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PubMedDate not supplied

[Preclinical study of the safety of the new Soviet tranquilizer gindarin].

The Soviet plant tranquilizer gindarin (an isoquinoline series alkaloid I-tetrahydropalmatine) isolated from the tubers of Stephania glabra Miers was subjected to a preclinical study. As regards the toxicity measured during a single administration to the laboratory animals, gindarin may be classified with moderately toxic substances. Daily intragastric administration of gindarin to rats in doses of 20 and 60 mg/kg for 3 months is likely to give rise to the changes in functions of the CNS, liver and blood. In doses of 1--50 mg/kg gindarin does not exhibit any allergizing, mutagenic or teratogenic properties. Administration of the drug in doses of 1--50 mg/kg from the 1st to the 20th day of pregnancy has shown it to produce marked embryotoxic action. In view of this fact gindarin is contraindicated in pregnancy.

Alkaloids↗

PubMed2001

[Preclinical studies of oxaliplatin in combination chemotherapy].

Therapeutic innovation in oncology often requires the optimization of combinations with active drugs based on in vitro and in vivo data. This is exemplified by oxaliplatin for which several preclinical studies of combinations have been realized. Oxaliplatin has been combined with 5-fluoro-uracile, gemcitabine, topoisomerase I inhibitors, taxanes demonstrating synergy or additivity. Synergistic and additive effects are often due to the optimization in the use of distinct mechanism of action or resistance and might be associated with no overlapping toxicity when combined in clinical trials.

Animals↗

PubMed2000

The oblique radiographic technique for bone height measurements on edentulous mandibles: a preclinical study and an introduction to the clinical use.

OBJECTIVE: The aim of this study was to quantify the effect of mandibular angulation, position, and shape of the edentulous mandible on the distortion of its image on lateral oblique radiographs in a preclinical study. Suggestions for the clinical use of this technique are made. STUDY DESIGN: Five edentulous dry mandibles were used, varying in size from small to wide and equipped with metal bars in and on top of the mandible. The mandibles were radiographed at 9 different positions by tilting the mandible around the intercondylar axis and by using the oblique projection technique in a cephalostat. RESULTS: The length of the images of the metal bars varied significantly when we tilted the mandibles from 20 degrees to -20 degrees. As a result of the effects of magnification and distortion, the image size varied from between 0.96% and 1.06% of the real size. Neither the size of the mandible nor the position of the bars was related to the degree of magnification. CONCLUSION: The oblique projection technique has limited geometric errors in depicting the edentulous mandible. For evaluative bone height measurements in patients with extremely resorbed mandibles treated with dental implants, it is a promising technique if the patient (specifically the mandible) can be positioned reproducibly in the apparatus.

Analysis of Variance↗

PubMed1996

Preclinical studies and potential clinical applications of c-mpl ligand.

The cloning of the gene for the endogenous c-mpl ligand, also known as thrombopoietin, was first reported less than 2 years ago. Recombinant mpl ligands based on this gene have been extensively evaluated in preclinical studies and are now in the early stages of clinical development. In vivo studies have confirmed that c-mpl ligand is a lineage-dominant cytokine and is the primary physiologic regulator of megakaryocytopoiesis. Recombinant mpl ligands can substantially reduce the severity and duration of thrombocytopenia due to myelosuppressive irradiation, chemotherapy, or both. Moreover, when recombinant mpl ligand is used in combination with r-metHuG-CSF, both thrombocytopenia and neutropenia can be prevented to the same degree as with either cytokine alone. In normal animals, the platelets produced in response to recombinant mpl ligand function appropriately and should not pose an undue risk for thrombosis when administered to thrombocytopenic patients. Initial clinical data confirm the safety and biologic activity of these new agents in humans. Clinical development will likely target the most myelosuppressive regimens, including those used in hematopoietic cell transplantation and acute myelocytic leukemia. Ultimately, the clinical benefit of these drugs will likely be judged on their ability to reduce the duration of severe thrombocytopenia and the need for platelet transfusions.

Animals↗

PubMed1999

[Development of 18F-FDG ([F-18]-2-fluoro-2-deoxy-D-glucose) injection for imaging of tumor reflecting glucose metabolism--results of preclinical studies].

