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At least 253 records · Page 14Linked to original sources
PubMed1992

Recombinant erythropoietin. Orphan product with a silver spoon.

The U.S. Food and Drug Administration's (FDA) approval to the orphan biological product recombinant erythropoietin (rEPO) in June 1989 resulted both in a breakthrough treatment for the chronic anemia of people who suffer from chronic renal failure and a powerful argument for change in the legislation that spawned its development: the Orphan Drug Act of 1983. At a cost of over $6,000 per patient per year, Congress could not understand how a product that no manufacturer wanted to produce was suddenly costing the federal government hundreds of millions of dollars each year. Congress attempted to change the act in 1990 to preclude a manufacturer from using its provisions to secure lucrative monopolies in certain drug markets. In early 1991, the FDA finally issued regulations to implement the act that addressed some of the very concerns that were caused by rEPO.

Anemia↗
PubMed2002

Two decades of orphan product development.

Over the past 20 years, incentives of the Orphan Drug Act (ODA), the largest single source of extramural clinical grants at the US Food and Drug Administration, have had a substantial impact on public health. ODA incentives have contributed to the development of many innovative biotechnology products, and as our understanding of the human genome evolves, it is anticipated that pharmacogenomics will result in the identification of more 'orphan diseases'.

Animals↗
PubMed2006

Development of the high throughput screening assay for identification of agonists of an orphan nuclear receptor.

Retina-specific nuclear receptor (RNR), also known as PNR and NR2E3, is an orphan nuclear receptor expressed exclusively in photoreceptor cells of the retina. Here we describe homogeneous cell-based resonance energy transfer assay for identification of RNR agonists using beta-lactamase as the reporter gene. Bacterial beta-lactamase reporter construct containing GAL4 response elements was randomly integrated into the genome with subsequent selection of responsive cell pools by fluorescence-activated cell sorting. Chimeric RNR (RNR hinge and ligand-binding domains fused to GAL4 DNA-binding domain) was stably transfected into mammalian Flp-In Chinese hamster ovary cells using Flp-mediated recombination into a single pre-integrated Flp recombination target site. Since no RNR ligand could be used as a control for monitoring the development of the RNR assay, we developed a parallel cell line with the functionally related well-characterized thyroid hormone nuclear receptor. This parallel thyroid hormone nuclear receptor system was used as a "guide" in optimizing the RNR assay for ultra-high-throughput screening in 3,456-well nanoplate format. The assay was successfully used to screen a large compound collection for RNR agonists. In this study we demonstrated the feasibility of developing and optimization of the high-throughput screening-compatible assay for the orphan nuclear receptor in the absence of its cognitive ligand.

Animals↗
PubMed1999

Orphan nuclear receptors: shifting endocrinology into reverse.

Steroid and thyroid hormones and vitamin A metabolites (retinoids) regulate the expression of complex gene programs by binding to members of the nuclear receptor family of ligand-activated transcription factors. The nuclear receptor family also includes many "orphan" members that currently lack known ligands but that represent candidate receptors for new hormones. Recently, natural and synthetic ligands have been identified for several orphan receptors and used to dissect their biological roles. This "reverse endocrinology" strategy has resulted in the discovery of unanticipated nuclear signaling pathways for retinoids, fatty acids, eicosanoids, and steroids with important physiological and pharmacological ramifications.

Animals↗
PubMedDate not supplied

A cost-effectiveness analysis of the orphan drug cysteamine in the treatment of infantile cystinosis.

OBJECTIVE: Cysteamine is a recently licensed orphan drug used to treat the inherited metabolic disease cystinosis. The drug delays the onset of renal failure in cystinotic patients and may provide many other significant health benefits. This study examined the cost-effectiveness of the administration of cysteamine to cystinotic patients prior to end-stage renal disease (ESRD). METHOD: Decision-tree analysis and cost-effectiveness analysis. Cost data were estimated from current clinical charges and Medicare public-access reports. Life expectancy outcomes were derived from both published and unpublished clinical studies and from the U.S. Renal Data System. RESULTS: Cysteamine therapy can extend the life of kidneys and delay renal transplantation, thereby increasing life expectancy for patients with cystinosis. Patients receiving cysteamine therapy prior to renal failure have lifetime-treatment drug costs of $234,000, in comparison with $238,000 for those who are not medicated. Costs of cysteamine therapy are offset by savings associated with delaying transplantation and costs of dialysis. CONCLUSIONS: Use of the orphan drug cysteamine both improves health outcomes and reduces health care costs for patients with cystinosis.

