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At least 613 records · Page 34Linked to original sources
PubMed1999

New drugs for osteoporosis. Comparison of the costs and required returns with those of other drugs intended for long-term use.

Specific regulatory guidelines dictate that developing a new drug for osteoporosis will be significantly more expensive and take at least 2 years longer in comparison with other long-term therapies developed using the International Committee on Harmonisation (ICH) general guidelines. Assuming similar attrition rates, the minimal additional uncapitalised cost is $US86 million for nonestrogen osteoporosis compounds following a minimum programme designed to gain indications for both treatment and prevention. The excess expenditure is created by the size requirements for phase III fracture trials in both the European Union (EU)/US and Japan. The after-tax cash flows to the point of launch discounted at 11% are $US102 million greater, reflecting the additional effect of delayed time to market. Assuming similar lifecycles, the peak sales required to return the investment on an osteoporosis drug will be a minimum of $US95 million greater per launched compound. Many ongoing osteoporosis programmes are substantially larger than the theoretical minimum. The costs of substantially increasing the sample size in phase III trials mean that blockbuster revenues will be required to break even. However, the potential cost of a delayed launch because of fracture efficacy being incompletely proved is so substantial that fracture trials need to be powered conservatively to decrease the chances of this eventuality.

Clinical Trials as Topic↗
PubMedDate not supplied

Drug-induced motor complications in dopa-responsive dystonia: implications for the pathogenesis of dyskinesias and motor fluctuations.

Dopa-responsive dystonia (DRD) is characterized by striatal dopamine depletion with preserved nigrostriatal terminals. Patients with DRD typically obtain a marked long-term benefit from low doses of levodopa, with no motor complications. By contrast, motor fluctuations and dyskinesias often occur in idiopathic parkinsonism (Parkinson's disease; PD). This suggests that nigrostriatal denervation may be necessary for the development of these levodopa-related motor complications. Six genetically confirmed DRD cases were studied. Three of the five patients who were on chronic levodopa therapy developed choreic dyskinesias, which disappeared on reduction of medication. Apomorphine also induced dyskinesias. In addition, two patients experienced acute dystonic reactions after exposure to dopamine receptor-blocking drugs. No patient showed dose-response motor flutuations during levodopa treatment. It is proposed that striatal dopamine deficiency might play a major role in the pathogenesis of drug-induced dyskinesias. Conversely, the loss of nigrostriatal dopamine terminals seems to be a prerequisite for the development of levodopa-related motor fluctuations.

Adolescent↗
PubMed1985

Obstructive sleep apnea.

This chapter provides an account of obstructive sleep apnea that is designed for clinicians. Current ideas about the mechanism of upper airway obstruction are reviewed, and the clinical features are discussed in a manner intended to facilitate the clinical assessment of such patients. Various forms of treatment are reviewed, with major emphasis given to the use of nasal positive airway pressure, a form of therapy developed by the authors.

Airway Obstruction↗
PubMed2002

Type 1 diabetes intervention trials: what have we learned? A critical review of selected intervention trials.

Developing therapies to stop or slow the immune destruction of islets has been a goal of investigators in type 1 diabetes for several decades. This review of clinical interventions in patients with type 1 diabetes indicates both negative and positive outcomes with a variety of different therapeutic agents. An underlying theme of this article is that differences in study design may impact the outcome more than the therapy being tested. Thus, each of these results need to be considered in the context of important variables in study design. To date, there is no clear answer as to what study design is best to determine if an agent is effective against the diabetes disease process; however, the Immunology of Diabetes Society has recently developed guidelines for the conduct of these trials to facilitate comparisons of therapies in the future.

Age Factors↗
PubMed2001

[The present situation and the prospect of pain control in this country and other countries].

It is thought that the pain control is tried naturally in a lot of countries, but it is distress to know detailed fact of the present situation and the prospect. Nerve block therapy developed really in Japan is felt so that it is understood in Southeast Asia than the U.S.A. and West Europe. But in late years, it is thought as revision on nerve block began in Europe and America various countries. Recently, mechanisms of pain becoming clear, but administration of NSAIDs to every pain that was wrong therapy are still continued. In the pain treatment in every country, drug developed based on mechanism of pain and central analgesics will become center in the near future.

