Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “THERAPEUTICS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,153 records · Page 64Linked to original sources
PubMed2004

Structure-immunogenicity relationships of therapeutic proteins.

As more recombinant human proteins become available on the market, the incidence of immunogenicity problems is rising. The antibodies formed against a therapeutic protein can result in serious clinical effects, such as loss of efficacy and neutralization of the endogenous protein with essential biological functions. Here we review the literature on the relations between the immunogenicity of the therapeutic proteins and their structural properties. The mechanisms by which protein therapeutics can induce antibodies as well as the models used to study immunogenicity are discussed. Examples of how the chemical structure (including amino acid sequence, glycosylation, and pegylation) can influence the incidence and level of antibody formation are given. Moreover, it is shown that physical degradation (especially aggregation) of the proteins as well as chemical decomposition (e.g., oxidation) may enhance the immune response. To what extent the presence of degradation products in protein formulations influences their immunogenicity still needs further investigation. Immunization of transgenic animals, tolerant for the human protein, with well-defined, artificially prepared degradation products of therapeutic proteins may shed more light on the structure-immunogenicity relationships of recombinant human proteins.

Animals↗
PubMed2004

Mishandling of the therapeutic peptide glucagon generates cytotoxic amyloidogenic fibrils.

PURPOSE: Some therapeutic peptides exhibit amyloidogenic properties that cause insolubility and cytotoxicity against neuronal cells in vitro. Here, we characterize the conformational change in monomeric therapeutic peptide to its fibrillar aggregate in order to prevent amyloidogenic formation during clinical application. METHODS: Therapeutic peptides including glucagon, porcine secretin, and salmon calcitonin were dissolved in acidic solution at concentrations ranging from 1 mg/ml to 80 mg/ml and then aged at 37 degrees C. Amyloidogenic properties were assessed by circular dichroism (CD), electron microscopy (EM), staining with beta-sheet-specific dyes, and size-exclusion chromatography (SEC). Cytotoxic characteristics were determined concomitantly. RESULTS: By aging at 2.5 mg/ml or higher for 24 h, monomeric glucagon was converted to fibrillar aggregates consisting of a beta-sheet-rich structure with multimeric states of glucagon. Although no aggregation was observed by aging at the clinical concentration of 1 mg/ml for 1 day, 30-day aging resulted in the generation of fibrillar aggregates. The addition of anti-glucagon serum significantly inhibited fibrillar conversion of monomeric glucagon. Glucagon fibrils induced significant cell death and activated an apoptotic enzyme, caspase-3, in PC12 cells and NIH-3T3 cells. Caspase inhibitors attenuated this toxicity in a dose-dependent manner, indicating the involvement of apoptotic signaling pathways in the fibrillar formation of glucagon. On the contrary to glucagon, salmon calcitonin exhibited aggregation at a much higher concentration of 40 mg/ml and secretin showed no aggregation at the concentration as high as 75 mg/ml. CONCLUSIONS: These results indicated that glucagon was self-associated by its beta-sheet-rich intermolecular structure during the aging process under concentrated conditions to induce fibrillar aggregates. Glucagon has the same amyloidogenic propensities as pathologically related peptides such as beta-amyloid (Abeta)1-42 and prion protein fragment (PrP)106-126 including conformational change to a beta-sheet-rich structure and cytotoxic effects by activating caspases. These findings suggest that inappropriate preparation and application of therapeutic glucagon may cause undesirable insoluble products and side effects such as amyloidosis in clinical application.

Amyloid↗
PubMed2002

[Low back pain: diagnostic and therapeutic concepts].

During the last couple of years the lumbar back pain has gained importance like no other complaints in rheumatology and orthopaedics. This is mainly due to the chronic futile course and a general increase in relation to socio-economic factors. This is also where new therapeutic concepts have been created, which not only emphasise the pure somatic proceeding but also include the bio-psycho-social concept of treatment that on the one hand takes a lot of time and trouble, yet on the other hand is the treatment most likely to be a therapeutic success. However, in diagnosis one always has to start out from the somatic possibility and construct a working hypothesis within the framework of clear diagnostic steps, which then can be used as a basis for further therapeutic proceeding. Backache of young people differs greatly from backache of adults. New examinations even question the general belief that there is only a pure somatic reason that leads to backache of young people. The ergonomic way of thinking absolutely has to start being used for therapeutic reflections. Moreover, not only the analysis of the place of work and the adaption, yet also the strain in the spare time has to be structured usefully and sensibly.

Adolescent↗
PubMed1995

Client as colleague. Therapeutic contracting with the seriously mentally ill.