Child↗
PubMed2004

The orphan nuclear receptor, liver receptor homolog-1, regulates cholesterol side-chain cleavage cytochrome p450 enzyme in human granulosa cells.

After ovulation, there is a shift in ovarian steroidogenesis from an estrogen-producing ovarian follicle to a progesterone-producing corpus luteum. The first step in human ovarian steroidogenesis is catalyzed by cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme. Steroidogenic factor-1 is an orphan nuclear receptor that regulates several steroidogenic enzymes, including CYP11A1. Liver receptor homolog-1 (LRH-1) is another orphan nuclear receptor that is expressed in the human ovary. After ovulation there is a down-regulation in steroidogenic factor-1, which is associated with an up-regulation of LRH-1 expression. These changes coincide with increased level of CYP11A1 expression in human corpus luteum. In this study, we examined the role of LRH-1 in the regulation of human granulosa cell CYP11A1 expression. Cotransfection of human granulosa cell tumor cells with CYP11A1 promoter and LRH-1 expression vector resulted in a significant increase in CYP11A1 expression. Deletion analysis revealed two putative LRH-1 binding sites at -1580 and -40, which was confirmed by EMSA. Dosage-sensitive sex-reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene-1 inhibited LRH-1 stimulated CYP11A1 expression, and that was not overcome by the presence of PKA agonist. We conclude that CYP11A1 expression in human granulosa cells is regulated by LRH-1. We propose that LRH-1 could be the major transcription factor for the post-ovulatory surge in human ovarian steroidogenesis.

Bucladesine↗
PubMed2004

Differential role of the loop region between helices H6 and H7 within the orphan nuclear receptors small heterodimer partner and DAX-1.

The orphan nuclear receptors small heterodimer partner (SHP) and dosage-sensitive sex-reversal adrenal hypoplasia congenital (AHC) critical region on the X chromosome gene 1 (DAX-1) contain extra amino acids between helices H6 and H7 of LBD, and here we investigated a possible role of these additional amino acids. Transient transfection assay demonstrated that, in contrast to wild type, in mutant SHP Delta128-139 deletion of 12 extra amino acids in H6-H7 failed to repress the transactivity of orphan nuclear receptors such as estrogen receptor-related receptor-gamma, hepatocyte nuclear factor 4alpha, and constitutive androstane receptor. Interestingly, yeast two-hybrid and glutathione-S-transferase pull-down assays demonstrated that wild-type and SHP Delta128-139 have similar abilities to interact with estrogen receptor-related receptor-gamma, hepatocyte nuclear factor 4alpha, and constitutive androstane receptor. Unexpectedly, in wild-type DAX-1 and mutant DAX-1 Delta338-362, deletion of 25 extra amino acids in H6-H7 had no significant difference in the interaction and repression of steroidogenic factor 1 transactivation. Mutant SHP that contains DAX-1 extra amino acids or polyalanine stretch in H6-H7 showed indistinguishable pattern of repression from wild-type SHP. Interestingly, the swapped SHP mutant with DAX-1 extra amino acids interacted with EID-1 (E1A-like inhibitor of differentiation 1), which is characterized as an SHP-interacting corepressor. However, interaction between SHP Delta128-139 and EID-1 was significantly diminished. Moreover, SHP-mediated repression of constitutive androstane receptor transactivation was significantly released by down-regulation of EID-1 expression with EID-1 small interfering RNA. The present study suggests that H6-H7 loop regions of SHP and DAX-1 play a different role in the repression of nuclear receptor transactivation.

Amino Acid Sequence↗
PubMed1994

Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors.

We have cloned Rev-erb beta, a novel isoform of the Rev-erb alpha orphan nuclear receptor. The DNA binding domains of Rev-erb alpha and beta are highly related to each other and to the retinoic acid related orphan receptor (ROR)/RZR subfamily of nuclear receptors. Indeed, we find that all three receptors bind as monomers to the sequence AATGT-AGGTCA. Whereas ROR alpha 1 constitutively activates transcription through this sequence, both isoforms of Rev-erb are inactive. When coexpressed, both Rev-erb isoforms suppress the transcriptional activity of ROR alpha 1. Our data define Rev-erb and ROR/RZR as a family of related receptors with opposing activities on overlapping regulatory networks.

Amino Acid Sequence↗
PubMed2004

Increasing the use of orphan drugs in clinical practice.

Orphan drugs allow people with rare disease to access well-tolerated, safely formulated and effective drugs. Over the next few years, orphan drugs will probably be increasingly adopted into everyday clinical practice, partly because of genomic stratification.

Chemistry, Pharmaceutical↗
PubMed1997

The psychological effect of orphanhood: a study of orphans in Rakai district.

