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PubMed1979

Potential for therapeutic gain similar to pions by daily combinations of neutrons and low-LET radiations.

Biological studies with negative pi mesons (pions) at the Los Alamos Meson Physics Facility (LAMPF) have shown a relatively constant reduction of shoulder of the survival curve for single cell cultures and relatively constant reduction in the no response region for multicellular tumor spheroids (MTS) with little change in sensitivity (or slope), in both single dose and fractionated experiments. In clinical studies, a trend toward therapeutic gain for pions has been demonstrated in patients treated at LAMPF, with marked, rapid turmor regression for relatively mild acute normal tissue injury and no untoward effects observed over 7 to 24 months. Since the pion beams used therapeutically at LAMPF are characterized by a small amount of high-linear-energy-transfer (LET) radiation (in the range 10 to 20%), it is hypothesized that pion radiation as compared to x-rays increased the differential tolerance to sublethal injury in favor of normal tissues, resulting in therapeutic gain. It is further proposed that the near simultaneous application of high-LET radiation (such as neutrons) and low-LET radiation (such as x-rays) might create a bilogical situation similar to that of pion treatment, potentially resulting in therapeutic gain, although without the added benefit of dose localization obtainable with pions.

Animals↗
PubMed1991

Keynote address: modulation of normal tissue toxicity by combined modality therapy: considerations for improving the therapeutic gain.

The aim of combined modality treatment schedules is to achieve increased killing in the tumor cell populations without an equivalent increase in normal tissue damage. There is, however, some increased risk of normal tissue toxicity that must be taken into account when assessing the therapeutic potential. An understanding of the mechanisms involved in combined modality therapy, for example, increased radiosensitivity, inhibition or stimulation of cellular proliferation, or independent additive toxicities, should improve the chances of of achieving a therapeutic gain. A review of the literature of normal tissue effects after combined treatment with drugs and radiation has lead to the following general conclusions: a) The sequence and timing of the two agents have a marked influence on the extent of normal tissue damage, with the most damage occurring when simultaneous drug and irradiation are given within a few days of each other; b) Separation of the two modalities can lead to an improved therapeutic gain since tumor effects are less strongly dependent on the interval between drug and X rays; and c) Chemotherapy can markedly alter the time of expression of radiation damage, particularly in slowly dividing normal tissues, where more rapid expression of injury occurs after combined modality therapy. The above concepts and some possible ways for improving the therapeutic gain in future trials are discussed in this review.

Animals↗
PubMed1994

The effects of therapeutic touch and relaxation therapy in reducing anxiety.

This study examines the effects of two noninvasive procedures on experienced anxiety. Thirty-one inpatients of a Veterans Administration psychiatric facility were randomly assigned to one of two treatment conditions, (therapeutic touch and relaxation therapy) or to a therapeutic touch placebo condition. An additional 13 patients were excluded because of failure to meet criteria for the study or failure to complete the procedures. Each subject completed a self-report anxiety measure and was rated for amount of motor activity before and after each of two 15-minute treatment sessions in a 24-hour period. Subjects' belief in the effectiveness of the intervention was measured. Expectancy did not correlate with outcome and was not analyzed further. Multivariate analysis of variance (MANOVA) showed that whereas relaxation therapy provided significant reduction of anxiety on the self-report measure and the movement measure, the nursing intervention of therapeutic touch resulted in significant reductions of reported anxiety. The control group showed small but nonsignificant effects. Results suggests that both relaxation and therapeutic touch are effective palliatives to experienced anxiety. Implications for nursing theory are discussed.

Adult↗
PubMed1991

Therapeutic potential of vitamin E against myocardial ischemic-reperfusion injury.

