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PubMed2003

[Synthesis, cloning, expression and antigenicity of the therapeutic multi-epitope gene of hepatitis B virus and of its products].

OBJECTIVE: To study the synthesis, cloning, expression and antigenicity of therapeutic multi-epitope gene of hepatitis B virus. METHODS: The therapeutic multi-epitope gene of hepatitis B virus was synthesized and cloned into the vector pWR450-1, then was expressed in E.coli and the products were purified. The immunogenicity of the expressed protein was analyzed by Western-blotting. RESULTS: Recombinant plasmid PWR/BPT was constructed successfully and the protein of multi-epitope gene of hepatitis B virus was expressed in E. coli, which showed ideal antigenicity by Western-blotting. CONCLUSIONS: The designed multi-epitope therapeutic gene of hepatitis B virus was proved to be correct and the expressed protein may be a good therapeutic vaccine.

Blotting, Western↗
PubMed2000

New perspectives on anti-HER2/neu therapeutics.

HER2/neu and the epidermal growth factor receptor (EGFR) are significantly overexpressed in several cancer cells. Overexpression of these two receptors accounts for progression of many types of cancer: breast, ovarian, skin, pancreas and brain. In recent years, several approaches to disable the receptor complexes have shown promise. Antibody-based therapy, kinase inhibitors and other inhibitors of signaling molecules are the major approaches. Our group developed the concept that an anti-p185HER2/neu monoclonal antibody might represent a therapeutic for cancer and this has culminated in a clinically useful therapeutic, the humanized monoclonal antibody Herceptin (trastuzumab). We have now developed a small-molecule form of an anti-HER2/neu peptidomimetic (AHNP) that exhibit functions comparable to those of the monoclonal antibody Herceptin. This approach may be considered a new paradigm in receptor-specific tumor therapeutics. A brief review of our approach in developing receptor-specific therapeutic agents for HER2/neu-related cancer is presented.

Journal Article↗
PubMed1992

[Ezhu intravenous injection in treating infantile respiratory syncytial virus pneumonia and its therapeutical mechanism].

Ezhu Intravenous Injection (EII) in treating respiratory syncytial virus (RSV) pneumonia was studied. 45 patients in therapeutic group were treated with 0.04% EII in dose of 20 ml/kg/day for 7-14 days. 20 patients in the control group were treated with Huayu decoction, its efficacy on RSV pneumonia has been confirmed. The results showed that all the patients of both groups were cured and there were no statistic differences in the average days of clearing up the temperature, dyspnea and wheezing (P > 0.05). Experimental studies showed that the isolation rate of RSV on the 5th and 8th day in the therapeutic group were lower than that of infected and glucose control groups. The difference was significant (P < 0.001 and P < 0.0001). Pathological examination showed that on 5th day in infected and control group there were epithelial damages and bronchial lumen obstruction, peri-bronchial and periseptal edema, eosinophilic leucocytes and inflammatory infiltrations. The endothelial cells of alveolar capillaries swelled, platelet aggregations and thrombi occurred in its lumens. On 8th day the platelet aggregations diminished, but cellular infiltrations and damages of bronchial epithelium still existed. In therapeutic group on 5th day most of the alveolar capillary endothelial cells were normal with mild edema only. The platelet aggregation were much less than the infected and control groups. No peribronchial and peri-septal edema was observed. The results of both clinical and experimental studies showed that EII had good therapeutic effect on RSV pneumonia with no adverse reaction.

Animals↗
PubMed1992

Therapeutic advantage of high-affinity anticarcinoma radioimmunoconjugates.

