[Undecylenic acid therapy of fungus diseases developing after antibiotic therapy].
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Anti-Bacterial Agents↗
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[Corticoids in topical dermatological therapy. I. The development of topical corticoid therapy].
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Adrenal Cortex Hormones↗
[Photons and protons in radiation therapy. The prospects for developing a proton therapy based on a new Russian accelerator].
Body distribution of absorbed energy of ionizing radiation determines relations between the desired effect and associated radiation lesions. Common methods of photon radiotherapy are characterized by strong irradiation of healthy tissues. Accelerated protons enables an increase in gradient of doses between the radiation-exposed subject and adjacent tissues. It is thought valid to promote wider use of the new Russian proton accelerator for upgrading radiotherapy.
Equipment Design↗
Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma.
PURPOSE: To assess whether pre-high-dose therapy (HDT)-related factors play a critical role in the development of therapy-related myelodysplasia (tMDS) or secondary acute myelogenous leukemia (sAML). PATIENTS AND METHODS: Twenty-nine of 230 patients with a primary diagnosis of non-Hodgkin's lymphoma (NHL) developed tMDS/sAML after HDT comprising cyclophosphamide and total-body irradiation (TBI) supported by autologous hematopoietic progenitor cells. G-banding and fluorescence in-situ hybridization (FISH) were used to detect clonal cytogenetic abnormalities. RESULTS: The majority of patients showed complex karyotypes at diagnosis of tMDS/sAML containing, in particular, complete or partial loss of chromosomes 5 and/or 7. Using single locus-specific FISH probes, significant levels of clonally abnormal cells were found before HDT in 20 of 20 tMDS/sAML patients screened, compared with three of 24 patients screened who currently have not developed tMDS/sAML, at a median follow-up of 5.9 years after HDT. CONCLUSION: Prior cytotoxic therapy may play an important etiologic role and may predispose to the development of tMDS/sAML. Using a triple FISH assay designed to detect loss of chromosomal material from 5q31, 7q22, or 13q14, significant levels of abnormal cells can be detected before HDT and may predict which patients are at increased risk of developing secondary disease. Further prospective evaluation of this FISH assay is warranted to determine its predictive power in this setting.
Chromosome Aberrations↗
Technology evaluation: cystic fibrosis therapy, Genzyme.
Genzyme is developing therapies to replace the defective forms of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein in CF patients. The company is developing a gene therapy, as well as a recombinant production of CFTR for protein replacement therapy. Both approaches have been granted orphan drug status by the FDA [156348]. The results of several clinical trials were discussed at the first annual meeting of the American Society of Gene Therapy in May 1998. A single dose nasal administration was well tolerated by volunteers, but had disappointing efficacy. In a study completed at the Royal Brompton Hospital, London, a single dose aerosol application of GL-67:DOPE was administered to eight patients, while another eight received GL-67:DOPE plus pCF1-CFTR. In the second group, a moderate increase in the potential difference in the lung was observed, with a slight trend towards bacterial adherence normalization in the airway cells. Seven of the patients in the second group, and three patients who received lipid alone, developed, flu-like symptoms within 24 h. A trial at the University of Alabama, using the same formulation, showed that flu-like symptoms developed in six of eight patients by day two, and in all patients by day seven [290120]. In 1995, the company began a clinical safety trial involving delivery of a normal CF gene to the patient's lungs via an adenovirus vector. The administration involves the inhalation of an aerosol containing the vector or, separately, delivery to one lobe of the patient's lung via a bronchoscope [191678]. To evaluate additional delivery methods for the gene, Genzyme has an exclusive research agreement for the use of Vical's cytofectins as non-viral delivery vectors for CFTR. Also under investigation are delivery systems for the nasal epithelium using liposomes or lipid-DNA complexes. These protocols are being developed in collaboration with the National Heart & Lung Institute, London, and an undisclosed partner [162590], [177633]. Following in vitro screenings by the company, two T-shaped molecules were identified (GL-67 and GL-53), the gene transfer activities of which could be enhanced by dioleoyl-PE (DOPE). A recently-completed clinical trial in 16 CF patients demonstrated that the GL-67:DOPE:DMPE-PEG5000-pCF1-CFTR compound accumulated in the lung with minimal toxicity and resulted in a 25% correction of CF symptoms [268093]. Genzyme has also developed recombinant cell lines that synthesize CFTR and has used transgenic expression techniques to breed mice, rabbits and goats which secrete the protein in their milk. Protein replacement therapy is currently in preclinical investigation and research efforts have been reduced infavor of the gene therapeutic approach [177633].