Fluorine-18-2-fluoro-2-deoxy-D-glucose (18F-FDG) injection was prepared by a modification of a method originally developed by Hamacher et al. The dosage form is the injectable solution (2 ml) containing 185 MBq of 18F-FDG at a calibration time. Preclinical studies of the agent were performed. Its radiochemical purity is more than 95% and expiration time is 4 hours after the calibration time at ambient temperature. No toxicity was observed with up to 200 mg/kg and 100 mg/kg of non-radioactive FDG intravenously injected to rats and dogs in single-dose toxicity tests, respectively. Biodistribution studies demonstrated that the radioactivity was mainly distributed into brain (3.0 to 3.3% I.D./Organ at 30 minutes) and heart (4.2 to 5.8% I.D./Organ at 1 to 3 hours) after intravenous injection of the agent to normal rats. In a tumor transplanted mouse model (colon 26), tumor uptake was 10.9 +/- 3.5% I.D./g at 1 hr after intravenous injection of the agent, the radioactivity was retained until 3 hours. The radiation absorbed dose was estimated according to the MIRD Pamphlet based on the biodistribution data both in humans reported by Mejia et al. and rats described in this report. The radiation absorbed dose was not higher than those of commercially available radiopharmaceuticals. In conclusion, the 18F-FDG injection is expected to be useful for further clinical application.

Animals↗

PubMed2004

A bioartificial liver support system using primary hepatocytes: a preclinical study in a new porcine hepatectomy model.

BACKGROUND: Bioartificial liver support systems providing a bridge to transplantation or even a definitive treatment of acute hepatic failure are a current focus of research. Different devices are used, although an impact on patient survival is doubtful for the time being. After developing a new flat membrane bioreactor, further preclinical studies have become necessary. Existing animal models of fulminant hepatic failure show common difficulties in defining a reproducible loss of functional liver tissue while considering systemic side effects. We now present a reproducible model with total hepatectomy in pigs, suitable to test the safety and efficacy of liver support systems. METHODS: Twelve pigs underwent total hepatectomy by using silicone tubes and a Y-adapter as vascular prosthesis; intracranial pressure was measured via a subdural probe. Anhepatic pigs were monitored under general anesthesia until death occurred. All were treated with a new flat membrane bioreactor (FMB) that contained porcine hepatocytes in 6 of the 12 cases. RESULTS: Our hepatectomy technique proved to be successful without requiring venovenous bypass circulation. Mean vascular clamping time was 9 minutes. The mean survival time was longer in animals treated with hepatocyte-equipped bioreactors than in untreated animals (24.8 +/- 4.3 vs 16.4 +/- 4.7 hours), which already showed increased intracranial pressure after 10 to 12 hours. Serum albumin levels indicated stable cell-specific functions of the FMB. CONCLUSIONS: The described technique of total hepatectomy is a well-reproducible animal model. The presented FMB maintained stable cell-specific functions and is a safe and efficient device.

Animals↗

PubMed1998

Preclinical studies of glimepiride.

The treatment of NIDDM is advancing on a number of fronts, ranging from the understanding of the mechanisms of action of existing agents to the development of new drugs. Glimepiride, the most recently U.S. approved sulfonylurea, is evaluated for its pancreatic and extrapancreatic activities in addition to safety, when compared with glibenclamide in preclinical studies. Glimepiride uniquely binds to the 65 kDa protein K(ATP) channel in pancreatic islet beta-cell membranes and directly stimulates insulin secretion. Glimepiride has a lower binding affinity and causes less insulin release than glibenclamide in normal dogs and humans. However, in various animal models, glimepiride produces a more rapid and pronounced blood glucose-decreasing activity than glibenclamide. In vivo studies indicate that glimepiride also significantly reduces HbA1c, blood glucose and fasting insulin levels via extrapancreatic activities. These insulin mimetic effects are supported by demonstration of stimulated lipogenesis in 3T3 adipocytes and glycogenesis in rat diaphragm, by more efficient translocation of GLTU4 in fat and skeletal muscle tissues, and by activation of key metabolic enzymes. The insulin sensitivity effects of glimepiride have been demonstrated in vivo by increased glucose disposal rates in euglycemic clamp studies and in vitro by increased sensitivity and responsiveness of insulin-induced glucose uptake. Moreover, glimepiride might stimulate insulin-mediated glucose utilization in hepatocytes. With exercise-induced hypoglycemia, a suppression of endogenous insulin secretion was observed for glimepiride only. Data accumulated from in vitro and animal studies suggest that glimepiride has the least cardiotoxic potential. Its relative activities in multiple cardiovascular studies do not correlate with its potency to lower blood glucose levels. Similar cardiovascular effects have been seen in human studies. In contrast to the lack of an acute action, chronic application of glimepiride to cultured cardiomyocytes was found to produce an approximate doubling of the basal glucose uptake rates by an insulin-independent pathway most probably involving increased protein expression of both GLUT1 and GLUT4. Like glibenclamide, glimepiride possibly has antiatherogenic activity by inhibiting platelet aggregation via suppression of arachidonic acid metabolism. Our recent studies on rats and humans indicated that glimepiride has immunomodulatory activity and this action appears to be related to lowering autoimmune responses rather than metabolic action. These studies have been extended to include glimepiride involvement with prevention of diabetes in BB rats using an islet transplantation model. Finally, sulfonylureas, including glimepiride, may be useful for treating and preventing NIDDM.