The effect of the relative affinity (Ka) on the antitumor efficacy of monoclonal antibodies (MAbs) has been questioned. It has previously been shown in experimental models that the use of MAbs with higher relative Kas manifests itself in a higher percentage of injected dose of MAb bound to tumor. On the other hand, mathematical models have proposed that the use of higher affinity MAbs may be disadvantageous for antitumor effects, since higher Ka MAbs would bind more antigen and prevent penetration of MAb through tumor. To test this hypothesis, three MAbs reacting to the human pancarcinoma antigen TAG-72 were used as radioimmunoconjugates for therapeutic efficacy versus the LS-174T human colon carcinoma xenograft. MAbs B72.3, CC49, and CC83 have all been shown by depletion studies to react to the same molecule and to all react with overlapping epitopes. While the relative Ka of B72.3 is 2.5 x 10(9) M-1, the relative Kas of CC49 and CC83 are 16.2 and 27.7 x 10(9) M-1, respectively. Each MAb was radiolabeled with 131I, and each radioimmunoconjugate was assayed at five dose levels for therapeutic efficacy using the human xenograft model. The results of these studies demonstrate substantial therapeutic advantage of the higher affinity MAbs CC49 and CC83 versus B72.3 at every dose level. While 500 microCi of B72.3 were required to reduce tumor growth in only a minority of tumor-bearing animals, the use of the same amount or less of the radioimmunoconjugates of CC49 or CC83 resulted in strong antitumor effects in 80 to 100% of tumor-bearing animals. Thus, stronger antitumor effects were seen using as little as 2.5- to 3-fold less of the higher Ka immunoconjugates CC49 and CC83 as compared with B72.3. While we acknowledge the potential disadvantages of higher Ka MAbs in some situations, at least the experimental studies and model system described here show that a distinct therapeutic advantage exists with the use of higher affinity immunoconjugates.

Adenocarcinoma, Mucinous↗
PubMed1992

[Studies on lymphokine-activated killer (LAK) cell: accumulation in tumor tissue and the therapeutic effects of adoptive immunotherapy].

We studied the therapeutic effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells combined with chemotherapy on BMT-11 fibrosarcoma in C57BL/6 mice. Compared with the untreated group, no significant therapeutic effect was brought about by CY therapy alone or LAK.rIL-2 alone and all mice belonging to these three groups died with a mean survival time (MST) of 45.3, 51.8 and 45.9 days respectively. CY plus LAK.rIL-2 brought about complete cures in 3 out of 8 mice (37.5%) and a significant prolongation of MST of mice which died (64.4 days) and the accumulation of LAK cells (% Dose/g) at tumor sites was enhanced more than 7-fold by combination with CY. On the other hand, the therapeutic effects of cytotoxic T lymphocytes (CTLs) was sufficiently high even in the CTL.rIL-2 alone and were only slightly enhanced by combination with CY compared with LAK cells. Also, we detected LAK-attractant activity in the conditioned medium (CM) of CY-treated tumor tissues but not in that of untreated tumor tissues, and peak activity was reached 5 days after CY-treatment. This attractant activity was located in two major 10,000-50,000 M. W. fractions of CM. We then observed that LAK-attractant was produced in CM of host reactive cell enriched fractions from CY-treated tumor tissues, but not in that of tumor cell enriched fractions. The above findings imply that the effects of adoptive immunotherapy depend upon the accumulation of transferred effector cells at tumor sites, and we believe that the production of LAK-attractant by tumor tissue, facilitated by chemotherapy, is one of the mechanisms responsible for enhanced LAK-cell-accumulation at tumor sites. We performed a preliminary clinical trial with adriamycin, autologous spleen-LAK cells and rIL-2 on 30 hepatocellular carcinoma patients after radical resection on the basis of the experimental results above. There were no significant therapeutic effects after adoptive immunotherapy during the postoperative course but tendency for temporary inhibition of recurrence. Thus it is shown that this method has probable value as effective adjuvant postoperative therapy.

Aged↗
PubMed1992

Therapeutic effects of oral rebamipide and in combination with cimetidine on experimental gastritis in rats.