Myocardial ischemia is a disease process characterized by reduced coronary flow such that the supply of nutritive blood to heart muscle (myocardium) is insufficient for normal myocardial aerobic metabolism. Prompt reestablishment of coronary flow by invasive and noninvasive clinical procedures is the most direct and effective means of limiting myocardial damage in ischemic heart disease patients, although reperfusion carries with it an injury component which may reflect, at least to some degree, the toxic effects of partially reduced oxygen species and their participation in degenerative cellular processes such as membrane lipid peroxidation. Vitamin E, a lipophilic, chain-breaking antioxidant, is a prominent membrane constituent in heart muscle, where it modulates/regulates various aspects of heart muscle-cell metabolism and function. Vitamin E's beneficial effects against experimentally induced oxidative damage to the heart, along with inverse epidemiological correlations between plasma vitamin E level and either anginal pain or mortality due to ischemic heart disease, suggest that vitamin E might have protective and therapeutic roles against myocardial ischemic-reperfusion injury. Laboratory investigations aimed at addressing this possibility have demonstrated that vitamin E supplementation protects isolated hearts against ischemic-reperfusion injury, and relatively more inconsistent and limited data document cardioprotective effects of vitamin E in some animal models of myocardial ischemia-reperfusion, especially when administered prior to the ischemic period. Clinical attempts to establish whether vitamin E has therapeutic benefit in ischemic heart disease patients remain inconclusive, having relied upon a variety of nonuniformly controlled protocols and a single, rather subjective endpoint (anginal pain). Consequently, although laboratory data constitute a conceptual context for and indirect support of the idea that vitamin E could be a cardioprotectant against ischemic-reperfusion injury, compelling clinical evidence regarding vitamin E's therapeutic potential in the ischemic heart-disease patient is lacking. Elective coronary revascularization would appear to provide an attractive clinical setting for evaluating the therapeutic efficacy of vitamin E in the context of cardiac ischemia-reperfusion. Further biochemical work would still be required to define how vitamin E exerts any cardioprotective effect observed in these patients.

Animals↗
PubMed2004

Therapeutic communication part 1: general approaches that enhance the quality of the consultation.

Consultations that place the patient at the centre of the interaction and actively explore their ideas, concerns, fears, cares and expectations strongly correlate with increased satisfaction, concordance, feelings of enablement and symptom resolution. Primary Care clinicians have developed these therapeutic consultation styles as a result of utilising the extensive research that has been undertaken in General Practice. In contrast, consultations in Accident and Emergency (A&E) have received little investigation and communication has a predominant bio-medical focus. This is the first of two papers which presents the results of a substantive review of the literature which explores therapeutic communication strategies appropriate to Emergency Care. This paper sets the scene by describing the current status of the Emergency Care consultation and reviews the proposed benefits of a consultation centred around the patient. The development of "Patient-Centred Communication" and its philosophical underpinnings are also discussed in order to provide further background. Finally, the general characteristics of therapeutic consultations identified in the substantive review of the literature review are analysed. The second paper describes five key communication strategies which when employed in clinical consultations in Emergency Care, could significantly enhance the therapeutic nature of the clinician-patient interaction.

Attitude of Health Personnel↗
PubMed2006

In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery.

