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Infection concomitant with pediatric renal allograft rejection.

Renal allograft rejection episodes are frequent in children and often lead to allograft failure. Frequent association of fever with rejection in our transplant program provoked a prospective evaluation of concurrent infection during rejection episodes. Because cytomegalovirus has an established role in rejection and allograft survival, evaluation of cytomegalovirus and other herpes viruses (human simplex virus type 1, varicella, Epstein-Barr virus, and human herpes virus type 6 [HHV-6]) was undertaken in addition to standard bacterial investigation. A total of 37 patients were followed over a 30-month period. Six of eight rejection episodes were associated with herpes viruses (HHV-6, n = 6, and Epstein-Barr virus, n = 1). Three of the herpes-group-associated rejection episodes were treated with antiviral therapy in addition to pulse steroid treatment, with full recovery. The three patients with HHV-6-associated rejection episodes who were treated with pulse steroids, but no antiviral therapy, developed chronic allograft rejection. The recipient's response to allograft antigens may be influenced by concomitant herpes infection, and specific antiviral therapy appears to be indicated when infection is confirmed in association with rejection. An antiviral treatment program coupled with modulation of standard antirejection immunotherapy has the potential to improve morbidity and mortality in the pediatric renal transplant population.

Adolescent↗

Molecular targets for AIDS therapy.

The development of antiretroviral therapy against acquired immunodeficiency syndrome (AIDS) has been an intense research effort since the discovery of the causative agent, human immunodeficiency virus (HIV). A large array of drugs and biologic substances can inhibit HIV replication in vitro. Nucleoside analogs--particularly those belonging to the dideoxynucleoside family--can inhibit reverse transcriptase after anabolic phosphorylation. 3'-Azido-2',3'-dideoxythymidine (AZT) was the first such drug tested in individuals with AIDS, and considerable knowledge of structure-activity relations has emerged for this class of drugs. However, virtually every step in the replication of HIV could serve as a target for a new therapeutic intervention. In the future, non-nucleoside-type drugs will likely become more important in the experimental therapy of AIDS, and antiretroviral therapy will exert major effects against the morbidity and mortality caused by HIV.

Acquired Immunodeficiency Syndrome↗

[Research status and prospects of gene therapy in spinal cord injuries].

Gene therapy develops very rapidly during the resent years. Great prospects have been demonstrated from basic study and clinic test. However, the gene therapy in CNS is still in stage of laboratory. The research status and prospects of gene therapy in spinal cord injury (SCI) were introduced. The basic principle is to transplant certain cells genetically modified with NTFs to the site of the injuried spinal cord, then NTFs are expressed in vivo and stimulate axon regrowing. Virus vectors are usually used for gene transfer because of their high rate of transfection, and the receptor cells include fibroblast, myoblast, etc. Nowadays, gene therapy in SCI is studied in many laboratories and the problems include: 1. The ideal components of transfer gene. 2. The choice of carrier. 3. Immune reaction, and prolonged survival and persistent expression of the receptor cells in the spinal cord. If these problems could be solved, the gene therapy would become the key method in the therapy of SCI.

Animals↗

The safety and efficacy of botulinum toxin type B in the treatment of patients with cervical dystonia: summary of three controlled clinical trials.

Cervical dystonia (CD) is characterized by abnormal, involuntary contractions of the cervical and/or shoulder muscles. Direct injection of Botulinum toxin type A (BTX-A) into the affected muscles has been used successfully to treat this condition. However, clinical resistance to BTX-A therapy develops in a limited number of patients. Moreover, an unknown proportion of treated patients have a suboptimal response to their present therapy. BTX-B is antigenically distinct from BTX-A and possesses a different mechanism of action. Three randomized, double-blind, placebo-controlled clinical trials evaluated the safety and efficacy of BTX-B (Elan's BTX-B evaluated as NeuroBloc) as a treatment for patients with CD. Patients received a single dose of BTX-B ranging from 2,500 to 10,000 U. The primary efficacy evaluation for each of these studies used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score. Additional efficacy measures included the TWSTRS severity, disability, and pain subscale scores, as well as the Patient Analog Pain Assessment and Patient's and Physician's Global Assessments of Change. In all three studies, groups receiving BTX-B displayed statistically significant improvements in TWSTRS total score and other efficacy end points compared with those who received placebo treatment. The clinical benefits after BTX-B treatment lasted 12 to 16 weeks and were observed in both BTX-A-responsive and BTX-A-resistant patients. In general, treatment with BTX-B was well tolerated and most of the reported adverse events were of short duration, mild to moderate in severity, and anticipated. The results from the three controlled clinical trials demonstrate the safety and efficacy of BTX-B in the treatment of patients with CD, including those who are resistant to BTX-A treatment.

Botulinum Toxins↗

Endoscopic therapy in patients with inoperable early gastric cancer.