The present study evaluated the therapeutic effects of rebamipide alone and in combination with cimetidine on experimental gastritis established by the administration of 5 mM sodium taurocholate (TCA) for 6 months in rats. Morphological and biochemical analyses were performed to determine the effects of rebamipide, administered alone or in combination with cimetidine, on chronic, atrophic and erosive gastritis. Rebamipide and cimetidine were administered to rats as a dietary admixture for 4 weeks after withdrawal of TCA. Rebamipide dose-dependently reduced the total length of the erosion, normalized the mucosal thickness and increased the number of parietal and total cells, and tended to reduce interstitial infiltration of inflammatory cells and proliferation of collagenous fibers. Moreover, histochemical and biochemical studies also showed rebamipide to be effective. Rebamipide increased the PAS-positive mucus and normalized the reduced gastric mucosal SOD activity. The therapeutic effect of rebamipide on the experimental gastritis was enhanced by the combined use of cimetidine. These results suggest that rebamipide has a therapeutic effect on chronic atrophic erosive gastritis induced by TCA, and that the mechanism of the therapeutic effect is partially due to the increase in PAS-positive mucus and gastric mucosal SOD activity. Furthermore, the enhanced effect of the combination therapy of rebamipide with cimetidine was considered to be due to the actions of both cimetidine and rebamipide.

Administration, Oral↗
PubMed1992

Therapeutic alternatives for hormone-refractory prostatic cancer.

The currently available prognostic factors allow the identification of patients who are destined to do poorly with primary hormone therapy. Standardization of these factors is required so that they become incorporated into routine practice. For patients who relapse in osseous sites radiolabeled diphosphonates are one therapeutic alternative that can provide palliation. Future use will be directed to optimize treatment schedules, and use earlier in the course of the disease so that more durable palliation of bony metastases can be achieved. Evolving data on the use of PSA show that elevations antedate clinical relapse for most patients. In these cases, sequential changes can be used to assess therapeutic effects, which in turn can allow novel therapies to be screened more rapidly in the clinic. Criteria for the degree of change that is indicative of response must be standardized. Preliminary data suggest a 50% decline be the minimum that is used. The results with agents such as suramin, which interrupts autocrine and paracrine growth factor loops, are a therapeutic strategy that need further study. Future efforts will focus on defining which patients are best suited for specific therapeutic approaches.

Antigens, Neoplasm↗
PubMed1992

Cough variant asthma: usefulness of a diagnostic-therapeutic trial with prednisone.

Cough variant asthma is characterized as a persistent, nonproductive cough with minimal or no wheezing and dyspnea. The diagnosis can be overlooked or misdisagnosed. We describe the severity of cough, the misery of some patients who have this syndrome and the usefulness of a diagnostic-therapeutic trial in ten patients with cough variant asthma. We evaluated ten patients whose chief complaint was persistent nonproductive cough. During the course of evaluation, all patients received a diagnostic-therapeutic trial of prednisone for cough variant asthma after other major causes of cough had been excluded. The duration of cough ranged from 2 months to 20 years. Some patients had significant side effects from coughing including interference with social life, work and sleep, urinary incontinence, stool incontinence, hoarseness, and vomiting. After a diagnostic-therapeutic trial with prednisone, nine patients reported significant improvement of cough in three days. One patient required 2 weeks of therapy for optimal improvement. All were subsequently controlled primarily with inhaled conticosteroids. The diagnosis of cough variant asthma may not be made for a prolonged time. A short course of prednisone as a diagnostic-therapeutic trial can establish a diagnosis and be followed by an effective method of control of cough by inhaled corticosteroids.

Adolescent↗
PubMed2003

[Therapeutic gene clusters as drug action mechanisms].

Pharmacogenomics is defined to identify the therapeutic gene clusters which are involved in determining the responsiveness and to distinguish responders and non-responders to a given drug. Genome sequencing, transcriptome, proteome and metabolome analysis are of particular significance in pharmacogenomics. Sequencing is used to locate polymorphisms, and monitoring of functional gene expression can provide clue about the genomic response to disease and treatment. The transcriptome analysis can be done by methods of random cDNA sequencing, mRNA display(fluorescent differential display et al.) and differential hybridization(cDNA microarray, oligomicrochip et al.). We used transcriptome/proteome/metabolome analysis to identify therapeutic target genes by studying change of gene expression in animal models and human model cells of various diseases and found novel drug target candidates through this pharmacogenomic strategy. The present study describes combined transcriptome and metabolome analysis for therapeutic target validation in hypoxia-induced vascular remodeling. The pharmacogenomic analysis and pharmainformatics has the potential for strategy to define novel therapeutic gene clusters in various diseases and holds the promise that drugs might be tailor-maid for individuals and adapted to each person's own genetic makeup. These techniques provided an excellent strategy for screening and validation of targets.