This article introduces the therapeutic contracting program as a comprehensive treatment system for persons with serious mental illness. Therapeutic contracting offers a promising framework for integrating medical, psychological, and social therapies in a manner that fosters clients' active involvement in treatment. This article outlines a multistage therapy program that mobilizes clients' adaptational resources through experimental interventions, structured goal-setting exercises, and skills-building experiences. Data illustrate the effectiveness of therapeutic contracting for (a) securing clients' treatment compliance, (b) promoting positive clinical outcomes, (c) reducing overall treatment costs. The therapeutic contracting model is discussed as a potential vehicle for expanding the professional role of psychologists in psychiatric settings, particularly in areas of clinical and administrative decision making.

Chronic Disease↗
PubMed1990

Predictive validity of therapeutic alliance in group marital therapy.

The relation between marital distress, therapeutic alliance formation, and treatment outcome was investigated in a group marital skills training program in which 63 couples met for 9 weekly 3-hr sessions. Treatment outcome was assessed before and after completion of treatment through a series of self-report measures. The quality of the therapeutic alliance as viewed by the couples and the therapists was monitored at the 3rd session. Results indicate that levels of marital distress neither impaired nor facilitated alliance formation. In addition, it was demonstrated that patients' and therapists' ratings of the strength of the therapeutic alliance constitute a determinant of successful treatment. It appears, however, that the strength of the alliance is a more powerful predictor of therapeutic success among men than among women.

Adult↗
PubMed1992

Therapeutic empathy and recovery from depression in cognitive-behavioral therapy: a structural equation model.

This study demonstrated that therapeutic empathy has a moderate-to-large causal effect on recovery from depression in a group of 185 patients treated with cognitive-behavioral therapy (CBT). The authors simultaneously estimated the reciprocal effect of depression severity on therapeutic empathy and found that this effect was quite small. In addition, homework compliance had a separate effect on clinical recovery, over and above the effect of therapeutic empathy. The patients of novice therapists improved significantly less than did the patients of more experienced therapists, when controlling for therapeutic empathy and homework compliance. Ss who terminated therapy prematurely were less likely to complete the self-help assignments between sessions, rated their therapists as significantly less empathic, and improved significantly less. Ss with borderline personality disorder improved significantly less, but they rated their therapists as just as empathic and caring as other patients. The significance of these findings for psychotherapy research, treatment, and clinical training is discussed.

Adolescent↗
PubMed1997

Contribution of the therapeutic alliance to outcome in active versus control psychotherapies.

Few studies have examined the role of the therapeutic alliance scores in active versus control psychotherapies. Using data from a randomized clinical trial of psychotherapy and pharmacotherapy for cocaine dependence, it was found that therapeutic alliance scores were rated as significantly more positive in cognitive-behavioral treatment than clinical management, a psychotherapy control condition. However, level of the therapeutic alliance was associated with outcome for the control but not the active psychotherapy. These data suggest that control conditions, which are intended to control for common factors of psychotherapies such as the therapeutic alliance, may exert their effect on outcomes primarily through the level of those common factors.

Adult↗
PubMedDate not supplied

Outpatient commitment: a therapeutic jurisprudence analysis.

This article analyzes the legal and therapeutic jurisprudence considerations raised by outpatient commitment. Although older forms of outpatient commitment have both legal and therapeutic advantages, preventive outpatient commitment raises serious legal problems and potential antitherapeutic consequences that may outweigh its claimed therapeutic value. As a result, alternatives are proposed, including wider availability of community treatment and outreach and case management services, assertive community treatment, police and mental health court diversion programs, and creative uses of advanced directive instruments and behavioral contracting. Proposals also are made for how preventive outpatient commitment can be applied more therapeutically, including hearings that accord patients a sense of procedural justice and techniques designed to motivate individuals facing such hearings to agree to accept treatment voluntarily.

Advance Directives↗
PubMed1998

Analysis of histological therapeutic effect, apoptosis rate and p53 status after combined treatment with radiation, hyperthermia and 5-fluorouracil suppositories for advanced rectal cancers.

