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PubMed2006

Therapeutic radiation physics primer.

Therapeutic radiological physics is the branch of physics as applied to radiation therapy. Therapeutic radiological physics involves the understanding of the radiation sources, types, and characteristics of radiation, interaction of radiation with matter, and thereafter the deposition of energy in matter. In clinical practice, therapeutic radiological physics deals with the technical tasks of preparing a patient to undergo radiation therapy. These tasks include simulation, patient data acquisition, individualized planning, verification, and dose delivery. The role of a therapeutic radiological physicist is to manage the technical aspects of patient care: providing technical expertise to the development of the institution, recommending and introducing new treatment techniques, and ensuring that all patients undergoing radiation therapy receive the best standard of care.

Health Physics↗
PubMed2006

Therapeutic and pathogenetic animal models for Dolichos pruriens.

The therapeutic and pathogenetic effects of Dolichos pruriens were evaluated using experimental models in rats. In the therapeutic experiment Wistar rats were housed in a heated environment (25+/-3 degrees C) to induce itch, and treated with ascending potencies D. pruriens (6 cH, 9 cH, 12 cH and 30 cH), each for 10 days. The positive control group received vehicle (ethanol 30% in water). The negative control group received no treatment and were kept at a standard temperature. In the pathogenetic experiment, all animals were kept at a temperature of 20+/-3 degrees C and treated for 30 consecutive days with D. pruriens 6 or 30 cH, or ethanol vehicle, or no treatment. The experiments were performed blind. The statistical analysis used Bartlett's test, followed by ANOVA/Tuckey-Krammer or Kruskal-Wallis/Dunn. The results point to the existence of therapeutic effects, with inhibition of the itching, skin lesions and fur thinning produced by heat, more evident in later observations, with the 9 12, and 30 cH potencies (Kruskal-Wallis/Dunn; P=0.001). No changes were observed in the other parameters, such as open field activity and laterality of the itching. In the pathogenetic experiment, no changes were observed in any parameters examined. We conclude that the proposed experimental model demonstrates the therapeutic effect of D. pruriens, but not its pathogenetic effects.

Analysis of Variance↗
PubMed2006

Assessing the impact of training on mental health nurses' therapeutic attitudes and knowledge about co-morbidity: a randomised controlled trial.

BACKGROUND: Substance misuse can trigger or be causally associated with mental health problems. Therapeutic attitude is important in predicting effective engagement with people with alcohol and drug problems but health professionals' attitudes towards this client group are often negative. Education regarding substance misuse has often been neglected and nurses may lack knowledge to provide appropriate care. OBJECTIVES: To test the impact of training for staff who work with people who have co-existing mental health and substance use problems. DESIGN: A randomised controlled trial. SETTING: An NHS Primary Care Division in the West of Scotland. PARTICIPANTS: Forty-nine mental health nurses. METHODS: Intervention. A four-day training programme. MEASUREMENTS: (a) therapeutic attitudes measured by the co-morbidity problems perceptions questionnaire; (b) knowledge of alcohol, drugs and co-morbidity measured by a structured questionnaire. RESULTS: Significant effects for group (F=30.42, p<0.001) were found in therapeutic attitude scores and also over time (F=10.66, p<0.001). A significant interaction was also found (p<0.001). Post-hoc testing revealed that the mean pre-training attitude score was significantly different from post-training (p=0.001; 95% CI 5.53, 25.38) and from six-months follow-up (p<0.001; 95% CI 11.26, 32.49) but that post-training and follow-up mean scores were not significantly different (p=0.358; 95% CI -4.71, 17.55). For knowledge, a significant group effect was found (F=10.32, p=0.002), and also a significant time effect (F=3.35, p=0.039) but no significant interaction effect was present (p=0.169). The post-hoc testing revealed that only a pre-training to six-month follow-up time effect was statistically significant (p=0.005; 95% CI 1.37, 9.29). CONCLUSIONS: The training programme was effective in improving the therapeutic attitudes of participants to working with clients who have co-existing mental health and substance use problems, both immediately after the training was delivered, and at six-months follow-up. It was also effective in improving participants' overall knowledge of alcohol, drugs and co-morbidity.

