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Biomedical subjects

S Hirschfeld

Publications and source records attributed to S Hirschfeld.

At least 19 recordsLinked to original sources
PubMed2001

Developmental therapeutics in childhood cancer. A perspective from the Children's Oncology Group and the US Food and Drug Administration.

Drug development in pediatric oncology has been reviewed, concentrating on overall development issues and COG studies of cytotoxic compounds. A variety of interesting molecules with more specific targeting are becoming available. The challenges that remain include the availability of such compounds for pediatric trial and their study in a timely fashion, and the subsequent incorporation of the new agents into more up-front regimens, with the ultimate shared goal of curing more children with less toxicity.

Adolescent↗
PubMed2001

Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene.

This report summarizes information on drugs recently approved by the Food and Drug Administration, Office of Drug Evaluation I, Division of Oncology Drug Products. Five applications supporting new claims will be discussed: Trisenox (arsenic trioxide) for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression; Nolvadex (tamoxifen citrate) in women with ductal carcinoma in situ, following breast surgery and radiation, to reduce the risk of invasive breast cancer; Arimidex (anastrazole) for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer; Taxol (paclitaxel), 175 mg/m(2) by 3 h infusion in combination with cisplatin for first-line treatment of advanced ovarian cancer; and Targretin gel (bexarotene) for the topical treatment of cutaneous lesions in patients with stage IA and IB cutaneous T-cell lymphoma who have not tolerated other therapies or who have refractory or persistent disease. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Anastrozole↗
PubMed2000

Pediatric oncology: regulatory initiatives.

The majority of children with cancer receive therapy as participants in clinical research protocols coordinated by national pediatric cooperative groups. One of the highest priorities of these groups is the development of novel therapies. Due to differences in the biology of pediatric and adult tumors and in physiology between adults and children, it is usually necessary to evaluate the safety and effectiveness of new drugs separately in adult and pediatric populations. To stimulate the development of new therapies for pediatric indications and encourage the submission of clinical data to support pediatric product labeling, the U.S. Food and Drug Administration has undertaken two initiatives. In 1998 the FDA issued a regulation (The 1998 Final Pediatric Rule) that mandated if a drug or biological is under review for a claim and the disease exists in both pediatric and adult populations, pediatric studies must be performed. Section 111 of the FDA Modernization Act of 1997 states that if a drug product has exclusivity based on a patent or marketing license, the exclusivity can be extended by six months for the submission of pediatric data to the FDA. The incentive applies to both approved drugs and those under development. These initiatives are intended to enhance access to new anticancer therapies and promote labeling for pediatric oncology indications.

Child↗
PubMed1999

Clinical study of an organic arsenical, melarsoprol, in patients with advanced leukemia.

Inorganic arsenic trioxide (As(2)O(3)) induces a high proportion of complete remissions in relapsed patients with acute promyelocytic leukemia (APL). Previously, we have shown that both As(2)O(3 )and melarsoprol, an organic arsenical used for the treatment of trypanosomiasis, exhibit broad antileukemic activity against both chronic and acute myeloid and lymphoid leukemia cell lines. Given the breadth of this activity, we initiated a clinical study to evaluate the pharmacokinetics, safety, and potential efficacy of melarsoprol in patients with refractory or resistant leukemia. Using the antitrypanosomal dose and schedule, patients received escalating intravenous doses daily for 3 days, repeated weekly for 3 weeks. Doses were 1 mg/kg on day 1, 2 mg/kg on day 2, and 3.6 mg/kg on day 3 and on all days thereafter, up to a maximum daily dose of 200 mg. Eight patients [6 AML (2 morphologic APL), 1 CML, 1 CLL] were treated. Mean peak plasma concentrations of the parent drug were obtained immediately after injection, ranged from 1.2 microg/ml on day 1 to 2.4 microg/ml on day 3, were dose proportional, and decayed with a t(1/2) congruent with 15 min. A minor clinical response (regression of splenomegaly and lymphadenopathy) was observed in a patient with chronic lymphocytic leukemia. Central nervous system (CNS) toxicity proved limiting on this dose and schedule. Three patients experienced generalized grand mal seizures during the second week of therapy. We concluded that this dose and schedule of melarsoprol is associated with excessive CNS toxicity and that verification of the striking preclinical activity in patients with leukemia will require developing an alternative dose and schedule.