The tumour-suppressor gene p53 encodes a transcription factor that plays a critical role in the induction of G1 cell cycle arrest and apoptosis after DNA damage. To clarify the role of the p53 gene and apoptosis in combined hyperthermia, chemotherapy and radiation (hyperthermochemoradiotherapy, HCR therapy) for rectal cancer, we examined the histological response, rate of apoptosis, DNA fragmentation and p53 status in tumours from 28 patients undergoing HCR therapy before surgery and from 22 patients who did not have preoperative treatment. The therapeutic effect of HCR therapy was closely correlated with the rate of apoptosis; the correlation was statistically significant, suggesting that this effect occurs through apoptosis. The incidence of p53 mutations in the treated group were as follows: in tumours resistant to HCR therapy, four of seven (57.1%); intermediately sensitive, 7 of 13 (53.9%); or sensitive, three of eight (37.5%), suggesting that the therapeutic effect and apoptosis rate were related to the p53 status of the tumours to some extent, but the relation was not statistically significant. In the 22 control tumours (non-treated group), the apoptosis rate was 2.0 +/- 1.1%, and there was no significant difference in p53 status compared with the HCR group. Our study indicates that the pathological response to HCR therapy correlates with the rate of apoptosis with statistical significance and that it induces the therapeutic effect more significantly in rectal cancer cells with wild-type p53, although HCR therapy-induced apoptosis also occurs in some rectal cancers with mutated p53. Therefore, this combination therapy can induce an additive or synergistic anti-tumour effect in rectal cancers with wild-type p53 as well as in those with mutated p53 through apoptosis, offering new therapeutic opportunities and a better prognosis.

Antimetabolites, Antineoplastic↗
PubMed2025

Digestive cancers: mechanisms, therapeutics and management.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

Humans↗
PubMed2025

RNA chemistry and therapeutics.

RNA-based therapeutics have made substantial clinical advances, primarily due to the unique chemical and biological profiles of RNA molecules. As evidenced by the approval of various RNA drugs, some initial challenges related to RNA-based therapeutics, including issues associated with large-scale production, effective delivery and immunogenicity properties, are now being addressed. Extensive efforts have focused on chemically modifying RNA molecules to enhance their stability, increase protein production, extend circulation time and improve target specificity. Three RNA categories - small RNA, translatable RNA and CRISPR guide RNA - are now being extensively developed for therapeutic applications. This Review summarizes the synthetic methods applied to these three RNA categories, describes key chemical modification strategies being used to enhance their properties and highlights current therapeutic applications and future opportunities.

Humans↗
PubMed1999

Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics.

Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative and qualitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical and clinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m(-2)) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was subsequently tolerated in patients. For the 20 drugs where clinical DLT was reached, the median ratio of the human MAD to the mouse MTD/LD10 was 2.6 (range 0.2-16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3-160). In contrast, in 13 subsequent phase I trials with 11 of the initial 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6-56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary.

Animals↗
PubMed2003

Hematopoietic stem cell gene therapy: progress toward therapeutic targets.

The concept of hematopoietic stem cell gene therapy is as exciting as that of stem cell transplantation itself. The past 20 years of research have led to improved techniques for transferring and expressing genes in hematopoietic stem cells and preclinical models now routinely indicate the ease with which new genes can be expressed in repopulating stem cells of multiple species. Both modified murine oncoretroviruses and lentiviruses transmit genes into the genome of hematopoietic stem cells and allow expression in the host following transplantation. Using oncoretroviruses, therapeutic genes for severe combined immunodeficiency, common variable gamma chain immunodeficiency, chronic granulomatous disease, Hurler's and Gaucher's Disease have all been used clinically with only modest success except for the patients with immunodeficiency in whom a partial T-cell chimerism has been dramatic. Since stem cell selection in vivo appears important to the therapeutic success of gene transfer, drug resistance selection, most recently using the MGMT gene, has been developed and appears to be safe. Future trials combining a drug resistance and therapeutic gene are planned, as are trials using safety-modified lentiviruses. The therapeutic potential of hematopoietic stem cell gene therapy, particularly given recent advances in stem cell plasticity, remains an exceptionally exciting area of clinical research.

Genetic Therapy↗
PubMed2001

Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling.

Knowledge of the emerging pathways of cell death downstream of the p53 tumor suppressor and the TRAIL death-inducing ligand is suggesting ways to improve therapeutic design in cancer. In contrast to its unique G1 cell cycle arresting mechanism that is maintained by p21(WAF1), there are signals transduced by p53 to multiple apoptotic effectors perhaps due to the importance of apoptosis in suppressing tumors. There is evidence for cytoplasmic as well as mitochondrial activation of caspases downstream of p53, although in some cell lineages the signal ultimately involves the mitochondria. The TRAIL signaling pathway appears promising for therapeutic development despite sharing some similarities with the toxic Fas and TNF pathways, in terms of effector molecules and downstream signals. One of the key findings is the tissue specificity of cell death responses, a feature that could be exploited in strategies to widen the therapeutic window of combination cancer therapies. Efforts continue to develop p53-targeted cancer therapy, and novel clues to enhance or block specific effectors may improve therapeutic design.

