusion), Cardiac failure (chronic phase)

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.

Aortic aneurysm

Calcium chloride-induced

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.

Hindlimb ischemia model

Ligation of femoral artery

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.

Aortic arch stenosis

Aortic arch stenosis model

Respiratory System

Cough

Citric acid- or capsaicin-induced

Asthma

Acute lung disease

Lipopolysaccharide (LPS) Exposure (Acute)

Acute respiratory distress syndrome (ARDS) is a type of respiratory failure that occurs suddenly in patients with clinically severe conditions. In particular, the conditions before and after the onset of the disease are referred to as acute lung injury. We create an acute lung injury model by inhalation of lipopolysaccharide (LPS).

Expectorant

Pulmonary fibrosis

Bleomycin-induced pulmonary fibrosis model

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.

Renal Urinary System

Nephritis

Spontaneous diabetes model
STZ-induced type I diabetes nephropathy model
Systemic lupus erythematosus (SLE) 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.

Chronic GVHD Model

Graft-versus-host disease (GVHD) is a general term for a condition in which the immune response of a donor (organ donor) organ attacks the recipient (patient). The mouse model of chronic GVHD develops lupus nephritis-like symptoms.

Adenine-induced renal failure

The adenine renal failure model develops hyperphosphatemia secondary to adenine loading, resulting in severe renal failure.

Pyuromycin nephritis

Nephrosis can be induced in rats by administration of puromycin.

Renal ischemia-reperfusion model

Acute renal injury occurs when a state of reperfusion develops from decreased renal blood flow due to cardiac failure, dehydration, hemorrhage, or renal artery stenosis or occlusion.

Voiding symptoms

Dysuria models include the overactive bladder model (OAB: cerebral infarction-induced), the cystitis model (hydrochloric acid, cyclophosphamide, acetic acid-induced, or hydrogen peroxide-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 mediford.

Overactive bladder
Dysuria in spinal cord
Cystitis (hydrochloric acid, cyclophosphamide, acetic acid-induced, or hydrogen peroxide-induced)
Lower urinary tract symptoms (benign prostatic hyperplasia)
Stress urinary incontinence

Immunity (immunosuppression)

Antigen sensitization - Antibody production

We can provide services such as "Antibody Production", "Development of Immunoassay Method - Sample Assay (GLP compliant)", "Characterization of Biopharmaceuticals and Storage Stability", "Assay of Clinical Samples", etc.

Systemic lupus erythematosus (SLE)

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.

Psoriasis model

Psoriasis vulgaris is a chronic cutaneous keratotic disease with a typical presentation of a red rash with overlying white scales (exfoliated keratinocytes of the skin epithelium). As the symptoms are visible, this disease significantly reduces quality of life.
We create a mouse model of imiquimod-induced psoriasis vulgaris using an antiviral agent, and evaluate the drug efficacy of the test substance.

GVHD model

Graft-versus-host disease (GVHD) is a general term for a condition in which the immune response of a donor (organ donor) organ attacks the recipient (patient). We have various types of GVHD (acute and chronic) using mice.

Blood System

Inflammation and Allergy

Inflammation and edema

Carrageenin-induced edema

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.

Yeast-induced pain
Adjuvant arthritis

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.

Type II collagen-induced arthritis

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 (MIA induced, hindlimb weight distribution, plantar mechanical stimulation)

Osteoarthritis (OA: Osteoarthritis) is a disease characterized by degeneration and loss of cartilage in joints and is one of the most frequent lifestyle diseases among bone and joint diseases. We have an OA model created by monoiodoacetate sodium salt (MIA) administered into the knee joint cavity.

UV-induced erythema

We are able to produce a guinea pig model of erythema by UV irradiation and evaluate the drug efficacy of test substances using skin reaction scores as parameters.

Spontaneous atopic dermatitis

Pruritus observed in atopic dermatitis and other conditions significantly reduces quality of life (QOL). We maintain a conventional housing environment and have a pathological model of spontaneous onset of atopic dermatitis by housing NC mice in a conventional environment.

Allergic encephalomyelitis (EAE) model (Score evaluation)

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune model induced by immunization with protein antigens and peptides derived from central nervous tissue, and is similar to Multiple Sclerosis (MS) and is used for research on MS, etc., as its pathological symptoms are similar to those of Multiple Sclerosis (MS). We have two types of sclerosis models: the relapse-remission type model (SJL mice) and the chronic model (C57BL mice).

X ray-induced oral mucositis model

Allergic reaction

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.

Passive cutaneous anaphylaxis (PCA) Type I
Delayed type hyper responsiveness, Type IV
Pruritic response (Substance P-induced/development of spontaneous dermatitis)

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.

Conjunctivitis

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.

OVA-induced allergic conjunctivitis
DNP-Ascaris-induced allergic conjunctivitis
Ragweed pollen-induced allergic conjunctivitis

Digestive System

Gastrointestinal ulcer

Pylorus-ligated gastric ulcer
Aspirin-induced gastric ulcer
Indomethacin-induced gastric ulcer
Dextran sulfate sodium-induced coitis

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.

Gastrointestinal motility

Measurement by telemetry of gastrointestinal motility in unanesthetized and unrestrained conditions

Using a telemeter designated for gastrointestinal motility and the PowerLab system, the effects of test substances on gastrointestinal motility can be investigated by measuring gastrointestinal motility in the gastric body, gastric antrum, duodenum, and jejunum in unanesthetized and unrestrained dogs under fasting conditions.