The efficacy and safety of endoscopic therapy was investigated prospectively in 42 patients with 44 early gastric cancers who were not candidates for surgery. Thirty-five of the 44 lesions (80%) were treated by endoscopic therapy alone. Adequate tumor resection was possible in lesions less than 2 cm in diameter, in those of the protruding, flat, and erosive types, and in those located in the antrum. None of the 35 patients who were judged completely cured by the initial therapy developed recurrence or lymph node metastases in the follow-up period (range, 3-114 months; mean, 37 months). Therefore, endoscopic therapy appears effective in the treatment of patients with early gastric cancer when the risks of surgery are too high.

Aged↗

Targeting large molecules to mitochondria.

Mitochondrial function is central to a range of cell processes and mitochondrial dysfunction contributes to a number of human diseases. Consequently there is growing interest in delivering large molecules such as nucleic acids, proteins, enzyme mimetics, drugs and probes to mitochondria within cells. The reasons for doing this are to understand how mitochondria function in the cell and to develop therapies for diseases involving mitochondrial damage. Here we review the methods that have been used to target large molecules to mitochondria and discuss some approaches under development.

Animals↗

Development of isolated ACTH deficiency in a man with type I diabetes mellitus.

A 45-year-old man with type I diabetes mellitus of 25-yr duration and well controlled by conventional insulin therapy developed an isolated adrenocorticotropic hormone (ACTH) deficiency. He presented with a 3-month history of weight loss, weakness, anorexia and persistent tendency to hypoglycemia that he had never experienced before. Basal and dynamic endocrine testing disclosed absent cortisol secretion caused by an isolated ACTH deficiency due to a primary pituitary defect. Corticosteroid replacement therapy allowed again a good glycometabolic control. The possible causes of hypoglycemia in insulin-treated diabetes and the pathogenetic basis of the reported association are discussed.

Adrenocorticotropic Hormone↗

[Kaposi's sarcoma developing during corticosteroid therapy in idiopathic thrombocytopenic purpura].

A case of Kaposi's sarcoma developing during corticosteroid therapy for idiopathic thrombocytopenic purpura is reported. The patient is a 58-year-old female who was admitted to Sapporo City General Hospital for bleeding tendency in March 1987. She had been treated before admission with prednisolone (over 40 mg/day) for idiopathic thrombocytopenic purpura since October 1986, but her platelet count was below 40,000/microliters. In April 1987, several dark red or blue nodules appeared on the tip of her nose, left forearm, right shoulder, trunk and tongue. These nodules rapidly grew. Biopsy specimens from the nodule of the left forearm showed the histologic changes of Kaposi's sarcoma. She was treated with irradiation. Splenectomy was done in May 1987 and prednisolone was decreased to 5 mg/day. Her platelet count was continually kept 50,000/microliters or more. Her Kaposi's sarcoma completely regressed in January 1988. The relationship of immunosuppressive therapy to Kaposi's sarcoma is discussed.

Female↗

[A mathematical model for predicting the efficacy of glucocorticoid therapy of glomerulonephritis].

A mathematical model is proposed for prediction of the efficacy of glucocorticoid therapy developed on the basis of the Bayes theorem and successive Wald's analysis. The model uses the retrospective values of the results of radioligand determination of the number of glucocorticoid receptor of lymphocytes and static renal scintigraphy. By means of the blind method the informative value of the mathematical model to predict the inefficacy of glucocorticoid therapy in nephrotic glomerulonephritis was 96%. A nomogram was developed.

Algorithms↗

Experience with lamivudine against hepatitis B virus.

After several nucleoside analogues have been tested against chronic hepatitis B virus (HBV) infection with minimal success, lamivudine seems to be a highly effective new therapeutic option. This review focuses on nucleoside metabolism and on the molecular action of lamivudine as well as on results of clinical studies for several indications. We report on results of trials on the use of lamivudine for chronic HBV infection, chronic HBV under immunosuppression and prophylaxis or treatment of HBV reinfection before or after orthotopic liver transplantation. Aspects of combination therapy of different nucleoside analogues as well as on combination of lamivudine with interferon are also highlighted. Although lamivudine seems to be highly effective in most patients at the start of therapy, development of resistance by mutations in the viral polymerase is a significant clinical problem. The mode of resistance development is compared with the situation in HIV infection. Possible cross-resistance with other nucleoside analogues and the perspectives of lamivudine therapy are also considered.

2-Aminopurine↗

Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine.

High response rates have been reported with hepatic intra-arterial infusions of floxuridine in patients having colorectal carcinoma metastatic to the liver. The major toxicity of this therapy has been described as "chemical hepatitis." In a randomized trial of intravenous v intra-arterial floxuridine, we observed that all 35 patients receiving intra-arterial therapy developed significant increases in alkaline phosphatase and, in some cases, serum glutamic oxaloacetic transminase and/or bilirubin. Seven patients receiving intra-arterial therapy were studied with cholangiography which, in all cases, demonstrated sclerosis of the intrahepatic and/or extrahepatic bile ducts. In addition, liver biopsies showed cholestasis and pericholangitis with minimal hepatocyte damage. These findings suggest that "biliary sclerosis" rather than "chemical hepatitis" is the predominant toxicity associated with hepatic intra-arterial infusions of floxuridine.