Analysis of Variance↗
PubMed2006

Therapeutic targeting of pattern-recognition receptors.

Innate immune system could recognize the pathogen-associated molecular patterns by pattern-recognition receptors like Toll-like receptor (TLR) and nucleotide-binding oligomerisation domain (NOD) protein. Information regarding the structure and signalling pathways of TLRs and NODs could provide opportunities for new therapeutic approaches to modulate the innate immunity. Therapeutic targeting could be done by prevention of ligand binding to leucine-rich repeats domains of receptors, blocking the interactions between receptors (like Toll/interleukin-1 receptor domains of TLRs) and adaptors in signalling pathways, blocking the enzymes in signalling pathways, and immunostimulation with vaccine adjuvants. These therapeutic approaches could be useful in the treatment of different human diseases like immunological disorders, infections, and cancers. Further research on these receptors and their signalling pathways could help scientists to identify new candidates for therapeutic targeting.

Adjuvants, Immunologic↗
PubMed2003

Introducing baselines for therapeutic use of regulatory T cells and cytokines in autoimmunity.

The concept of therapeutic immune regulation aiming to treat autoimmune diseases has been validated in multiple animal models, yet, the development of strategies for treatment of human autoimmune diseases remains problematic. Main obstacles are the contradictory findings in different model systems, as well as the contrasting functions of regulatory lymphocytes and cytokines. By drawing examples primarily from experimental type 1 diabetes, we propose that regulatory cells and cytokines can be classified according to the baseline at which they operate in healthy individuals and disease states that are not accompanied by severe systemic immune deficiency or skewing. Consequently, deletion or neutralization of regulatory cells or cytokines operative at high levels to maintain systemic homeostasis should constitute a therapeutic strategy for immune enhancement (e.g. tumor- and pathogen-specific immunity), whereas boosting these factors will have limited effects if the therapeutic goal is a downmodulation of immune responses (e.g. autoimmunity). Conversely, regulatory cells and cytokines operative at low homeostatic levels should unfold therapeutic capacities by further embellishment but not additional reduction.

Animals↗
PubMed2006

High throughput therapeutic drug monitoring of clozapine and metabolites in serum by on-line coupling of solid phase extraction with liquid chromatography-mass spectrometry.

The characteristics of automated on-line solid phase extraction with liquid chromatography-mass spectrometry (SPE-LC-MS) are very amenable for flexibility and throughput in therapeutic drug monitoring (TDM). We demonstrate this concept of automated, on-line SPE-LC-MS for the analysis of clozapine and metabolites (desmethylclozapine and clozapine-N-oxide) in serum. Method development, optimisation and validation are described and a comparison with previously published methods for the determination of clozapine and metabolites in serum and plasma is made. Optimisation of chromatographic and SPE conditions for increased throughput resulted in SPE-LC-MS cycle times of only about 2.2 min, demonstrating the great potential of automated on-line SPE-LC-MS for TDM. The new method is shown to be clearly favourable, in particular in terms of ease of sample handling, throughput and detection limits. Recovery is essentially quantitative. Detection limits are at about 0.15-0.3 ng ml(-1), depending on the ionisation source used. Calibration follows a quadratic model for clozapine and its N-oxide and a linear model for the desmethyl metabolite (all cases: R > 0.99). Accuracy, evaluated at three concentration levels spanning the whole therapeutic range, shows that bias is less than 10%. Precision (intra - and inter assay) ranges from about 5% R.S.D. at the high end of the therapeutic range (700-1,000 ng ml(-1)) to about 20% R.S.D. (OECD defined limit) at the lower limit of quantitation ( approximately 50 ng ml(-1)). The lower limit of quantitation is well below the low end of the therapeutic range at 350 ng ml(-1).

Antipsychotic Agents↗
PubMed2004

Alzheimer's disease pathogenesis and therapeutic interventions.