Americas↗
PubMed2003

Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias.

The majority of Parkinson's disease patients undergoing levodopa therapy develop disabling motor complications (dyskinesias) within 10 years of treatment. Stimulation of cannabinoid receptors, the pharmacological target of Delta 9-tetrahydrocannabinol, is emerging as a promising therapy to alleviate levodopa-associated dyskinesias. However, the mechanisms underlying this beneficial action remain elusive, as do the effects exerted by levodopa therapy on the endocannabinoid system. Although levodopa is known to cause changes in CB1 receptor expression in animal models of Parkinson's disease, we have no information on whether this drug alters the brain concentrations of the endocannabinoids anandamide and 2-arachidonylglycerol. To address this question, we used an isotope dilution assay to measure endocannabinoid levels in the caudate-putamen, globus pallidus and substantia nigra of intact and unilaterally 6-OHDA-lesioned rats undergoing acute or chronic treatment with levodopa (50 mg/kg). In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D1/D2 receptors. In 6-OHDA-lesioned rats, anandamide levels were significantly reduced in the caudate-putamen ipsilateral to the lesion; however, neither acute nor chronic levodopa treatment affected endocannabinoid levels in these animals. In lesioned rats, chronic levodopa produced increasingly severe oro-lingual involuntary movements which were attenuated by the cannabinoid agonist R(+)-WIN55,212-2 (1 mg/kg). This effect was reversed by the CB1 receptor antagonist rimonabant (SR141716A). These results indicate that a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB1 receptors.

Animals↗
PubMed2002

[Transplantation of highly purified CD34+ hematologic peripheral stem cells from haploidentical related donors in the treatment of children with non-malignant diseases].

BACKGROUND: Children suffering from rare inherited disorders can be cured using stem cell transplantation (SCT). For patients where HLA-identical donor could not be found, there is an excellent chance of identifying a family member who shares an identical haplotype with the patient but whose second haplotype is different. This situation is called an HLA-full haplotype mismatch. Risks of haploidentical transplantation are graft rejection and severe graft-versus-host disease (GVHD). Histocompatibility barriers can be overcome by infusing high doses of T-cell depleted peripheral CD34+ stem cells. METHODS AND RESULTS: Between December 1995 and March 2000, 5 children with rare inherited disorders were transplanted using highly purified CD34+ stem cells from haploidentical parents at the 2nd Department of Pediatrics, University Hospital Motol, Prague. Two children suffered from severe combined immunodeficiency (SCID), one child from malignant osteopetrosis, Wiskott-Aldrich syndrome and hemophagocytic lymphohistiocytosis, respectively. Positive selection of peripheral CD34+ stem cells from G-CSF stimulated donors was performed using the method of immunoabsorbtion (CellPro) (n = 2) or immunomagnetic separation (CliniMACS) (n = 3). Donor type engraftment was achieved in 4 children. In one of them early graft failure has developed successfully managed by second SCT from the same donor. One child with SCID had primary graft failure. Mild acute GVHD with good response to steroid therapy developed in 2 children. Three children are alive and 2 of them are cured. Two children died due to post-transplant complications--CMV pneumonia and encephalitis. CONCLUSIONS: Transplantation of highly purified CD34+ stem cells from haploidentical parents is a reasonable therapeutic option for children with some specific nonmalignant disorders lacking HLA identical donor. Risks of this type of SCT are the graft failure and severe infectious complications due to slow immunological reconstitution in comparison with SCT from HLA identical donors.

Antigens, CD34↗
PubMed2004

[Topical H1 antihistaminics in the therapy of acute conjunctival allergic reactions].