This paper examines the psychological effect of orphanhood in a case study of 193 children in Rakai district of Uganda. Studies on orphaned children have not examined the psychological impact. Adopting parents and schools have not provided the emotional support these children often need. Most adopting parents lack information on the problem and are therefore unable to offer emotional support; and school teachers do not know how to identify psychological and social problems and consequently fail to offer individual and group attention. The concept of the locus of control is used to show the relationship between the environment and individuals' assessment of their ability to deal with it and to adjust behaviour. Most orphans risk powerful cumulative and often negative effects as a result of parents' death, thus becoming vulnerable and predisposed to physical and psychological risks. The children were capable of distinguishing between their quality of life when their parents were alive and well, when they became sick, and when they eventually died. Most children lost hope when it became clear that their parents were sick, they also felt sad and helpless. When they were adopted, many of them felt angry and depressed. Children living with widowed fathers and those living on their own were significantly more depressed. These children were also more externally oriented than those who lived with their widowed mothers. Teachers need to be retrained in diagnosing psycho-social problems and given skills to deal with them. Short courses should be organized for guardians and community development workers in problem identification and counselling.

Adaptation, Psychological↗
PubMed2003

[European ordinance on orphan drugs: changes and threats].

The Orphan Drugs Act has been officially implemented in all countries of the European Union since the year 2000. The Act aims to promote the development of treatments for rare diseases (prevalence < 5:10,000). Successful therapies for such diseases are granted market-monopoly for 10 years, during which no me-too products are allowed. There are problems concerning approval and reimbursement. Drugs already in use can also be registered as orphan drugs for a specific indication. In addition to this, European approval for the market authorization of new drugs does not automatically mean that the costs of the drug are reimbursed within the Netherlands, whereas that might well be the case in other EU countries. However, a faster procedure with respect to the reimbursement of drug costs in the Netherlands may not lead to the responsibilities for the carrying out of additional trials being transferred to those handling the treatment.

Costs and Cost Analysis↗
PubMed2001

Orphan nuclear receptors: from new ligand discovery technologies to novel signaling pathways.

Members of the nuclear receptor superfamily of ligand-regulated transcription factors play critical roles in multiple aspects of development, cellular differentiation and homeostasis. The ligand-dependent transcriptional effects of nuclear receptors are, in part, mediated by interactions with a group of proteins collectively known as transcriptional coactivators. Receptor agonists promote coactivator binding and receptor antagonists suppress coactivator binding. Recently, biochemical assays that detect ligand-binding based on coactivator recruitment have been developed for several 'orphan' nuclear receptors, i.e., receptors for which no bona fide endogenous ligands are known. We review how these assays have been used to identify naturally occurring and synthetic ligands for the liver X receptor, farnesoid X receptor and estrogen receptor-related receptor subfamilies of orphans, the use of these ligands in the discovery of novel biological signaling pathways and the potential clinical implications of these findings.

Amino Acid Sequence↗
PubMed2006

[Orphan drugs--medications for patients with rare diseases].

Orphan drugs (ODs) are products developed for the diagnosis and/or treatment of rare diseases and conditions. Patients with this group of disorders have historically been denied access to medical therapy because prescription drug manufacturers could rarely make a profit from marketing such drugs. This changed in 1983, when the U.S. Congress passed the Orphan Drug Act, creating financial incentives for manufacturers. Since 2000 the EU has had a similar regulation, resulting in more than 20 ODs being granted marketing authorisation in the EU.

Advertising↗
PubMed1995

Rare diseases, drug development, and AIDS: the impact of the Orphan Drug Act.

The Orphan Drug Act provides public subsidies and incentives to spur the development of drugs for rare diseases--drugs that the private sector might otherwise consider unprofitable to produce. Although the act has achieved numerous successes, the high prices and extraordinary sales generated by some orphan drugs lead to a pivotal policy question: how can the act be used to meet the legislative goal of stimulating drug development for small patient populations without resulting in prices that make drugs inaccessible? This question is explored using the example of AIDS drugs, many of which received subsidies under the act, to illustrate central points. The history of the act, its weaknesses, and strategies for reform are described as well.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

[Orphan drugs: problem of public health and economic stakes].