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system associated with progressive cognitive and memory loss. Molecular hallmarks of the disease are characterized by extracellular deposition of the amyloid beta peptide (Abeta) in senile plaques, the appearance of intracellular neurofibrillary tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus and other areas of brain essential for cognitive and memory functions. Abeta deposition causes neuronal death via a number of possible mechanisms including oxidative stress, excitotoxicity, energy depletion, inflammation and apoptosis. Despite their multifactorial etiopathogenesis, genetics plays a primary role in progression of disease. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). Plaques are formed mostly from the deposition of Abeta, a peptide derived from APP. The main factors responsible for Abeta formation are mutation of APP or PS1 and PS2 genes or ApoE gene. All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. In addition to genetic influences on amyloid plaque and intracellular tangle formation, environmental factors (e.g., cytokines, neurotoxins, etc.) may also play important role in the development and progression of AD. A direct understanding of the molecular mechanism of protein aggregation and its effects on neuronal cell death could open new therapeutic approaches. Some of the therapeutic approaches that have progressed to the clinical arena are the use of acetylcholinesterase inhibitors, nerve growth factors, nonsteroidal inflammatory drugs, estrogen and the compounds such as antioxidants, neuronal calcium channel blockers or antiapoptotic agents. Inhibition of secretase activity and blocking the formation of beta-amyloid oligomers and fibrils which may inhibit fibrilization and fibrilization-dependent neurotoxicity are the most promising therapeutic strategy against the accumulation of beta-amyloid fibrils associated with AD. Furthermore, development of immunotherapy could be an evolving promising therapeutic approach for the treatment of AD.

Alzheimer Disease↗
PubMed2025

Potential therapeutic targets for ovarian hyperstimulation syndrome revealed by proteome-wide mendelian randomization and colocalization analysis.

Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with assisted reproductive technologies, characterized by metabolic, immune and vascular disorders. Understanding the molecular mechanisms underlying OHSS could reveal potential therapeutic targets and improve patient outcomes. In this study, We aimed to utilize proteome-wide Mendelian randomization (MR) and colocalization analysis to identify plasma proteins associated with OHSS and evaluate their potential as therapeutic targets through druggability assessment. We employed proteome-wide MR analysis summary data-based Mendelian randomization (SMR) analysis and phenome-wide association study (PheWAS) analysis to establish causal relationships between plasma proteins and OHSS. Colocalization analysis confirmed overlaps between proteins and genetic signals associated with OHSS. Pathway and network analyses were conducted to explore biological functions and protein interactions, while drug-target databases were queried for potential therapeutic interventions. Our results showed that 4 key proteins, including Suprabasin (SBSN), SLAMF4 (CD244), Enolase 3 (ENO3) and Thioredoxin domain-containing protein 12 (TXNDC12) were identified as significant contributors to OHSS. Pathway enrichment and interaction analyses further supported their involvement in metabolic, immune and structural pathways related to OHSS. Drug availability for colocalized proteins reveled potential drug targets for ENO3 (2-deoxy-D-glucose), CD244 (lenalidomide) and TXNDC12 (Auranofin), while no potential drug targets were identified for SBSN. Over all, our study identified15 plasma proteins, including SBSN, CD244, ENO3, and TXNDC12, as key contributors to the risk of OHSS through MR and colocalization analysis. These proteins were involved in metabolic regulation, immune response and antioxidant pathways, highlighting potential therapeutic targets and suggesting new directions for treatment strategies.

Humans↗
PubMed2006

Therapeutic effect of multiple resiniferatoxin intravesical instillations in patients with refractory detrusor overactivity: a randomized, double-blind, placebo controlled study.