Animals↗
PubMed2003

The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies.

Important insights into the cellular and molecular biology of cancer in general and of hematologic malignancies in particular have been gained in the past two decades. The genes, and their protein products, involved in the transformation of cells from normal to neoplastic, as well as in the progression of neoplastic cells to a more aggressive, therapy-resistant phenotype, are being elucidated in great detail. However, most hematologic malignancies, particularly adult acute leukemias, remain associated with high mortality rates and new therapeutic approaches are urgently needed. The challenge is therefore to carefully and efficiently translate the information gained into effective therapeutic strategies. The clinical success achieved by tyrosine kinase inhibitors, such as ST1571 in chronic myelogenous leukemia, has stimulated interest for kinase-based signaling pathways as therapeutic targets in hematologic malignancies. The mitogen-activated protein kinase (MAPK) pathway is a common point of convergence of many different mitogenic and anti-apoptotic signal transduction pathways in hematopoietic, as well as epithelial, cancer cells and can now be clinically targeted by highly selective small molecule inhibitors. The mounting preclinical evidence of anti-leukemic activity of MAPK inhibitors, alone or in combination with pro-apoptotic small molecules or with conventional chemotherapeutic agents provides rationale that MAPK inhibition-based treatment strategies could soon enrich our therapeutic armamentarium against human leukemias.

Antineoplastic Agents↗
PubMed2004

Therapeutic cancer vaccines.

Therapeutic vaccination against cancer-associated antigens represents an attractive option for cancer therapy in view of the comparatively low toxicity and, so far, excellent safety profile of this treatment. Nevertheless, it is now recognized that the vaccination strategies used for prophylactic vaccinations against infectious diseases cannot necessarily be used for therapeutic cancer vaccination. Cancer patients are usually immunosuppressed, and most cancer-associated antigens are self antigens. Therefore, various immunostimulation techniques are under investigation in an effort to bolster immune systems and to overcome immune tolerance to self antigens. Various strategies to stimulate antigen presentation, T-cell reactivity and innate immune activity are under investigation. Similarly, strategies to produce an immunological 'danger signal' at the site of the tumor itself are under evaluation, as it is recognized that while tumor-specific T-cells can be activated at the site of vaccination, they require appropriate signals to be attracted to a tumor. The detection, evaluation and quantification of specific immune responses generated by vaccination with cancer-associated antigens is another important area of therapeutic cancer vaccine evaluation receiving much attention and novel strategies. Multiple clinical trials have been undertaken to evaluate therapeutic vaccines in patients. Aggressive protocols such as those combining specific stimulation of T-cells and chemotherapy or strategies to block immune regulation are having some success.

Antigen Presentation↗
PubMed2004

[Construction, expression and targeting therapeutic of single-chain immunotoxin against hepatocellular carcinoma].

OBJECTIVES: To obtain high therapeutic effect and low toxicity single-chain immunotoxin against hepatocellular carcinoma (HCC). METHODS: Human mutant tumor necrosis factor-alpha (mTNFalpha) was linked with the 3' end of humanized single-chain Fv against HCC (hscFv25) in pGEX4T-1 vector. The anti-HCC immunotoxin was expressed in Escherichia coli and identified by western blot. The primary tumor regression trial in nude mice bearing HCC was evaluated the targeting therapeutic value of hscFv25-mTNFalpha. The tumor tissues were stained by immunohistochemical with TNFalpha antibody. RESULTS: The expression of single-chain immunotoxin hscFv25-mTNFalpha was 12% of total bacteria proteins. The tumor regression trials of hscFv25-mTNFalpha showed 5/5 effective. It had 2/5 completely remission and 3/5 partly remission. The therapeutic result of hscFv25-mTNFalpha was better than that of mTNFalpha (F=8.70, 0.05). The HCC tissue treated by hscFv25-mTNFalpha expressed TNFalpha positive reaction. The positive granule mainly existed in HCC cytoplasm. CONCLUSION: The single-chain immunotoxin hscFv25-mTNFalpha has high therapeutic effect and low toxicity. It has potentialities for clinical application.