Despite the interest in systemic delivery of therapeutic molecules including macromolecular proteins and peptides via the lung, the accurate assessment of their pulmonary biopharmaceutics is a challenging experimental task. This article reviews in vivo, in vitro and ex vivo models currently available for studying lung absorption and disposition for inhaled therapeutic molecules. The general methodologies are discussed with recent advances, current challenges and perspectives, especially in the context of their use in systemic pulmonary delivery research. In vivo approaches in small rodents continue to be the mainstay of assessment by virtue of the acquisition of direct pharmacokinetic data, more meaningful when attention is given to reproducible dosing and control of lung-regional distribution through use of more sophisticated lung-dosing methods, such as forced instillation, microspray, nebulization and aerosol puff. A variety of in vitro lung epithelial cell lines models and primary cultured alveolar epithelial (AE) cells when grown to monolayer status offer new opportunity to clarify the more detailed kinetics and mechanisms of transepithelial drug transport. While continuous cell lines, Calu-3 and 16HBE14o-, show potential, primary cultured AE cell models from rat and human origins may be of greater use, by virtue of their universally tight intercellular junctions that discriminate the transport kinetics of different therapeutic entities. Nevertheless, the relevance of using these reconstructed barriers to represent complex disposition of intact lung may still be debatable. Meanwhile, the intermediate ex vivo model of the isolated perfused lung (IPL) appears to resolve deficiencies of these in vivo and in vitro models. While controlling lung-regional distributions, the preparation alongside a novel kinetic modeling analysis enables separate determinations of kinetic descriptors for lung absorption and non-absorptive clearances, i.e., mucociliary clearance, phagocytosis and/or metabolism. This ex vivo model has been shown to be kinetically predictive of in vivo, with respect to macromolecular disposition, despite limitations concerning short viable periods of 2-3 h and likely absence of tracheobronchial circulation. Given the advantages and disadvantages of each model, scientists must make appropriate selection and timely exploitation of the best model at each stage of the research and development program, affording efficient progress toward clinical trials for future inhaled therapeutic entities for systemic delivery.

Absorption↗
PubMed2004

Defining "therapeutically inconsequential" head computed tomographic findings in patients with blunt head trauma.

STUDY OBJECTIVE: Many injuries detected by computed tomographic (CT) imaging of blunt head trauma patients are considered "therapeutically inconsequential." We estimate the prevalence of these findings and determine how frequently affected patients had "important neurosurgical outcomes," defined as either a directed intervention or a poor Glasgow Outcome Scale score. METHODS: We prospectively enrolled all blunt head trauma patients undergoing emergency head CT imaging at 18 centers participating in the National Emergency X-radiography Utilization Study II (NEXUS). From these cases, we identified all patients whose official CT reading met predefined criteria for "therapeutically inconsequential" injuries. We obtained detailed follow-up information on all such patients at 6 sites, including the need for neurosurgical intervention and Glasgow Outcome Scale scores. Among patients having "important neurosurgical outcomes," we assessed the frequency of 2 potential clinical identifiers: altered mental status and coagulopathy. RESULTS: "Therapeutically inconsequential" head CT findings were present in 155 of 8,374 subjects (1.85%; 95% confidence interval 1.57% to 2.16%). Sites participating in the follow-up study enrolled 81 of these patients, of whom 10 (12%) had "important neurosurgical outcomes." Follow-up information was available for 9 patients, all of whom had abnormal mental status at CT scanning. Coagulopathy was also present in 5 of 7 patients for whom coagulation status was known. CONCLUSION: "Therapeutically inconsequential" findings are identified in less than 2% of blunt head trauma patients who undergo CT scanning. A small proportion of these patients have an "important neurosurgical outcome," but it appears that such patients may be identified clinically by the presence of abnormal mental status or coagulopathy.

Adolescent↗
PubMed2004

Using mindfulness-based therapeutic interventions in psychiatric nursing practice--part II: Mindfulness-based approaches for all phases of psychotherapy--clinical case study.

Finding effective nursing interventions for the treatment of mental illness is a major concern for advanced practice psychiatric nurses (APPN). Increasingly, innovative psychotherapeutic treatment modalities are being used for the treatment of individuals with serious mental illness. One such innovative approach, Mindfulness-based therapeutic interventions, has been shown to relieve distress for individuals with medical and psychiatric illnesses. In Part I of this two-part article, the authors described principle concepts of mindfulness, reviewed current research in the usefulness of mindfulness practice for treatment of psychiatric illnesses. The structure and content of mindfulness-based cognitive therapy (MBCT) was also outlined and provided the theoretical basis for this treatment approach. This alternative therapeutic approach offers potential usefulness for the treatment of individuals suffering from mental illness. Part II of this article presents a more detailed explanation of mindfulness-based therapeutic approaches for all phases of psychotherapy and identifies relevant research questions that will provide an empirical base to guide clinical practice. A case study illustrates mindfulness-based therapeutic interventions.