PURPOSE: Previous study has shown that multiple intravesical instillations of resiniferatoxin (Sigma) at 10 nM has therapeutic effects in patients with detrusor overactivity. To our knowledge the placebo effect of multiple instillations of low dose resiniferatoxin for neurogenic and nonneurogenic detrusor overactivity has not been investigated. In this randomized, double-blind, placebo controlled study we evaluated the therapeutic effects of this resiniferatoxin treatment. MATERIALS AND METHODS: A total of 54 patients with detrusor overactivity refractory to anticholinergics were enrolled and randomly treated with 4 weekly intravesical instillations of 10 nM resiniferatoxin (26) or vehicle, consisting of 10% ethanol in normal saline, as the control group (28). The clinical effects of treatment on incontinence grade, incontinence episodes, general satisfaction, lower urinary tract symptoms and urodynamic parameters were assessed. RESULTS: Three months after completing the 4 intravesical treatments the resiniferatoxin treatment group had a significantly higher percent of patients with excellent and improved results compared to the control group (19.2% vs 7.1% and 42.3% vs 14.2%, respectively, each p < 0.001). Treatment remained effective at 6 months in 13 patients (50%) in the resiniferatoxin group but in only 3 (11%) in the control group (p < 0.001). Bladder capacity was significantly increased and symptom scores significantly improved 3 months after treatment in the resiniferatoxin group but not in the control group. CONCLUSIONS: Multiple intravesical instillations of 10 nM resiniferatoxin were effective for improving the incontinence grade in 62% of patients at 3 months, of whom 50% maintained a therapeutic effect 6 months after treatment. The therapeutic effect of resiniferatoxin was significantly superior to that of placebo.

Administration, Intravesical↗
PubMed2006

Compensation of endogenous IgG mediated inhibition of antibody-dependent cellular cytotoxicity by glyco-engineering of therapeutic antibodies.

A major limitation to the application of therapeutic IgG antibodies (Abs) is their reduced in vivo efficacy compared to their high efficacy as measured in vitro. Recently, Preithner et al. showed that the high amount of endogenous serum IgG impairs the antibody-dependent cellular cytotoxicity effector function (ADCC) of therapeutic Abs in vivo by competing for binding to Fcgamma-RIII on the effector cells. Modification of the glycosylation moieties attached to the Fc part of the Ab, e.g. de-fucosylation, has been shown to increase ADCC activity. We here show that the ADCC activity of a fucose-deficient, moss-produced therapeutic IgG is not impaired by normal human serum. The increased ADCC activity of the fucose-deficient Ab variant even in the presence of high endogenous IgG indicates that glyco-engineering of Abs may translate into improved clinical efficacy. Noteworthy, moss production of glyco-modified Abs should be applicable to a broad variety of therapeutic Abs currently in use indicative for the potential of this technology platform.

Antibodies, Monoclonal↗
PubMed2004

Salivary glands: novel target sites for gene therapeutics.

Directing the local or systemic expression of therapeutic proteins is a potentially important clinical application of gene transfer technology. Gene-based therapeutics theoretically offer many advantages over protein therapeutics. Numerous tissues have been evaluated for this purpose in animal models, most commonly the liver and skeletal muscle. Based on pre-clinical studies, we suggest that salivary glands are a valuable, yet under-appreciated, target tissue for both systemic and upper gastrointestinal tract gene therapeutic applications.

Animals↗
PubMed2026

Engineering extracellular vesicles for targeted siRNA delivery: Advances, therapeutic applications, and clinical translation.

Small interfering RNA (siRNA) therapeutics have emerged as a transformative approach for sequence-specific gene silencing, offering the potential to treat a broad spectrum of diseases by selectively suppressing disease-associated genes. However, the clinical translation of siRNA remains limited by rapid enzymatic degradation, poor cellular uptake, inadequate endosomal escape, and off-target effects, necessitating the development of efficient delivery systems. Extracellular vesicles (EVs) have gained considerable attention as natural nanocarriers owing to their excellent biocompatibility, low immunogenicity, intrinsic targeting capability, and ability to protect therapeutic cargo while traversing complex biological barriers. This review comprehensively discusses the biological characteristics of EVs, the molecular basis of RNA interference, and the major challenges associated with siRNA delivery [Fig. 1]. Recent advances in EV engineering, including cargo-loading strategies such as electroporation, sonication, extrusion, parent-cell engineering, and microfluidic approaches, together with surface functionalization using peptides, antibodies, aptamers, and hybrid nanoplatforms, are critically evaluated for improving targeting specificity and intracellular delivery. Furthermore, the therapeutic applications of engineered EV-mediated siRNA delivery in cancer, neurological disorders, liver diseases, cardiovascular diseases, inflammatory disorders, and infectious diseases are systematically summarized, highlighting their potential to enhance gene silencing while minimizing systemic toxicity. Current challenges related to large-scale manufacturing, cargo-loading efficiency, standardization, quality control, regulatory approval, and clinical translation are also discussed, together with emerging technologies involving synthetic biology, genome engineering, artificial intelligence, and multifunctional hybrid vesicles. Overall, engineered extracellular vesicles represent a highly versatile and biologically inspired platform for targeted siRNA delivery, providing a promising foundation for the development of next-generation precision RNA therapeutics and accelerating the clinical translation of gene-silencing strategies.