Adult↗
PubMed1998

Pain as a complication of HIV disease.

Pain as a symptom is common to many pathologic conditions. At its most elementary level, it is a signal from peripheral nerves with specialized receptors that there is a change in the local environment, such as pressure, pH, temperature, or some other noxious stimulus, that can be detrimental to function. Pain is particularly prevalent in patients with HIV infection. The assessment, evaluation, and treatment of pain should be an integral part of comprehensive patient care.

Adult↗
PubMed1996

Thyroid abnormalities in children infected with human immunodeficiency virus.

OBJECTIVE: To study thyroid function in children infected with human immunodeficiency virus (HIV) and determine whether there are correlates of thyroid dysfunction with disease progression. STUDY DESIGN: Total and free thyroxine, triiodothyronine, reverse triiodothyronine, thyrotropin, and thyroxine binding globulin (TBG) were measured in 167 children with HIV infection (age, 1 to 19 years; mean, 9.15 years). SETTING: Pediatric Branch, National Cancer Institute. RESULTS: Free thyroxine was at or below the lower limit of normal (normal, 1.0 to 1.9 ng/dl) in 18% of the children; thyrotropin and TBG levels were above the normal range in 31% and 30%, respectively. There was an inverse correlation between CD4+ cell count and thyrotropin, and between CD4+ cell count and TBG. No correlation was found between thyroid function and other disease symptoms or medications. CONCLUSION: These findings indicate that thyroid abnormalities occur more frequently in children with HIV infection than was previously reported, have a different profile from the thyroid abnormalities associated with other chronic disease conditions, and correlate with disease progression.

Adolescent↗
PubMed1996

Dysregulation of growth and development in HIV-infected children.

Growth dysregulation is quite common in HIV-infected children and growth failure is one of the most sensitive indicators of disease progression. Beginning at birth, HIV-infected infants often have smaller size and lower birthweight than noninfected children born to HIV-infected women. The causes of growth dysregulation are varied, and can be due to alterations in gastrointestinal function, chronic or repetitive infections, and alterations in metabolic and endocrine function. The metabolic and endocrine effects may be the consequence of the primary infection or secondary to the use of any of the medications required to treat HIV infection and its complications. Correlational studies have identified an inverse relationship between viral burden and linear growth and body mass index, i.e., the use of antiviral medications that reduce viral burden is associated with improvements in anthropometric indices of growth. Alterations in cytokine profiles, possibly related to reported abnormalities in thyroid indices, fat metabolism, and the somatomedin axis, may be indicative of dysregulation on a cellular level. Pubertal delay, especially among boys, is common, and may contribute to the overall growth failure associated with HIV infection. If the basis for growth failure resides in metabolic and regulatory abnormalities, then interventions beyond increasing caloric intake will be necessary to increase linear growth rate and reverse growth failure in HIV-infected children.

Antiviral Agents↗
PubMed1996

Use of human recombinant growth hormone and human recombinant insulin-like growth factor-I in patients with human immunodeficiency virus infection.

Infection with the human immunodeficiency virus (HIV) can lead to global alterations in metabolism as well as immunodeficiency. There is dysregulation of endocrine function in adults and children, the extent and magnitude correlating with disease progression. Some of the more prominent abnormalities occur in the thyroid, gonadal, and somatomedin axes. Clinical manifestations of these abnormalities are growth failure in children, which is one of the most sensitive indicators of disease progression, and a wasting syndrome in adults and children. Although there are case reports of growth hormone (GH) deficiency in HIV-infected children, most patients with growth failure have normal serum levels of GH and normal to low levels of insulin-like growth factor-I (IGF-I). Antiretrovial therapy can improve the growth rate in children for a period of time if there is a drop in viral titer, but as the viral load increases, the growth rate decreases again. Administration of GH or IGF-I to these patients can improve the growth rate and lean body mass, and in some patients improve immune function. Although studies on resting energy expenditure in HIV-infected patients have shown increases, these are not proportional to disease progression, but may be dependent upon cytokine activation and other abnormalities. Adult patients with wasting have been shown to have relatively normal total energy expenditure, but decreased intake. Appetite stimulants have been shown to have some benefit, but do not increase lean body mass. The most significant clinical benefit has come from administration of GH in short-term trials. GH and IGF-I are both able to inhibit apoptosis and reconstitute the immune system in rodents treated with ablative therapy. In addition, GH can modulate the marrow suppressive effects of zidovudine and may enhance its ability to inhibit viral reverse transcriptase. Current clinical trials are ongoing in both adults and children. GH and IGF-I may have a role in regimens intended for immune reconstruction, and could be useful as adjuvant therapy in selected patients with HIV infection.