AIM: To determine, whether the immediately originated allergic reaction of conjunctivas may be treated with local H1 antihistaminic drugs in a monotherapy (Allergodil gtt, Emadine gtt). GROUP AND METHODS: The group included 30 patients at the age of 17 to 40 years at the mean age of 33.2 years, where chemosis and hyperemia of bulbar conjunctiva originated suddenly as well as edema of eyelids. The reported subjective symptoms were itching, burning sensation in the eyes, lacrimation, and the feeling of pressure under the eyelid. Local treatment with azelastin (Allergodil gtt. oph., Pliva), was applied in 15 patients, the other 15 patients were treated locally with emedastin (Emadine gtt. oph., Alcon) at the dose of one drop twice daily into the conjunctival sac of both eyes. The time of onset of the therapeutic effect and the disappearance of subjective symptoms and objective signs were observed. RESULTS: The disappearance of subjective symptoms after the start of therapy developed within 20 minutes after Allergodil gtt and within 5 minutes after Emadin. Subjective complaints disappeared in the range of 86-100% after Allergodil gtt and in the range of 90-100% after Emadin gtt. A substantial diminution or even complete disappearance of objective symptoms developed in 74-80% cases after the treatment with Allergodil gtt and in 80-87% subjects after Emadin gtt. CONCLUSION: The investigated local H1 antihistaminic drugs proved to be effective in monotherapy of acute phase of allergic conjunctivitis. The drugs influence subjective complaints faster and more efficiently than the objective signs. The therapy of objective manifestations requires longer period of time for the effect to develop.

Acute Disease↗
PubMed2006

New developments in palliative therapy.

Over the past 5 years, new developments in the palliative treatment of incurable cancer of the oesophagus and gastro-oesophageal junction have been introduced with the aim of palliating dysphagia and improving the survival of patients. Stent placement is currently the most widely used treatment for palliation of dysphagia from oesophageal cancer. A stent offers rapid relief of dysphagia; however, current recurrent dysphagia rates vary between 30 and 40%. Recently introduced new stent designs are likely to reduce recurrent dysphagia by decreasing stent migration and non-tumoral tissue overgrowth. Intraluminal radiotherapy (brachytherapy) has been demonstrated to compare favourably with stent placement in long-term effectiveness and safety. A disadvantage of brachytherapy, however, is that one-fifth of patients need an additional treatment because of persistent tumour growth in the oesophagus. A solution may be to administer brachytherapy not in a single fraction but in multiple fractions. Finally, efforts have been undertaken to improve survival of patients by using chemotherapy. In the future, a multimodal approach--for example by combining stent placement with chemotherapy or radiotherapy--may improve the prognosis of patients without jeopardizing their quality of life.

Antineoplastic Agents↗
PubMed1998

[Jugulotympanic paraganglioma: therapy concepts under development].

BACKGROUND: The operative treatment and radiation therapy of jugulotympanic paragangliomas (JTP) are still a matter of controversial discussion. In spite of various improvements during the last 50 years, selecting the appropriate treatment modality (surgery, radiation, or observation) is still a challenge. PATIENTS: During a 16-year period, 44 patients with 45 JTP (10 at level A/B and 35 at level C/D according to Fisch) were seen at the ENT-department in Fulda. Forty-one cases were treated surgically. RESULTS: Complete resection was possible for level A/B in 100% of the patients (n = 10). Residual tumor was demonstrated for level C in 23% of the patients (5/22) and for level D in 40% (4/10) with a median follow-up time of 69 months. In two cases residual tumor was treated by radiation. Six patients with residual paraganglioma tissue were maintained under observation without any evidence of tumor progression (median follow-up time 39 months). We report one death after the attempt to resect a large residual paraganglioma that had already caused brain stem compression. A sufficient duraplasty could not be achieved following radiation therapy. CONCLUSIONS: Complete tumor resection of jugulotympanic paragangliomas of levels A and B is often possible without injury to the cranial nerves. Extensive tumors present difficulties in complete tumor resection and increase the risk of cranial nerve injuries. Advanced paragangliomas therefore require an individualized therapeutic regime including surgery, radiation therapy, and observation of tumor growth.

Adult↗
PubMed2001

Preventing labyrinthitis ossificans: the role of steroids.