Extracellular vesicle engineering↗
PubMed2006

Therapeutic arthrography and bursography.

Arthrography and bursography as therapeutic venues have found their place in the musculoskeletal procedure armamentarium. Therapeutic arthrography not only rules in and rules out the origin of pain but can provide 6 to 9 months of pain relief in diseased joints. Therapeutic arthrography allows injections of anesthetic, corticosteroid, or alternatively hyaluronic acid to be delivered accurately to the source of pain. Corticosteroids have a long history of use in osteoarthritis. Alternative therapy with hyaluronic acid is anew procedure. This article reviews the technique of arthrography in different joints and bursae and discusses the pros and cons of the use of corticosteroids versus viscosupplementation in therapeutic arthrography.

Adjuvants, Immunologic↗
PubMed2006

Clinical relevance of rehabilitation programs for patients with idiopathic Parkinson syndrome. II: Symptom-specific therapeutic approaches.

Clinical symptoms of the idiopathic Parkinson's syndrome (IPS) are numerous. Clinical experience as well as pharmacological research identified symptoms not responsive to dopaminergic stimulation. These symptoms in particular were the target of rehabilitative therapy approaches. Several of these approaches have been evaluated in prospective studies. In the present paper, these studies and the respective therapeutic interventions were categorized and rated concerning their clinical relevance and their study design supporting a differential therapeutic approach. Symptoms were arranged relating to their clinical relevance and specific therapeutic approaches were described and rated. The rating was based on a novel developed approach to check for clinical relevance. In addition, areas in need of further and more intensive scientific research, as depression, cognitive deficits, and tremor, were identified. On the contrary, conclusive therapeutic approaches were available for the treatment of symptoms like gait and postural disturbances and dysarthria. Some advice for the therapy of muscular weakness, dexterity problems and dysphagia was given, but further studies are warranted in these fields.

Clinical Trials as Topic↗
PubMed2006

Patient and professional perspectives on prescribed therapeutic footwear for people with diabetes: a vignette study.

OBJECTIVE: This article draws on a qualitative study to identify and discuss patient and health professional views of the use of therapeutic footwear for people with diabetes-related foot complications. METHODS: Semi-structured interviews were conducted with 15 patients and 15 health professionals using a 'vignette' technique. The interviews were audio-taped, and framework analysis was used to identify main themes and categories. RESULTS: The prescription of therapeutic footwear was an important issue for patients, and health professionals were aware of this. The main issues were the differing perspectives between patients and professionals in terms of the expectations and reality of preventive behaviour, and difficulties in fitting shoes when feet are constantly changing shape. CONCLUSIONS: Patients often have difficulty changing their shoe-wearing behaviour in line with guidelines, particularly within the limits of available therapeutic shoes. The choice of available shoes may not meet the varied and specific needs of patients. Patient perspectives therefore need to be taken into account in shoe provision. PRACTICE IMPLICATIONS: The concept of concordance would appear to be useful in allowing patient needs to be identified before designing and prescribing therapeutic shoes. More choice in styles, and involving patients in footwear design and selection, might encourage the use of appropriate footwear.

Activities of Daily Living↗
PubMed2004

Combination of therapeutic mild hypothermia and delayed fluid resuscitation improved survival after uncontrolled haemorrhagic shock in mechanically ventilated rats.