Animals↗
PubMed1992

Digoxin therapeutics: straightening out the facts.

This article is essentially a review of the pharmacokinetic rationale behind digoxin therapeutics. It covers the various approaches to digoxin therapeutics including the therapeutic endpoint and the use of plasma concentrations of digoxin, the various problems involved in dosage design (particularly pharmacokinetic variability), prescribing aids (and their total impact on the variability in plasma concentrations achieved), and finally, the alternative use of blood-level data to separate and identify the variation in absorption-disposition from the variation in the relationship of plasma concentration to effect. On the basis of available data, it is concluded that by both turning to prescribing aids that have been formulated from clinical data gathered under more nearly ideal conditions and selecting the dosage to give a target concentration based on single measurements of serum digoxin concentrations, may not result in much improvement over fixed or intuitive dosing as far as achieving a predetermined target level is concerned. The probable causes for this lack of precision are explored, and finally an optimum approach to digoxin therapeutics is defined.

Animals↗
PubMed2003

[The therapeutic efficacy of tumor-derived heat shock protein70 combining interleukin-2 on tumor-bearing mice].

AIM: To investigate the therapeutic efficacy of the combination of tumor-derived HSP70 and IL-2 on tumor-bearing mice. METHODS: HSP70 was purified from the murine tumor cell line by liquid chromatography. And then identified by SDS-PAGE and Western blot,the purity of purified product was analyzed by capillary electrophoresis. The anti-tumor efficacies of mono-administration of HSP70 or IL-2 and their combination were observed by zoopery. RESULTS: Combination of HSP70 and IL-2 was more effective than either of the two therapeutic agents alone in treating tumor-bearing mice. 10 microg HSP70 displayed obviously therapeutic effect no matter applied alone or combined with IL-2. The averaged life span of the mice treated with IL-2 was only 36.6+/-13.0 days, while 40% of the mice treated with 10 microg HSP70, tumors disappeared eventually and their survival time was more than 90 days, and the averaged life span of this group was over 59.2+/-29.6 days. HSP70 plus IL-2 could get tumors disappeared completely in 60% of mice, averaged life time of this group was over 70.8+/-26.5 days. CONCLUSION: The Combination of HSP70 and IL-2 demonstrated apparently therapeutic effect on tumor-bearing mice. The results will be of greater value to the study on the immunotherapy of human malignant tumors.

Animals↗
PubMed2004

[Levothyroxine poisoning: clinical manifestations and therapeutic management].

Intoxication with L-tyroxine has a low prevalence, high prevalence is observed in pediatric age. Toxic dose is unclear, asymptomatic patients have been observed with doses under 5 mg. Systems with high prevalence of symptoms are cardiovascular system, sympathetic nervous system and gastrointestinal tube. Symptoms could appear from hours to days after ingestion. Early hours after L-tyroxine ingestion, levels of T4 and T3 are not related with severity. However, monitoring seric levels is necessary to lead therapeutic approach and to give a prognosis. Daily determinations of T3, T4 and TSH are necessaries. Determinations of temperature, arterial pressure and blood heart rate are needed to control complications. Beta-blockers and intestinal decontamination drugs are used during therapeutic approach. Other therapeutic options are iopanoic acid and propylthiouracil. In summary, intoxication with L-tyroxine could be a severe situation. It is necessary to describe therapeutic protocols in this entity.

Adrenergic beta-Antagonists↗
PubMed1992

Therapeutic monitoring of antiepileptic drugs. I--Clinical aspects.