OBJECTIVE: To identify a possible relationship between the administration of steroids at the time of diagnosis of bacterial meningitis and the development of labyrinthitis ossificans. DESIGN: Retrospective analysis of the charts of 38 children requiring cochlear implantation who presented with bacterial meningitis and then developed bilateral profound deafness. The patients' charts were reviewed for age at diagnosis, the type of antibiotic administered, and the administration, dosage, and duration of steroid (dexamethasone) therapy. Labyrinthitis ossificans was established by preoperative computed tomographic and/or magnetic resonance imaging and by the intraoperative findings as described in the operative report. PATIENTS AND METHODS: Patients were 38 children who received cochlear implantation by a single senior otolaryngologist for bacterial meningitis-related deafness. Ten patients' charts (26%) were available for full review; 9 of these 10 patients had documented pneumococcal meningitis and the other patient had Haemophilus influenzae-type meningitis. RESULTS: One of the 6 patients who received steroid therapy at the time of initial illness had documented evidence of labyrinthitis ossificans either radiographically or at the time of surgery. All 4 patients who failed to receive steroid therapy developed labyrinthitis ossificans. The results achieve statistical significance by chi2 analysis and a t test (P<.01). CONCLUSION: The results of this retrospective study are highly suggestive of a role for steroids in preventing the development of labyrinthitis ossificans in children with pneumococcal meningitis.

Anti-Inflammatory Agents↗
PubMed1982

Burkitt cell leukemia following therapy for Hodgkin disease.

Two adults with advanced Hodgkin disease-one treated with combination chemotherapy, and one with chemotherapy and radiation therapy-developed Burkitt cell leukemia four and seven years after diagnosis, proved by cytochemical and ultrastructural study. Acute lymphocytic leukemia must be considered in the evaluation of therapy-related leukemias.

Burkitt Lymphoma↗
PubMed1981

Recurrent unilateral lung disease.

A 25-year-old patient, with multiple pulmonary metastases from osteogenic sarcoma who two years ago developed respiratory failure with unilateral left lung involvement and was successfully treated with independent lung ventilation, was readmitted to an ICU with recurrent unilateral lung disease. Conventional therapy failed to reverse the respiratory failure; independent ventilation temporarily improved the patient's oxygenation. At autopsy, different involvement of the two lungs by the tumor was evident so that blood flow of the right lung and lymphatic flow of the left lung were impaired. When respiratory failure unresponsive to conventional therapy develops, anatomical abnormalities should be considered.

Adult↗
PubMed1985

Anaesthesia and amiodarone.

Two recent reports support and one report disputes the existence of dangerous interactions between the new benzofuran antiarrhythmic amiodarone and the anaesthetic state. We have reviewed our experience with 17 anaesthetics administered to 16 patients taking amiodarone. Haemodynamics and serum amiodarone levels were evaluated where available. Twelve cases involved cardio-pulmonary bypass; of these, three patients died. There were no deaths in the non-cardio-pulmonary bypass group. The charts of 30 patients with poor left ventricular function, who were not receiving amiodarone but who were undergoing coronary artery bypass surgery, were reviewed to establish a comparison group. Interactions were manifested in three forms: nodal rhythm and/or complete heart block developed in ten of 15 patients (one patient had a preoperative pacemaker inserted for the sick sinus syndrome), poor cardiac output requiring intra-aortic balloon pump augmentation developed in six of 12 cardio-pulmonary bypass patients, or, a state of alpha adrenergic blockade leading to a low systemic vascular resistance despite alpha agonist therapy developed in two of 16 patients. We conclude that dangerous, fatal interactions may occur in patients taking amiodarone who undergo general anaesthesia with cardio-pulmonary bypass. Anaesthesia for non-cardiac surgery may be associated with haemodynamically significant bradyarrhythmias. We recommend aggressive invasive monitoring, including pulmonary artery catheterization and consideration of an atrio-ventricular pacemaker in high risk patients.