Orphan drugs (OD) qualify as drugs scientifically viable but not viable from an economic point of view either because the number of patients who might benefit is too small or because the populations concerned are too poor to afford the drugs. Sick people who could be treated by OD and their families have been fighting for years to induce authorities in charge of health to set up a programme to stimulate research into new treatment for rare diseases. The United States, initiated work in order to confer status on OD leading to the Orphan Drug Act in 1983. It defined the conditions for attribution of the OD status and also made attractive proposals to pharmaceutic industries in order to improve their development. More recently, in 1993, Japan took similar decisions, while the European Union and France are also on the way, as recent meetings of European ministers of health show. In contrast, developing countries are still excluded from medical research as very few tropical diseases have treatment. Legislation for OD, first planned to make up for the high costs of research and development, proved its efficiency. But ODs must move to a new status as some are now becoming the object of important economic stakes.

France↗
PubMed1997

Molecular cloning and brain localization of HZF-2 alpha, a new member of the Rev-erb subfamily of orphan nuclear receptors.

We have isolated a novel cDNA homologous to the family of nuclear hormone receptors which we have designated hippocampal zinc finger-2 alpha (HZF-2 alpha). HZF-2 alpha encodes a protein 494 amino acids in length and predicted molecular size of 56 kD. HZF-2 alpha shares sequence similarities with orphan nuclear receptors related to thyroid hormone and retinoic acid receptors. An additional HZF-2 cDNA clone, HZF-2 beta, was isolated. HZF-2 beta differs from HZF-2 alpha in a nine-amino-acid region carboxyl to the DNA-binding domain thought to participate in enhancing the interaction of nuclear receptors with DNA. Northern blot analysis with a probe homologous to both HZF-2 alpha and beta identified two transcripts, sizes 4.4 and 5.5 kb in several rat tissues. HZF-2 alpha/beta mRNA levels are low in embryonic rat brain, increase during neonatal brain development and remain elevated in the adult rat brain. In situ hybridization analyses localized HZF-2 alpha/beta mRNA expression to all hippocampal subfields. Within the hippocampus heaviest expression was observed within the dentate gyrus. High levels of HZF-2 alpha/beta mRNA were also detected in Purkinje cells and the granular cell layer of the cerebellum. In summary, HZF-2 alpha/beta are novel orphan nuclear receptors which may play an important role in hormone-dependent aspects of developmental processes modulating hippocampal and cerebellar plasticity.

Aging↗
PubMed2001

Activation of the orphan nuclear receptor RORalpha induces growth arrest in androgen-independent DU 145 prostate cancer cells.

BACKGROUND: RORalpha is a transcription factor which belongs to the family of orphan nuclear receptors. The regulatory functions of this receptor are still poorly understood. However, response elements for RORalpha are present on the promoter of cell cycle-related genes suggesting that it might be involved in the control of cell proliferation. In this study, we investigated the expression and the possible function of RORalpha in a human androgen-independent prostate cancer cell line (DU 145). The thiazolidinedione-derivative CGP 52608 has been utilized as the specific ligand and activator of RORalpha. METHODS: The effects of CGP 52608 on DU 145 cell proliferation and cell cycle distribution were analyzed by hemocytometer and by FACS analysis, respectively. The expression of RORalpha as well as the effects of RORalpha activation on the expression of cell cycle-related genes were evaluated by RT-PCR. To clarify whether RORalpha activation might affect the proliferation of prostate cancer cells also in vivo, nude mice bearing DU 145 tumor xenografts were treated with CGP 52608 at different doses and the growth of the tumors was followed by caliper measurement. RESULTS: RORalpha is expressed in DU 145 cells and the treatment of the cells with the thiazolidinedione-derivative CGP 52608 brought about a dose-dependent and significant decrease of cell proliferation. Ligand-induced activation of RORalpha affected cell cycle distribution, inducing an accumulation in the G(0)/G(1) phase and a decrease in the S phase. This effect was accompanied by an increased expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and a decreased expression of cyclin A. The growth of DU 145 tumors in nude mice was significantly reduced by treatment with CGP 52608. CONCLUSIONS: These data indicate that, in androgen-independent DU 145 prostate cancer cells, activation of the orphan nuclear receptor RORalpha inhibits cell growth, both in vitro and in vivo. RORalpha also induces cell cycle arrest, possibly through the modulation of the expression of cell cycle-related genes.

Animals↗
PubMed1997

Dueling orphans--interacting nuclear receptors coordinate Drosophila metamorphosis.

At least seven orphan members of the nuclear receptor superfamily are transcriptionally regulated by the steroid hormone ecdysone and expressed during the onset of Drosophila metamorphosis. A recent paper provides functions for two of these receptors, E75B and DHR3, through trans-regulation and heterodimerization. DHR3 appears to function as a switch that defines the transition from a late larva to a prepupa, and E75B functions as a timer that modulates this transition. This study provides a biological function for orphan receptor interactions during development.

Animals↗