The management of epilepsy has been markedly improved during the last twenty years, although no new drug has been developed. These therapeutic advantages have been made possible by applying the concept of "therapeutic range" of antiepileptic drugs. This range was the result of some pioneer studies showing a good relationship between clinical effects and drug concentrations. Today, the approach to the drug therapy of epilepsy is heavily dependent on the application of this concept. Infact, important factors as patient compliance, variability in drug bioavailability and drug metabolism, drug interactions, disease interactions, etc, that may influence the clinical effect of a given dose, may be controlled by regular monitoring of antiepileptic drugs. However, the concept of "therapeutic range" should not be applied mechanically to patient treatment. The best results are obtained when the analytical results, the therapeutic situation and the clinical status of the patient are considered together. In this case, an important improvement of the quality of life of the epileptic patients can be reached.

Anticonvulsants↗
PubMed2004

Production and efficacy of a dendritic cell-based therapeutic vaccine for murine chronic hepatitis B virus carrierer.

Recently a new field of immunological research and clinical application of vaccines for therapeutic purposes (vaccine therapy) has been developed for treating several chronic viral infections including chronic hepatitis B virus (HBV) infection. Administration of vaccine containing hepatitis B surface antigen (HBsAg) for 1 year has resulted in negative HBsAg and development of antibody to HBsAg (anti-HBs) in some, but not in all, HBV transgenic mouse (HBV-Tg). In order to develop more potent regimen of vaccine therapy for chronic HBV carrier, we prepared a dendritic cell (DC)-based therapeutic vaccine and evaluated their therapeutic potential in HBV-Tg. DCs were isolated from single cell suspensions of murine spleen cells by collagenase digestion, density centrifugation and depletion of lymphocytes. Spleen DCs were cultured with HBsAg (100 microg) for 24 h to produce HBsAg-pulsed DCs. HBV-Tg expressing HBsAg and HBV DNA in the sera were randomly assigned to receive either HBsAg-pulsed DCs (n = 20) or unpulsed DC (n = 20) or vaccine containing HBsAg (n = 39) or complete Freund's adjuvant (n = 20) or left untreated (n = 20). Only two intraperitoneal injections of HBsAg-pulsed DCs resulted in negative HBsAg and production of anti-HBs in the sera in all HBV-Tg (n = 20). However, administration of un-pulsed DCs (n = 20) or vaccine containing HBsAg (n = 39) or only complete Freund's adjuvant did not induce negative HBsAg or production of anti-HBs in any HBV-Tg within 6 months of therapy commencement. Taken together, this study showed that HBsAg-pulsed DCs represent a highly potent therapeutic vaccine for chronic HBV infection and inspire optimism of using this vaccine in clinical conditions. A clinical trial of HBsAg-pulsed DC in patients with chronic hepatitis B is warranted.

Animals↗
PubMed2004

[Therapeutic efficiency of amphotericin B liposome modified by RMP-7 to transport drug across blood brain barrier].

AIM: To study the therapeutic efficiency of amphotericin B liposome (AmB-L) targeting to the brain in mice with meningitis. METHODS: Amphotericin B liposome targeting to the brain were prepared by film-sonication method. Their concentration and encapsulation percentage were determined. The Candida albicans was injected into the brain of BALB/c mice and the meningitis model was set up. Then the therapeutic efficiency of amphotericin B liposome targeting to the brain was studied. RESULTS: The encapsulation percentage of amphotericin B liposome was 93.3%. The meningitis model was set up after the Candida albicans was injected into the brain of BALB/c mice for 2 h. The therapeutic efficiency was increased after conjugating RMP-7 (the commercial nama is Cereport) to the surface of amphotericin B liposome. CONCLUSION: The therapeutic efficiency of Amphotericin B liposome targeting to the brain in the mice with meningitis was better than that of the common amphotericin B liposome and the life of the mice in AmB-L-PEG-RMP-7 group was longer than that of the mice in AmB-L-PEG group and AmB-L-PEG + RMP-7 group.

Amphotericin B↗