Journal Article↗

PubMed1993

Development of a clinical protocol for hepatic gene transfer: lessons learned in preclinical studies.

Strategies for hepatic gene therapy have been proposed that involve isolation of primary hepatocytes and introduction of recombinant genes into these cells in culture, followed by autologous hepatocellular transplantation (HCT). Consideration of clinical applications requires data suggesting that HCT can be performed safely in human subjects in addition to data indicating that recombinant gene expression can reverse a disease process. This report describes preclinical studies that underlie a clinical trial of HCT in which hepatocytes would be labeled with a marker gene to facilitate assessment of engraftment in the recipient. Human hepatocytes were harvested from liver segments preserved in Belzar's solution and transduced with an amphotropic retroviral vector carrying a recombinant marker gene (neomycin phosphotransferase II). Human hepatocytes were recovered from monolayer culture, stained with the fluorescent dye 1,1'-dioctadecyl-3,3,3,3'-tetra-methylindo-carbocyanine perchlorate (DiI) and transplanted into severe combined immunodeficient mice by splenic injection. Engrafted hepatocytes were identified in the liver and spleen of severe combined immunodeficient mice but not immunocompetent controls. Two large animal models of HCT are described. In a dog model, neomycin phosphotransferase II-containing hepatocytes were identified in the liver 7 wk after transplantation. In a baboon model, autologous HCT with DiI-stained cells demonstrated that transplanted cells assume a normal morphology and constitute up to 5% of hepatocytes. These data demonstrate transduction and transplantation of human hepatocytes and the feasibility of HCT in large animals. On the basis of these studies, the proposed clinical trial for gene transfer and transplantation in human subjects has been approved by the National Institutes of Health and the Food and Drug Administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

[Preclinical studies of the anticancer adenovirus cancerolysin preparation].

The anticancer drug Cancerolysin has been developed, by using the mutant Adel2 variant of human adenovirus serotype 5 designed at the State Research Center of Virology and Biotechnology. Cancerolysin possesses a high degree of replication activity for complementary cells 293 and p53-deficient tumor cells and, at the same time, has significant replication limitations in normal human cells. Preclinical studies of the drug on laboratory animals (mice, rabbits, guinea pigs) have demonstrated its harmlessness and safety. When stored at -40 and -70 degrees C, the drug showed no significant activity throughout the control observational period (1 year).

Adenoviridae↗

PubMed1989

"Casodex" (ICI 176,334)--a new, pure, peripherally-selective anti-androgen: preclinical studies.

The relative merits of the steroidal anti-androgen, cyproterone acetate, and the non-steroidal anti-androgens flutamide and nilutamide, are reviewed. It is concluded that pure anti-androgens offer some advantages over cyproterone acetate but that they each have some features which merit improvement. A new compound which was a pure anti-androgen, peripherally selective, well tolerated with a long half-life would have significant advantages. Preclinical studies in rats and dogs show that Casodex (ICI 176,334) is a potent pure anti-androgen which is well tolerated and has a long half-life. Casodex induces marked regression of the prostate yet fails to cause the substantial elevation in serum LH and testosterone seen with flutamide and nilutamide; it is thus peripherally selective. Casodex is as effective as surgical or medical castration with Zoladex in limiting the growth of the transplantable androgen-responsive Dunning rat prostate tumour. Such a profile makes Casodex a strong candidate as the future anti-androgen of choice for the treatment of prostate cancer and benign prostate hypertrophy.

Androgen Antagonists↗

PubMed1997

Bioresorbable fracture fixation in orthopedics: a comprehensive review. Part I. Basic science and preclinical studies.