Clinical Trials as Topic↗
Breast cancer developing after therapy for Hodgkin's disease.
Two patients developed breast cancer 14 and 8 years after treatment of Hodgkin's disease. Both had received mediastinal irradiation and MOPP chemotherapy. Because of the increased risk of breast cancer in women treated for Hodgkin's disease, as reported in the literature, we suggest the early initiation of periodic screening for breast cancer, to detect possible neoplasms at a more treatable stage.
Adolescent↗
The development of conformal radiation therapy.
The development and clinical use of conformal radiation therapy, and the application of modern computer-controlled radiation therapy treatment techniques to the delivery of conformal therapy, has been a major research area in the field of radiation oncology in recent years. The introduction of three-dimensional (3-D) patient imaging, 3-D treatment planning systems, computer-controlled treatment machines equipped with multileaf collimators, and the continuing increase in computer power and software sophistication has finally allowed the clinical implementation of the kinds of conformal treatment planning and delivery that were envisioned decades ago. The use of 3-D treatment planning in conjunction with conformal treatments and the analysis of clinical normal tissue complications has also begun to give the field the clinical complication (and eventually tumor control) probability data which can be used to truly optimize radiation treatments. At this centennial anniversary of the discovery of the x ray, it is appropriate to look back at the contributions which have led to the current developments in conformal therapy. Few if any of the "new developments" associated with modern computer-controlled conformal therapy (CCRT) are actually new. However, modern technology has finally progressed to the point that we can integrate all of the features that are necessary to really make the concepts work in the clinic. This paper traces some of the developments which have led to the current interest and progress in CCRT treatments. A brief summary of the current status of conformal therapy and the work still to be done is also included.
History, 19th Century↗
Family medicine and family therapy: comparative development, methods, and roles.
Family medicine and family therapy have evolved separately, but the fields are now increasingly in contact with each other. Today's family physician needs a deeper grasp of their similarities and differences. This paper compares the two disciplines in terms of their (1) membership criteria for treatment, (2) considered appropriateness for treatment, (3) contractual process, and (4) evolution of membership over time. Also explored are the disciplines' notions of illness and change; their differing attitudes toward technique are analyzed as well. Family therapists and family physicians appear likely to have increased exposure to one another. As they do, common approaches may develop, and conceptual differences may present a mutual stimulus for growth and change.
Behavior Therapy↗
Docetaxel in breast cancer and a rationale for combination therapy.
Development of the taxoids has progressed rapidly in the 1990s. In vitro studies have demonstrated that docetaxel (Taxotere) has a longer residence time and higher accumulation within tumor cells than paclitaxel (Taxol), possibly accounting for its greater cytotoxicity. Animal studies have shown docetaxel to possess high antitumor activity. In clinical studies, docetaxel as a single agent has been shown to be highly active against a variety of solid tumors. It is at least as active in metastatic disease as other agents currently used, and it has demonstrated effectiveness against tumors resistant to anthracyclines or paclitaxel. Docetaxel shows some activity in cell lines resistant to fluorouracil (5-FU), vincristine, cisplatin (Platinol), and etoposide (VePesid). Its unique mechanism of action and lack of cross-resistance or overlapping toxicities with many agents may also contribute to its efficacy and safety in combination therapy.
Animals↗
Successful complex decongestive physiotherapy for lymphedema and lymphocutaneous reflux of the female external genitalia after radiation therapy.
Development of secondary lower extremity lymphedema after cervical cancer is common. However, severe lymphedema of the female genitalia and vesicular cutaneous lymphatic reflux without lower limb lymphedema after treatment of cervical cancer is rare. We report successful complex decongestive physiotherapy (CDP) in a 53-year-old female who developed recurrent folliculitis, lymphocutaneous reflux, warty change of the right labium majora, and lymphedema involving the external genitalia after receiving hysterectomy, pelvic lymph node dissection, and radiation. CDP included skin care, manual lymphatic drainage, exercise, and use of a hip spica bandage and panty girdle garment. Oral antibiotics were prescribed to control the skin infection. Lymphatic discharge and folliculitis were markedly improved after a 3-week course of treatment. Traditional conservative treatment with pneumatic compression and massage is ineffective and not suitable in controlling lymphedema of the external genitalia. Use of CDP may help to relieve the symptoms and recurrent infection in patients with this condition.