Adult↗
PubMed1996

Pain in pediatric human immunodeficiency virus infection: incidence and characteristics in a single-institution pilot study.

OBJECTIVE: Children with human immunodeficiency virus (HIV) infection have multiple complications associated with the disease process. Many of these complications are potentially painful and could affect the patient's quality of life. We examined the incidence and characteristics of the perception of pain in a cohort of families with children with HIV infection. METHODOLOGY: A questionnaire was developed and validated with a cohort of families with children with cancer. In a survey of families at the Pediatric Branch of the National Cancer Institute, 61 children with HIV infection and their care givers, along with 19 children with cancer and their care givers, were interviewed to determine the incidence and impact of pain. RESULTS: Fifty-nine percent of the HIV-infected children and 55% of their care givers described pain as a component of their illness that impacted on their lives. Younger children and girls tended to report more pain. There was also a tendency for biological parents to expect and to treat more pain than foster parents, although there was no difference in the incidence of pain that biological and foster parents reported for their children. No differences were found between parents who were HIV positive and those who were not. In addition, no correlations were noted in incidence, expectation, or impact of pain with disease progression or surrogate markers such as CD4 counts. Pain in HIV-infected patients tended to be either in the gastrointestinal tract or limbs and usually responded to nonsteroidal anti-inflammatory therapy. The patients with cancer reported an incidence (47%) and impact of pain similar to those of previously reported studies on pediatric patients with cancer. CONCLUSION: Pain is common among children infected with HIV and can adversely impact on their lives, and its management should be a component of the general care of these patients.

Adolescent↗
PubMed1995

Concordant loss of imprinting of the human insulin-like growth factor II gene promoters in cancer.

The human insulin-like growth factor II (IGFII) gene has been shown to be imprinted for the promoters P2, P3, and P4 but not for the promoter P1 in liver and chondrocytes. Loss of imprinting of the IGFII gene has been found in a variety of human tumors including rhabdomyosarcoma and lung cancer. In this report, we determined whether loss of imprinting in tumors displays a promoter-specific pattern. We examined allelic expression of all four IGFII promoters in rhabdomyosarcoma, lung cancer, and normal skeletal muscle. We demonstrate that the imprinting of all IGFII promoters is relaxed in rhabdomyosarcoma and lung cancer. These data suggest that loss of imprinting of IGFII gene promoters may be regulated coordinately by a common mechanism in these tumors. Unexpectedly, we also found that P1, in addition to P2, P3, and P4 is monoallelically expressed in three informative adult skeletal muscle tissues. This indicates that imprinting of the IGFII promoter P1 occurs in a tissue-specific manner.

Adult↗
PubMed1995

Pharmacologic therapy for inflammatory bowel disease.

The pharmacologic management of ulcerative colitis and Crohn's disease is usually carried out in a stepwise fashion. Initially, oral sulfasalazine or 5-aminosalicylic acid (5-ASA) products are given and, for patients with rectal disease, treatment may include topical therapy with either 5-ASA enemas or hydrocortisone suppositories. Patients with more active inflammatory disorders may also require oral corticosteroid therapy. Patients with fulminant disease may require intravenous steroids and antibiotic therapy. If frequent relapses prevent discontinuation or significant reduction of prednisone therapy, azathioprine or 6-mercaptopurine may offer benefit as steroid-sparing agents. Also, intravenous cyclosporine has proved useful in patients with fulminant inflammatory bowel disease that is unresponsive to other therapy. Metronidazole has value in the treatment of perianal disease secondary to Crohn's disease. Balancing the risks and benefits of single or combination therapy is an ongoing challenge in patients with inflammatory bowel disease.

Administration, Topical↗