Aged↗
PubMed2004

Targeting of therapeutic gene expression to the liver by using liver-type pyruvate kinase proximal promoter and the SV40 viral enhancer active in multiple cell types.

To achieve the liver-directed expression in sufficient amounts of therapeutic genes for successful and safe gene therapy, natural liver-specific promoters can be used to direct the expression of therapeutic genes in the liver, whereas strong viral enhancers were used to obtain sufficient amounts of expressed therapeutic gene products. However, very often use of either the former or the latter does not guarantee both potent and liver-specific therapeutic gene expression. Here we conglomerate them and thus create a potent tissue-specific promoter by characterizing and using the liver-type pyruvate kinase proximal promoter (LPKPP) harboring its TATA box and a HNF-1alpha binding site. Alone it hardly activated its reporter gene expression in non-hepatocytes or hepatocytes. However, in the presence of the SV40 viral enhancer (SV40VE), which is active in multiple cell types, it was able to potently activate its reporter gene expression specifically in hepatocytes. The tissue-specific activation of the LPKPP by the viral enhancer was attributed to HNF-1alpha binding to the LPKPP. Taken together, these results support the idea that the constitutively active SV40VE could be used to activate the LPKPP in a tissue-specific manner in the presence of HNF-1alpha. To our knowledge, this is the first study to utilize HNF-1alpha and its binding site, in the context of the LPKPP, to generate a basal promoter that is transcriptionally activated potently in a tissue-specific manner by a viral enhancer that is active in multiple cell types.

Cell Line, Tumor↗
PubMed2005

Nanovector therapeutics.

An ideal injected therapeutic drug would travel through the vasculature, reach the intended target at full concentration, and there act selectively on diseased cells and tissues only, without creating undesired side effects. Unfortunately, even the best current therapies fail to attain this ideal behavior, by a wide margin. A primary reason is the fact that the target recognition abilities of the current therapeutics molecules are quite limited. Furthermore, the natural defenses of the body present a sequence of formidable obstacles on the drug's pathway to the intended lesion. Requiring any molecule to have sufficient therapeutic efficacy, target recognition specificity, as well as all of the tools required to bypass multiple biological barriers is probably unrealistic. A different approach is to decouple the problem (i.e. employ the drug molecules for their therapeutic action only, and deliver them to the intended site by vectors that can be preferentially concentrated at desired body locations through the concurrent action of multiple targeting mechanisms). These vectors must also be large enough to comprise all the requirements for the evasion of the body defenses, while still sufficiently small so as not to create undesired blockages of even the smallest of blood vessels - and thus, by definition, nanotechnological.

Animals↗
PubMed2005

Intrabodies as drug discovery tools and therapeutics.

Within the biomedical and pharmaceutical communities there is an ongoing need to find new technologies that can be used to elucidate disease mechanisms and provide novel therapeutics. Antibodies are arguably the most powerful tools in biomedical research, and antibodies specific for extracellular or cell-surface targets are currently the fastest growing class of new therapeutic molecules. However, the majority of potential therapeutic targets are intracellular, and antibodies cannot readily be leveraged against such molecules, in the context of a viable cell or organism, because of the inability of most antibodies to form stable structures in an intracellular environment. Advances in recent years, in particular the development of intracellular screening protocols and the definition of antibody structures that retain their antigen-binding function in an intracellular context, have allowed the robust isolation of a subset of antibodies that can function in an intracellular environment. These antibodies, generally referred to as intrabodies, have immense potential in the process of drug development and may ultimately become therapeutic entities in their own right.

Animals↗
PubMed2006

Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs.