Metal alloys are currently the most popular materials for manufacture of fracture-fixation devices. Two major disadvantages of these materials are their extreme stiffness, which causes stress shielding of the underlying bone, and the necessity, in a significant number of cases, of removing metallic implants after fracture healing is complete. These shortcomings of metal alloys have led to the study of bioresorbable materials for use in fracture fixation. Currently, polylactic acid, polyglycolic acid, and polydioxanone implants are available to the orthopedic surgeon for the fixation of small cancellous bone fractures. Part I of this article provides an overview of the basic science of bioresorbable materials and presents a comprehensive review of preclinical studies reported in the orthopedic literature. Clinical studies will be reviewed in Part II.

Alloys↗

PubMed2006

A novel plasma filtration therapy for hepatic failure: preclinical studies.

There is a need to develop artificial means of liver replacement and/or assistance with the aim of either supporting patients with borderline functional liver cell mass until their liver regenerates, or until a donor liver becomes available for transplantation. Selective plasma filtration is a novel approach to blood purification therapy designed to reduce the level of circulating toxins of hepatic and renal failure, mediators of inflammation and inhibitors of hepatic regeneration. The results of preclinical studies indicate that treatment of pigs with experimentally-induced fulminant hepatic failure is safe and effective in extending survival time and arresting brain swelling. In addition, the amount of ammonia, aromatic amino acids, IL6, TNFalpha and C3a removed during the 6-h treatment in the present study was higher by 34% to 175% than the total plasma content of those substances at the start of therapy.

Animals↗

PubMed2005

New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies.

Intracerebral hemorrhage (ICH) remains a major medical problem, for which there is no effective treatment. However, extensive experimental and clinical research carried out in recent years has brought to light new exciting ideas for novel potential treatments. First, it was well documented that the management of hypertension helps to prevent new and recurrent ICH. Also, development of new guidelines for management of hypertension after the onset of the ICH may help in more effective ICH treatment. Existing contemporary data collected from preclinical studies indicates that ICH-induced inflammation represents a key factor leading to secondary brain damage, suggesting that some anti-inflammatory approaches can be used to treat hemorrhagic stroke. In this article, beyond discussing implications related to hypertension, we will summarize important (but not all) new discoveries connecting the role of inflammation to ICH pathology. Selected aspects of inflammatory response including the role of cytokines, transcription factor nuclear factor-kB, microglia activation, astrogliosis, and complement activation will be introduced. We will also discuss the role for reactive oxygen species and metalloproteinases in ICH pathogenesis and introduce basic knowledge on the nature of ICH-induced cell death including apoptosis. Potential targets for intervention and translation will be discussed.

Animals↗

PubMedDate not supplied

Anticonvulsant and acute neurotoxic characteristics of nicotinic acid benzylamide: a preclinical study.

The aim of this study was to evaluate time-course and dose-response relationships of nicotinic acid benzylamide (Nic-BZA) with regard to its anticonvulsant activity in the maximal electroshock (MES)-induced seizures and acute neurotoxic effects in terms of motor coordination impairment in the chimney test in mice. The experimental determination of both median effective dose (ED(50)) and median toxic dose (TD(50)) allowed for the calculation of protective index (PI) values characterizing a preclinical profile of Nic-BZA. Results indicated that Nic-BZA produced the time-dependent and clear-cut anticonvulsant activity in the MES test and its ED(50) values ranged between 35.7 and 84.0 mg/kg (after the ip administration of the agent at 5 and 60 min, respectively), and between 72.0 and 152.1 mg/kg (at 5 and 60 min, respectively, following the po administration of Nic-BZA). In the chimney test, the TD(50) values for Nic-BZA, after its ip administration ranged between 188.5 and 509.9 mg/kg, whereas following its po administration the TD(50) values for Nic-BZA were between 552 and 1222.1 mg/kg. The PI values for Nic-BZA, calculated at various times after its ip and po administrations (ranging between 3.56 and 17), revealed that the agent has a favorable profile, when considering its both anticonvulsant and acute neurotoxic effects in this preclinical study. Based on this study, one can conclude that Nic-BZA might occur advantageous as a potential antiepileptic drug for breaking seizure attacks in patients with epilepsy.

Administration, Oral↗

PubMed1993

Fluorescence detection of tumors. Early diagnosis of microscopic lesions in preclinical studies.