We challenged the current management of uncontrolled haemorrhagic shock (UHS) and put forward a hypothesis that therapeutic mild hypothermia combined with delayed fluid resuscitation will improve the survival rate. After an initial blood withdrawal of 3 ml/100g for 15 min, the rat's tail was amputated up to 75% to induce UHS phase I. The mean arterial blood pressure (MAP) was maintained at 40 mmHg or 80 mmHg, according to the assigned study group. This was followed by homeostasis of the tail wound and increase of the MAP up to 100 mmHg during resuscitation phase II. Finally, phase III was an observation of phase up to 72 h. Rats were anaesthetised and randomised into four groups. Group 1 received immediate fluid resuscitation and normothermia. Group 2 received immediate fluid resuscitation and therapeutic mild hypothermia. Group 3 received limited fluid solutions to maintain MAP at 40 mmHg and normothermia. Group 4 also received limited fluid solution, but the rats were subjected to therapeutic mild hypothermia. In groups 2 and 4, the body temperature was kept at 34 degrees C throughout the UHS phase I and resuscitation phase II. At the end of the observation phase III, the brains of the animals were fixed and analysed histologically. The blood loss from the tail during the UHS phase I was significantly higher in groups 1 and 2. The survival rate was 33.3, 83.3, 58.3 and 91.7%, respectively in groups 1-4. In all surviving rats, no histological brain damage was observed. These results indicate that therapeutic mild hypothermia or delayed fluid resuscitation increase the survival rate in this model. However, when mild hypothermia and limited fluid resuscitation were combined, the survival rate was the highest.

Analysis of Variance↗
PubMed2004

Toxicology of antisense therapeutics.

Targeting unique mRNA molecules using antisense approaches, based on sequence specificity of double-stranded nucleic acid interactions should, in theory, allow for design of drugs with high specificity for intended targets. Antisense-induced degradation or inhibition of translation of a target mRNA is potentially capable of inhibiting the expression of any target protein. In fact, a large number of proteins of widely varied character have been successfully downregulated using an assortment of antisense-based approaches. The most prevalent approach has been to use antisense oligonucleotides (ASOs), which have progressed through the preclinical development stages including pharmacokinetics and toxicological studies. A small number of ASOs are currently in human clinical trials. These trials have highlighted several toxicities that are attributable to the chemical structure of the ASOs, and not to the particular ASO or target mRNA sequence. These include mild thrombocytopenia and hyperglycemia, activation of the complement and coagulation cascades, and hypotension. Dose-limiting toxicities have been related to hepatocellular degeneration leading to decreased levels of albumin and cholesterol. Despite these toxicities, which are generally mild and readily treatable with available standard medications, the clinical trials have clearly shown that ASOs can be safely administered to patients. Alternative chemistries of ASOs are also being pursued by many investigators to improve specificity and antisense efficacy and to reduce toxicity. In the design of ASOs for anticancer therapeutics in particular, the goal is often to enhance the cytotoxicity of traditional drugs toward cancer cells or to reduce the toxicity to normal cells to improve the therapeutic index of existing clinically relevant cancer chemotherapy drugs. We predict that use of antisense ASOs in combination with small molecule therapeutics against the target protein encoded by the antisense-targeted mRNA, or an alternate target in the same or a connected biological pathway, will likely be the most beneficial application of this emerging class of therapeutic agent.

Animals↗
PubMed2005

Therapeutic cloning: the ethical limits.

A brief outline of stem cells, stem cell therapy and therapeutic cloning is given. The position of therapeutic cloning with regard to other embryonic manipulations - IVF-based reproduction, embryonic stem formation from IVF embryos and reproductive cloning - is indicated. The main ethically challenging stages in therapeutic cloning are considered to be the nuclear transfer process including the source of eggs for this and the destruction of an embryo to provide stem cells for therapeutic use. The extremely polarised nature of the debate regarding the status of an early human embryo is noted, and some potential alternative strategies for preparing immunocompatible pluripotent stem cells are indicated.

Cloning, Organism↗