Animals↗
PubMed2004

The 'effectiveness' scale--therapeutic outcome of pharmacologic therapies for ED: an international consensus panel report.

Despite availability of outcome measures and scales for assessing erectile dysfunction (ED) treatment efficacy, guidelines are not available for assessing broader therapeutic outcomes or defining treatment failure in ED. An International Consensus Advisory Panel was convened to develop guidelines, definitions and a new algorithm for evaluating treatment effectiveness in ED. These new guidelines are recommended for use in both research and clinical practice. A multidisciplinary, international panel, consisting of 11 senior researchers and clinicians, was convened to address pertinent issues concerning therapeutic outcome assessment for ED. The panel utilized a modified Delphi method of consensus development and proposed a new model for outcomes assessment. This model is inherently testable, using existing instruments and current methods of assessment. Following a comprehensive literature review and discussion, the Panel recommended adoption of a new treatment effectiveness conceptual framework or theoretical model for assessing therapeutic outcomes in ED. Treatment effectiveness is presumed to be a combined function of two other factors, treatment response and treatment satisfaction. Treatment response is based on the combined assessment of efficacy and tolerability, and treatment satisfaction on the combined assessment of patient and partner satisfaction. Taken together, these two domains define an overall domain of treatment effectiveness. This therapeutic index would be derived by independently assessing treatment efficacy and satisfaction by means of event logs, questionnaires or the more typical patient interview methods. In conclusion, the Ad Hoc Advisory Consensus Panel recommends adoption of a new framework or conceptual model for conducting ED outcome trials or clinical research. The concept of 'treatment effectiveness' is proposed as a new 'umbrella concept' or distal outcome to be evaluated.

Consensus Statements as Topic↗
PubMed2001

The bone marrow stromal microenvironment influences myeloma therapeutic response in vitro.

The bone marrow microenvironment supports growth and differentiation of normal hematopoietic cells and can contribute to malignant growth. Since myeloma cells localize and accumulate in bone marrow, it is important to understand the influence of the bone marrow microenvironment not only on the growth of the malignant cells, but also on the therapeutic response of myeloma cells. Growth factors such as interleukin-6 (IL-6) produced by bone marrow stromal cells can protect myeloma cells from glucocorticoid-induced apoptosis. We examined the effect of myeloma cells-bone marrow stromal cells interaction in vitro on several therapeutic treatments. An interleukin-6-dependent myeloma cell line ANBL6 was used and treated with dexamethasone, doxorubicin, and melphalan in the presence of bone marrow stromal cells. Stromal cells were able to protect ANBL6 from dexamethasone, but significantly enhanced the effect of doxorubicin and melphalan. IL-6-induced bcl-XL and cyclin D2 expression in ANBL6 cells, but dexamethasone was able to suppress both bcl-XL and cyclin D2 expression in ANBL6. Doxorubicin and melphalan were able to suppress bcl-XL expression only in the presence of IL-6. We also looked at the effect of activating mutations of N-ras in myeloma cells interacting with stromal cells on therapeutic responses. Surprisingly, ANBL6 N-ras shows significant resistance to all drugs used. Notably, the presence of stromal cells did not alter ANBL6 Nras cells' drug resistance. These results suggest both the bone marrow microenvironment and genetic alterations of myeloma cells can independently impact on therapeutic responses.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Benzodiazepine types in high versus therapeutic dose dependence.

Two types of benzodiazepine dependence have been described: high vs. therapeutic dose dependence. So far, no systematic research has been conducted regarding the frequency with which the various benzodiazepines are represented in one type or the other. In this study, 153 dependent patients using 14 different benzodiazepines were evaluated to assess the prevalence of their use among high vs. therapeutic dose dependents. Triazolam was the single drug most frequently used by high-dose dependents, followed by Lorazepam. No significant differences were found among benzodiazepines regarding their use by therapeutic dose dependents. Our data shows that pharmacokinetic and pharmacodynamic factors appear to be related to the frequency with which the different benzodiazepines are used by high and therapeutic dose dependents.

Adult↗
PubMed1998

Best practice in therapeutic drug monitoring.

It is the goal of Therapeutic Drug Monitoring (TDM) to use drug concentrations to manage a patient's medication regimen and optimise outcome. Limited resources require that drug assays should only be performed when they do contribute to patient management. For this to be the case a therapeutic drug monitoring service has a far greater role than just therapeutic drug measuring. This article describes the roles and functions of a Best Practice TDM service. The features which can and should be strived for in each step of the TDM process-the decision to request a drug level, the biological sample, the request, laboratory measurement, communication of results by the laboratory, clinical interpretation and therapeutic management-are discussed.

Drug Monitoring↗