BACKGROUND: The growth of microscopic tumor lesions at or beyond treatment field margins poses a major problem in the diagnosis and treatment of cancer. Early detection techniques that clearly define the location or field spread of disease may improve the planning of disease treatment. METHODS: In vivo fluorescence photometry is a non-imaging technique that digitally displays relative fluorescence values in volts proportional to the luminescence intensity detected by a silicon photodiode. The sensitivity of the instrument has allowed the detection of micrometastases in preclinical studies. RESULTS: Statistical analysis demonstrates that the photosensitizer Photofrin (dihematoporphyrin ether and/or ester) (Quadra Logic Technologies, QLT, Vancouver, B.C., Canada), currently used for photodynamic therapy, administered in doses lower than those used in clinical studies, is useful for the detection of occult disease. With the drug doses used, cutaneous photosensitivity was avoided in the animal models tested. The results in Lobund-Wistar rats with transplantable prostatic adenocarcinoma (PA-III) demonstrated the utility of this technique in detecting clinically occult disease, with a prediction rate of approximately 94% with drug doses as low as 0.25-0.5 mg/kg. CONCLUSIONS: With the use of the hamster buccal cavity model involving the initiation and promotion of premalignant and malignant conditions by 9,10 dimethyl-1,2-benzanthracene, the technique could discern these two stages of disease with significance levels that were less than 0.05 and 0.01, respectively.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Human monoclonal antibody developed against a metastasizing paraganglioma: preparation and preclinical studies.

A tumor cell line, named HS, was established from a bone metastasis of a patient with metastasizing paraganglioma. In vitro immunization of normal human peripheral blood mononuclear cells by coculturing with viable HS cells, followed by fusion with mouse myeloma cells, yielded a stable human/murine heterohybridoma producing the highly specific monoclonal anti-body KM-155. This MAB KM-155 is a member of the IgG3 subclass and shows no alpha GAL glycosylation that is specific for mouse but not for human antibodies. In pilot preclinical studies it could be demonstrated that MAB KM-155 is highly efficient in targeting a KM-155 antigen-expressing human tumor developing in nu/nu mice after xenografting. Moreover, the growth of KM-155 antigen-expressing human tumors in nu/nu mice was largely inhibited when the concentration of circulating MAB KM-155 was maintained at a high enough level by serial injections.

Animals↗

PubMed2006

Cancer vaccines: preclinical studies and novel strategies.

The development of cancer vaccines, aimed to enhance the immune response against a tumor, is a promising area of research. A better understanding of both the molecular mechanisms that govern the generation of an effective immune response and the biology of a tumor has contributed to substantial progress in the field. Areas of intense investigation in cancer immunotherapy will be discussed here, including: (1) the discovery and characterization of novel tumor antigens to be used as targets for vaccination; (2) the investigation of different vaccine-delivery modalities such as cellular-based vaccines, protein- and peptide-based vaccines, and vector-based vaccines; (3) the characterization of biological adjuvants to further improve the immunogenicity of a vaccine; and (4) the investigation of multimodal therapies where vaccines are being combined with other oncological treatments such as radiation and chemotherapy. A compilation of data from preclinical studies conducted in vitro as well as in animal models is presented here. The results from these studies would certainly support the development of new vaccination strategies toward cancer vaccines with enhanced clinical efficacy.

Animals↗

PubMed1987

Overview of preclinical studies with ciprofloxacin.

Ciprofloxacin is a new 6-fluoro-7-piperazino-4-quinolone that is highly active against a broad array of microbial pathogens. Minimal inhibitory concentrations (MICs) of ciprofloxacin are generally below 0.5 micrograms/ml for Hemophilus, Neisseria, and Enterobacteriaceae and are 1.0 microgram/ml or less for many non-fermentative gram-negative bacteria. Most staphylococci, including strains resistant to methicillin, are inhibited by 1.0 microgram/ml or less of ciprofloxacin, whereas streptococci are somewhat less susceptible. Obligate anaerobes are generally not susceptible to ciprofloxacin at concentrations below 1.0 microgram/ml. The antimicrobial potency of ciprofloxacin is twofold to fourfold greater than that of norfloxacin and is considerably greater than that of cephalosporins and aminoglycosides in tests with most gram-negative bacteria. Factors diminishing the in vitro activity of ciprofloxacin include acidic pH, high levels of magnesium ions, and an inoculum size of 10(7) colony-forming units/ml or greater. Ciprofloxacin is bactericidal at concentrations near its MIC for most bacteria. In vivo tests with experimentally induced infections in animals confirm the potency of ciprofloxacin. Doses required to protect 50 percent of animals from death are generally less than 2.0 mg/kg for gram-negative infections and range from 0.7 to 7.0 mg/kg for staphylococcal infections. The antimicrobial spectrum and potency of ciprofloxacin demonstrated in these preclinical studies make this quinolone a promising new antimicrobial agent.

Animals↗