OBJECTIVES: A volunteer trial was performed to compare the pharmacokinetics of 5 drugs--warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin--when administered at a microdose or pharmacologic dose. Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was or is likely to be problematic. METHODS: In a crossover design volunteers received (1) 1 of the 5 compounds as a microdose labeled with radioactive carbon (carbon 14) (100 microg), (2) the corresponding (14)C-labeled therapeutic dose on a separate occasion, and (3) simultaneous administration of an intravenous (14)C-labeled microdose and an oral therapeutic dose for ZK253, midazolam, and erythromycin. Analysis of (14)C-labeled drugs in plasma was done by use of HPLC followed by accelerator mass spectrometry. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of ZK253, midazolam, and erythromycin at therapeutic concentrations, whereas HPLC-accelerator mass spectrometry was used to measure warfarin and diazepam concentrations. RESULTS: Good concordance between microdose and therapeutic dose pharmacokinetics was observed for diazepam (half-life [t((1/2))] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 microg and t((1/2)) of 35.7 hours, CL of 1.3 L/h, and V of 123 L for 10 mg), midazolam (t((1/2)) of 4.87 hours, CL of 21.2 L/h, V of 145 L, and oral bioavailability [F] of 0.23 for 100 microg and t((1/2)) of 3.31 hours, CL of 20.4 L/h, V of 75 L, and F of 0.22 for 7.5 mg), and development compound ZK253 (F = <1% for both 100 microg and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 microg and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 microg and 17.9 L for 5 mg) was probably a result of high-affinity, low-capacity tissue binding. The oral microdose of erythromycin failed to provide detectable plasma levels as a result of possible acid lability in the stomach. Absolute bioavailability for the 3 compounds examined yielded excellent concordance with data from the literature or data generated in house. CONCLUSION: Overall, when used appropriately, microdosing offers the potential to aid in early drug candidate selection.

Administration, Oral↗
PubMed2003

Evolving therapeutic paradigms for HIV and HCV.

The continued development of enabling molecular technologies that can be employed to better understand viral replication and the action of currently available therapeutic agents promises to lead to the development of the next generation of drugs with improved therapeutic utility against human immunodeficiency virus (HIV) and hepatitis C virus (HCV). New therapeutic approaches have been developed for treating HIV and HCV infections, but key technical and therapeutic challenges must be addressed to further advance treatment options in each of these areas.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Therapeutic potential of nitric oxide in cancer.

In recent years, several novel approaches have been developed to overcome tumor cell resistance to conventional therapeutics. Such approaches include genetic manipulations, vaccine development and exploitation of the anti-tumor host immune response. The overall development of tumor cell resistance to therapeutics is, in large part, the result of the ability of tumor cells to develop specific mechanisms to overcome cell death or apoptosis. Therefore, the possibility to interfere selectively in the regulation of the apoptotic signaling pathways may result in either the direct induction of cell death and/or sensitization of the cells to cytotoxic stimuli. A novel approach based on modifying gene products that regulate resistance to apoptosis involves nitric oxide (NO). NO is a ubiquitous molecule with diverse cellular effects that depend on the source, concentration, latency, cell type and phenotype. This review describes the role played by NO in cancer including carcinogenesis, pathogenesis, angiogenesis, chemoprevention and as a novel therapeutic to overcome resistance when used alone or as a sensitizing agent used in combination with other therapeutics.

Animals↗
PubMed2005

Success of a multidisciplinary heart failure clinic for initiation and up-titration of key therapeutic agents.