Aged↗

[Acute posttraumatic myocardial infarct: the necessity of an early interventionist posture].

We describe five cases of posttraumatic anterior acute myocardial infarction in young patients, without previous heart disease. One case was treated with intracoronary thrombolysis and angioplasty, 3 cases received systemic thrombolysis, and the last one did not have any re-permeabilization therapy, having arrived to the hospital 72 hours after the episode. The coronary angiograms showed at the left anterior descending artery: thrombosis in 3 cases, coronary dissection in one case, and slow flow with no morphological lesions in the other. The case which not received thrombolytic therapy developed a severe left ventricular dysfunction. In conclusion we emphasize an early angiographic study, in order to decide the re-permeabilization therapy.

Accidents, Traffic↗

[Metabolic encephalopathy: oxcarbazepine (Trileptal)-induced hyponatremia].

A patient is described with metabolic encephalopathy which developed as a result of hyponatraemia induced by oxcarbazepine (OXC). The literature reveals that up to 80% of the patients in OXC therapy develop hyponatraemia. Elderly patients and patients receiving high doses of OXC are at particular risk in this respect. The majority of patients are asymptomatic and the hyponatraemic condition does not demand changes in treatment. Control of serum natrium levels prior to and during treatment with OXC is recommended, particularly when side-effects occur.

Adult↗

New therapies in tendon reconstruction.

Despite the use of various types of grafts, no surgical treatment currently exists to restore a tendon to its normal condition. Tissue engineering techniques are being used to develop therapies for tendon reconstruction. Biologic and synthetic scaffolds can both repair tendon defects and improve healing by allowing for the regeneration of the tendon's natural biologic composition to restore its mechanical capacity. This process can be further enhanced through augmentation methods such as cell seeding, growth factor implantation, and gene therapy.

Genetic Therapy↗

[Diagnosis and therapy of audiogenic communication development].

The diagnosis and therapy of audiogenic communication development require close interdisciplinary cooperation between physicians, specialist teachers, psychologists, psycholinguists, speech-language pathologists and logopedists. With regard to the treatment of speech problems, initial emphasis is on the development of an understanding of speech, enlargement of vocabulary, promotion of auditive discrimination and the development of syntax. In the case of deaf children too, promotion of speech communication by means of sounds is to the fore. However, the use of an additional sign language should not be denied a deaf child. The decision whether a def child should be sent to a "normal" School or to a special institution for the deaf will be determined largely by the speech competence of the child, and will include his/her intellectual, emotional and social skills. The aim of all supportive measures is to achieve the full integration of hearing-impaired children in society.

Child↗

[Combined immunosuppressive therapy in patients with pemphigus vulgaris and its side effects].

Pemhigus vulgaris is an autoimmune bullous disease of the integument. When not treated, it has a high mortality, the treatment with corticosteroids and immunosuppressives has serious side effects. Our casuistry gives a case of patients with histologically verified diagnosis of pemphigus vulgaris. In this case the stabilization of the disease was difficult and side effects of the combined immunosuppressive therapy developed very early.

Adrenal Cortex Hormones↗

Current status of polymeric gene delivery systems.

Gene therapy provides great opportunities for treating diseases from genetic disorders, infections and cancer. To achieve successful gene therapy, development of proper gene delivery systems could be one of the most important factors. Several non-viral gene transfer methods have been developed to overcome the safety problems of their viral counterpart. Polymer-based non-viral gene carriers have been used due to their merits in safety including the avoidance of potential immunogenecity and toxicity, the possibility of repeated administration, and the ease of the establishment of good manufacturing practice (GMP). A wide range of polymeric vectors have been utilized to deliver therapeutic genes in vivo. The modification of polymeric vectors has also shown successful improvements in achieving target-specific delivery and in promoting intracellular gene transfer efficiency. Various systemic and cellular barriers, including serum proteins in blood stream, cell membrane, endosomal compartment and nuclear membrane, were successfully circumvented by designing polymer carriers having a smart molecular structure. This review explores the recent development of polymeric gene carriers and presents the future directions for the application of the polymer-based gene delivery systems in gene therapy.

Animals↗

Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations.

Drug resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol mutations of HIV-1 strains from patients treated for 1 year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine resistance or a zidovudine resistance pol mutation at codon 215 (P = .6). In contrast, a ddI resistance mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P < .001). Two patients receiving combination therapy developed resistance to zidovudine and ddI; they had HIV strains with amino acid mutations at codons 62, 75, 77, 116, and 151. Combination therapy with zidovudine and ddI selects for zidovudine-resistant HIV-1 strains lacking a ddI resistance mutation and for multidrug-resistant strains containing novel pol mutations.

Amino Acids↗