Diarrhea

Enteral infusion high-speed injection load diarrhea
Defecation (enema)

Difficulty in defecation and fecal incontinence significantly reduce quality of life. It is estimated that there are approximately 5 million potential patients with fecal incontinence in Japan, and it is predicted that the number of patients will increase further due to the aging of the population. Currently, drug treatments are inadequate, and the development of new treatments is desired. Screening using model animals is important for the development of new therapeutic agents, but until now, only experimental designs using small animals under anesthesia were available.
We have established a gastrointestinal and internal anal sphincter measurement system in dogs using a gastrointestinal motility measurement system, which enables us to examine the effects of test substances on internal anal sphincter motility under consicous conditions that better reflect biological responses.

Constipation

Low-fiber diet
Morphine (Dihydrocodeine)

Small bowel obstruction model

Reflux esophagitis model

Ligature

This experimental system is a method to evaluate the inhibitory effect of the test substance on esophageal mucosal damage using a rat model of reflux esophagitis.

Hepatic disorder

Thioacetamide-induced liver fibrosis

Thioacetamide (TAA) is metabolized in the liver and this process is known to produce hepatic disorder. The disorder resembles human liver fibrosis in its histopathological findings in the hepatic hilus and biochemical changes in the blood. We conduct pre-clinical studies on thioacetamide-induced liver fibrosis in order to develop drugs that improve liver function.

D-galactosamine-induced hepatitis

D-galactosamine is specifically metabolized in the liver and this process is known to produce hepatic disorder. The disorder resembles human viral hepatitis in its histopathological findings in the liver and biochemical changes in the blood, and has been used in general use along with carbon tetrachloride-induced models. This study system is designed to search for the effects of various test substances for hepatoprotective effects in the D-galactosamine-induced acute liver injury model.

Concanavalin A (ConA) induced liver injury
Non-alcoholic steatohepatitis (NASH)

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.

Carbon tetrachloride-induced hepatitis (acute, chronic)

Skin

Wound healing

Models of cut, skin defect, and decubitus - bedsore -

Chlasoma (skin whitening)

Models of erythema - UV irradiation -, moisture retention, decreased collagen synthesis, and skin pigmentation

Sunburn can be divided into two types: "sunburn" in which the skin is exposed to ultraviolet (UVB) rays from the sun, causing erythema within minutes to hours, and "suntan" in which melanin pigmentation occurs several days after the sunburn has disappeared. We conduct evaluation studies of test substances using pigmented guinea pigs as a model of pigmentation caused by UV irradiation.

AEW dry skin model

A (acetone) and E (ether) mixed solution and W (water) are repeatedly exposed to the skin of mice to disrupt the skin barrier and induce dryness. The amount of water evaporation and itching behavior due to skin dryness are evaluated.

Scleroderma model

Systemic scleroderma is an intractable disease characterized by fibrosis of the skin and various organs, as well as immune abnormalities and vascular disorders. We have scleroderma-like models of systemic scleroderma induced by subcutaneous administration of bleomycin and GVHD models.

Glucose and Lipid Metabolism System

Diabetes, obesity

Type-1 and type-2 diabetes model

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.

High-calorie diet loading

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)).

Respiratory metabolism measurement

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.

Oral glucose tolerance test (OGTT), Insulin tolerance test (ITT)

Hyperlipidemia, arteriosclerosi

Spontaneous
High-cholesterol diet loading
Corn oil emulsion loading (inhibition of digestion-absorption of lipid)

Cancer (Cancer-bearing model)

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) and PDC (Patient-Derived Cell) is also possible. (Drug discovery support services using PDX)

Subcutaneous, intraperitoneal, and orthotopic implantations of human tumor cell line

Subcutaneous, intraperitoneal, and orthotopic implantations of mouse tumor cell line

Subcutaneous implantation of rat tumor cell line

Metastasis - lung metastasis, liver metastasis -

We have achieved satisfactory results with the hematogenous lung metastasis model, spontaneous lung metastasis model, and 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.

Rabbit VX2 cancer transplantation - liver, kidney, spleen, stomach, intestine, muscle, subcutis -

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.

Rabbit VX2 cancer metastasis - lung, liver, brain -

Sensory Organ

Auditory brainstem response (ABR) measurement

ABR measurements can be used to evaluate auditory threshold in mice and rats.

Muscle Disorder

Muscular dystrophy model

Using mdx mice (CLEA Japan, Inc.), muscle strength measurements, rotarod test, blood CK, and histopathological examination of skeletal muscle can be performed.

In vitro

In vitro antitumor study (various types of cells)

Using cancer cell lines provided, 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.

Clot lysis test (blood of various animal species)

Cytotoxicity study using primary cultured cells (liver parenchyma, adrenal cortex, and neuron)

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, and monkey), adrenal cortex cells (rat, guinea pig, dog, and monkey), neurons (rat), Schwann cells (rat), and Leydig cells (rat).

Platelet aggregation study (various agglutinins)

ADCC (Antibody-Dependent Cellular Cytotoxicity) activity measurement

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.

CDC (Complement-Dependent Cytotoxicity) activity measurement (cells of various types)

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.

Gene expression profiling

Measurement
real-time PCR/RT-PCR analysis

Cell surface marker profiling

Measurement
flow cytometry