BACKGROUND: Heart failure has a poor prognosis, yet drugs known to improve outcomes are either not prescribed, or prescribed at sub-therapeutic doses. The National Service Framework (NSF) for coronary heart disease recommended specialist heart failure clinics to address this problem but their efficacy has not been evaluated. OBJECTIVES: To determine the effectiveness of a protocol-driven heart failure clinic staffed by nurse and pharmacist specialists for improving symptoms and optimising treatment with key therapeutic agents, without adversely affecting renal function. RESULTS: Of the 234 patients with at least one follow-up visit, 127 (57%) were receiving none or only one key therapeutic agent when first seen, this was reduced to 25 patients (11%) at most recent follow-up. The improvement in prescription rates was accompanied by significant up-titration of dose, the proportion of patients on "medium" or "high" doses rising from 43 (18%) to 134 (57%) for beta-blockers, and from 129 (55%) to 201 (86%) for ACE-inhibitors/angiotensin receptor blockers. Clinical improvement was reflected in reductions in patients with NYHA functional classes III and IV (93 (40%) to 53 (23%)), and in patients with moderate or severe symptoms. Significant reductions in alcohol consumption and cigarette smoking were recorded. Up-titration of treatment was associated with reductions in heart rate and systolic blood pressure; increases in serum potassium and creatinine concentrations were small. CONCLUSION: In a heart failure clinic staffed by nurse and pharmacist specialists, it is possible to achieve target doses of key therapeutic agents and improve symptoms without adversely affecting electrolytes or renal function.

Adrenergic beta-Antagonists↗
PubMed2005

The therapeutic antibodies market to 2008.

The therapeutic biologics market is currently dominated by recombinant protein products. However, many of these products are mature, and growth of the biologics market will increasingly rely on the expansion of the therapeutic monoclonal antibody sector. Successive technology waves have driven the growth of the monoclonal antibody sector, which is currently dominated by chimeric antibodies. Chimeric products, led by Remicade and Rituxan, will continue to drive market share through to 2008. However, over the forecast period, humanized and fully human monoclonal antibodies, together with technologies such as Fabs and conjugated antibodies, will play an increasingly important role, driving monoclonal antibody market growth at a forecast compound annual growth rate of 20.9%, to reach $16.7 billion by 2008. In terms of therapeutic focus, the monoclonal antibody market is heavily focused on oncology and arthritis, immune and inflammatory disorders, and products within these therapeutic areas are set to continue to be the key growth drivers over the forecast period. Underlying the growth of the market is the evolution of the monoclonal antibody company business model, set to transition towards the highly successful innovator model.

Animals↗
PubMed2005

The therapeutic potential of RNA interference.

In recent years, we have witnessed the discovery of a new mechanism of gene regulation called RNA interference (RNAi), which has revitalized interest in the development of nucleic acid-based technologies for therapeutic gene suppression. This review focuses on the potential therapeutic use of RNAi, discussing the theoretical advantages of RNAi-based therapeutics over previous technologies as well as the challenges involved in developing RNAi for clinical use. Also reviewed, are the in vivo proof-of principle experiments that provide the preclinical justification for the continued development of RNAi-based therapeutics.

Animals↗
PubMed2005

Intestinal immunity of Escherichia coli NISSLE 1917: a safe carrier for therapeutic molecules.

The development of novel approaches that allow accurate targeting of therapeutics to the intestinal mucosa is a major task in the research on intestinal inflammation. For the first time, a live genetically modified bacterial strain has been approved by Dutch authorities as a therapeutic agent for experimental therapy of intestinal bowel disease (IBD) in humans. Genetically modified probiotics can very well be used as carriers for localized antigen delivery into the intestine. Therapeutic safety, however, of such a carrier organism, is crucial, especially when a specific probiotic strain has to be used under diseased conditions. In this study, we tested the potential of Escherichia coli NISSLE 1917 to serve as a safe carrier for targeted delivery of recombinant proteins to the intestinal mucosa. In a well-defined and very sensitive immunological system, we demonstrate that intestinal recombinant E. coli NISSLE 1917 has no effect on migration, clonal expansion and activation status of specific CD4+ T cells, neither in healthy mice nor in animals with acute colitis. Furthermore, recombinant E. coli NISSLE 1917 has no effect on the induction or breakdown of peripheral T-cell tolerance in an autoimmune environment. The excellent colonization properties of E. coli NISSLE 1917 render this strain an ideal candidate as carrier organism for gut-focused in situ synthesis of therapeutic molecules.

Animals↗