Adult↗
PubMedDate not supplied

Anticoagulation and incidence of late cerebrovascular accidents following the Fontan procedure.

Thromboembolic events are a well-reported complication following the Fontan procedure, but no previous studies have compared the incidence of thromboembolic events relative to the prophylactic anticoagulation strategy utilized. We examined the time-adjusted incidence of late thromboembolic events relative to chronic anticoagulation strategy. All patients who have undergone Fontan palliation and are followed at our institution were reviewed. All thromboembolic and major bleeding events were recorded and compared among different subgroups (anticoagulant medication utilized, Fontan variant, and the presence of a residual right-to-left shunt). The incidence of late cerebrovascular accidents (CVAs) per patient-year was calculated for each subgroup. The records of 132 patients were analyzed (median follow-up, 7.6 years; 1066.5 total patient-years). There were no major bleeding complications. One patient receiving no anticoagulation therapy developed a symptomatic thrombus 6 months after Fontan. Three patients suffered late CVAs (range, 3-7 years); 2 were receiving aspirin, and the other received no anticoagulation therapy. All 3 had lateral tunnel Fontan and a residual right-to-left shunt. The overall incidence of late CVA was 2.3%, with an event rate of 0.28% per patient-year. Late CVA was not related to anticoagulation strategy or time from Fontan procedure but was associated with a residual right-to-left shunt and lateral tunnel-type Fontan palliation (p < 0.001). Regardless of anticoagulation strategy utilized, symptomatic CVA is a rare long-term complication following the Fontan procedure.

Adolescent↗
PubMed1981

Prognostic factors of infantile spasms from the etiological viewpoint.

We investigated the prognostic factors for mental and physical development and seizure control by dividing the subjects into various etiologic groups in 200 patients with infantile spasms, all of whom (except 48 who died) were aged six years or older. The results were as follows: 1) Intermediate (4-12 mos) onset was found to be a favorable prognostic factor for seizure control in cryptogenic cases, although there was no relation between the age of onset and prognosis in other etiologic groups. 2) There was a significant correlation between the treatment lag and long-term prognosis for mental and physical development only in cryptogenic cases. A short treatment lag (0-2 mos) was associated with a good prognosis. All cryptogenic patients who had no relapse after ACTH therapy developed normally, although in symptomatic cases, there was no correlation between the relapse and the outcome.

Adrenocorticotropic Hormone↗
PubMed1991

Saliva and dental diseases.

Recent studies have greatly extended our understanding and appreciation of the various functions of saliva and its role in preventing dental disease. Elucidating the functions of the various salivary components as well as the mechanisms underlying normal salivary gland physiology is essential for developing rationales for the prevention and treatment of oral pathology. Individuals suffering from the consequences of a variety of forms of salivary gland dysfunction will benefit from therapies developed as the result of these advances. The application of relatively simple techniques for evaluating the functional status of salivary glands and salivary composition will aid in the identification of individuals most susceptible to oral disease.

Animals↗
PubMedDate not supplied

[On the way to gene therapy in cystic fibrosis].

Cystic fibrosis (CF) is the most common recessively inherited lethal disease among the Caucasian population. CF is caused by mutations in the CFTR gene. Although several organs and tracts are affected, severe lung disease is the cause of the most of the morbidity and mortality in CF individuals. Current treatment is aimed at slowing the inevitable progression of lung disease, rather than halting it, or preventing its onset. The isolation of the gene responsible for CF suggested the feasibility of new therapeutic possibilities based on the CFTR gene transfer to CF patients. At present, somatic CF gene therapy clinical trials, using mostly animals but also CF patients, are being conducted. Gene therapy development is restricted by the lack of the appropriate gene vector systems, which could be successfully used to transfer in vivo and protect the therapeutic gene. This is because of the many extracellular, intracellular and immunological barriers, which protect living organisms against invasion of foreign genetic material. Future improvement in gene therapy depends on the more effective ways of the gene transfer methods, creation animal models of the human diseases and development of strategies involved in the new gene construct formulation, which facilitate to control gene transcription activity.

Cell Nucleus↗