Carcinoma, Squamous Cell↗
[Double cancer in small cell lung cancer patients treated with intensive chemotherapy with or without radiation therapy].
Development of double cancer was evaluated in 311 small cell lung cancer patients who had received intensive chemotherapy with or without radiotherapy. Of those, 10 patients (3.2%) developed a second malignancy:stomach cancer in four, non-small cell lung cancer in three, acute myelogenous leukemia in two, and liver cancer in one. The cumulative risk for the development of double cancer was 1.0% at 1-year, 17.0% at 3-years, and 100% at 8.1 years. The relative risk for the development of double cancer calculated by person-year method utilizing age and sex adjusted cancer incidence in Japan was 2.96-fold (p less than 0.01). The risk of non-small cell lung cancer (6.65-fold) and acute myelogenous leukemia (54.9-fold) was particularly high. Of 21 patients who survived disease-free for more than 2 years, 8 patients died; four patients (50%) died of second malignancy, two died of infectious disease, and only two patients died from recurrent small cell lung cancer. These results indicate that a cautious follow-up program for the detection of double cancer is indicated in patients surviving small cell lung cancer.
Adult↗
Angiogenesis--a new target for future therapy.
Development of blood vessels from in situ differentiating endothelial cells (EC) is called vasculogenesis, whereas sprouting of new blood vessels from the pre-existing ones is termed angiogenesis or neovascularisation. Angiogenesis, the growth of new blood vessels, is essential during tissue repair, foetal development, and female reproductive cycle. In contrast, uncontrolled angiogenesis promotes tumor and retinopathies, while inadequate angiogenesis can lead to coronary artery disease. A balance between pro-angiogenic and anti-angiogenic growth factors and cytokines tightly controls angiogenesis. With the identification of several proangiogenic molecules such as the vascular endothelial cell growth factor (VEGF), the fibroblast growth factors (FGFs), and the angiopoietins, and the recent description of specific inhibitors of angiogenesis such as platelet factor-4, angiostatin, endostatin, and vasostatin, it is recognized that therapeutic interference with vasculature formation offers a tool for clinical applications in various pathologies. Inhibition of angiogenesis can prevent diseases such as cancer, diabetic nephropathy, arthritis, psoriasis, whereas stimulation of angiogenesis is beneficial in the treatment of coronary artery disease (CAD), cardiac failure, tissue injury, etc. One of the most specific and critical regulators of angiogenesis is vascular endothelial growth factor (VEGF), which regulates endothelial proliferation, permeability, and survival. Substantial evidence also implicates VEGF as an angiogenic mediator in tumors and intraocular neovascular syndromes, and numerous clinical trials are presently testing the hypothesis that inhibition of VEGF may have therapeutic value.
Adiponectin↗
Genotypic and phenotypic analysis of human immunodeficiency virus type 1 isolates from patients on prolonged stavudine therapy.
Development of stavudine resistance was studied using human immunodeficiency virus type 1 isolates from 13 patients treated with stavudine for 18-22 months. Drug sensitivity testing on 11 of these pre- and posttherapy isolates identified only 2 posttreatment isolates with decreased stavudine sensitivity (ED50s < 4-fold higher than the average pretreatment ED50). Genotypic analysis of all 13 pairs of isolates identified multiple mutations in the reverse transcriptase (RT) gene. However, no genetic basis was identified to account for the observed changes in stavudine susceptibility. A recombinant virus containing the entire RT gene of the posttherapy isolate displaying the greatest resistance remained sensitive to stavudine. Five of the stavudine posttreatment isolates developed resistance (9- to 176-fold) to zidovudine, although the relationship between stavudine treatment and the appearance of zidovudine resistance remains unexplained. Analysis of 10 additional pairs of isolates did not confirm this relationship. The low frequency and modest degree of change in stavudine sensitivity following prolonged treatment is very encouraging.
Acquired Immunodeficiency Syndrome↗
A model for the design and evaluation of algorithms for closed-loop cardiovascular therapy.
Developing a clinically useful closed-loop drug delivery system can be extremely time consuming and costly. One approach to reducing the time and cost associated with developing closed-loop systems is to reduce the number of animal experiments and perform an extensive set of simulation studies. Through simulations, a closed-loop controller's performance can be evaluated over a complete spectrum of the patient population, including boundary conditions. Simulation studies are repeatable, offering significant advantages in comparing modifications in control algorithms. Finally, simulation studies can be performed in a fraction of the time required for animal studies, at a fraction of the cost. We have developed a simulator, that included a nonlinear pulsatile-flow cardiovascular model, a physiological regulatory mechanism, and the pharmacology of four frequently titrated cardiovascular drugs. This simulator has already been used in the design and evaluation of two closed-loop algorithms-a self-tuning regulator (STR) and a multiple model adaptive controller (MMAC)-for blood pressure control during and after cardiac surgery.
Algorithms↗
Safety screening of drugs in cancer therapy.
Development of new drugs requires a thorough investigation of efficacy and safety of pharmaceuticals. The potential risks and benefits of drugs used in chemotherapy are carefully considered such that the benefits of using a new drug outweigh the risks in terms of the side effects caused by the drug. Damage to normal cells, tissues, organs and/or the whole organism is a big concern. Several tests are now routinely performed and are required for drug approval by various regulatory agencies around the globe. The primary goals of such preclinical safety evaluation of drugs are: (1) to identify an initial safe starting dose and subsequent dose escalation scheme to humans; (2) to identify potential target organs of toxicity and reversibility of toxicity; (3) to identify potential damage to the genetic material (genotoxicity); and (4) to identify parameters of clinical monitoring. In this paper, various models for genotoxicity assays are presented. These include: Ames assay, in vitro chromosome aberration assay and an in vivo micronucleus assay. New technologies, such as DNA adduct formation, DNA strand breakage, apoptotic changes, p53 gene expression and transgenic animal models, are also considered.
Aneuploidy↗
[Complications in thyroid surgery. Incidence and therapy].
Developments in thyroid surgery during the last 20 years have reduced the number of complications significantly with rates from the literature of less than 1 % of laryngeal nerve paralysis and hypoparathyroidism. Specific problems are connected, however, with patients presenting with recurrent goitres, requiring extended operations for Graves' disease and for malignant diseases. Our own experience in almost 6,000 operations during the last 12 years confirms the results from the literature with regard to more complicated thyroid surgery. Thus, laryngeal nerve paralysis in recurrent thyroid surgery is between 2 and 8 %, depending on the extent of surgery, which is necessary. In surgical treatment of hyperthyroidism, permanent laryngeal nerve paralysis may be reduced to less than 1 %, while hypoparathyroidism is still a severe problem in patients with Graves' disease, and due to the necessity for an extensive operation is approximately 2 % in all cases. The same is true for patients with thyroid malignancies who suffer from permanent laryngeal nerve paralysis in 2-5 % and permanent hypoparathyroidism in 1-4 %, the range related to primary, secondary completion, or recurrent operation. The danger of postoperative bleeding still deserves special attention because it may be followed by life-threatening acute asphyxia. It is essential that surgeons also take care of all operative consequences at least by recommending additional treatment.
Humans↗
New targets and delivery systems for antifungal therapy.
Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium.
Antifungal Agents↗
The biology of signal transduction inhibition: basic science to novel therapies.
Developing drugs to specifically inhibit oncogenes has been a major goal of cancer research for many years. Identifying the appropriate intracellular targets and understanding the signal transduction pathways in which these molecules participate are critical to this process. A large number of the activated oncogenes implicated in the pathogenesis and progression of malignancy are tyrosine kinases. Bcr-Abl, the causative molecular abnormality in chronic myeloid leukemia (CML), is a prototypic oncogenic kinase and an attractive drug target. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) was recently approved for the treatment of CML and provides proof of principle for the strategy of targeted signal transduction inhibition. This drug is effective in the chronic phase of CML, a single gene disorder driven by Bcr-Abl, and in the advanced phases of CML, showing that inhibition of a single oncogene in a multigene disorder also may be of benefit. The success of imatinib mesylate in CML led rapidly to clinical trials in other cancers associated with activation of two other tyrosine kinases known to be sensitive to imatinib mesylate, c-Kit and the platelet-derived growth factor receptor. Gastrointestinal stromal tumors, which have activating mutations in c-Kit, are now also being found to respond to kinase inhibition with the drug. The general approach of specifically targeting activated kinases with small-molecule drugs is likely to be effective in other tumors in the future.
Antineoplastic Agents↗