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Biomedical subjects

W Krivit

Publications and source records attributed to W Krivit.

At least 73 records · Page 4Linked to original sources
PubMed1990

Busulfan disposition in children.

Children receive busulfan orally as part of myeloablative therapy before bone marrow transplantation for malignant and nonmalignant conditions. Children have been reported to have a low incidence of severe toxicity and significant rates of failure to achieve full engraftment. We evaluated the disposition of busulfan in children between 2 months and 3.6 years of age with lysosomal storage diseases, leukemia, and immunodeficiency disorders receiving oral doses of 1 or 2 mg/kg using a gas chromatographic assay. Peak concentrations were lower than those previously reported for adults, ranging from 1.4 to 5.2 mumol/L. The harmonic mean of the elimination half-life was 92 minutes, which is only slightly faster than that for adults (140 minutes). However, the area under the curve ranged from 400 to 1,000 (715 +/- 240) mumol.min/L, substantially lower than in adults receiving 1 mg/kg (range, 710 to 5,100 mumol.min/L; mean +/- SD, 2,180 +/- 1,200). The apparent volume of distribution (assuming complete bioavailability) ranged from 0.28 to 3.53 L/kg (1.42 +/- 0.86), which is more than twice that reported for adults (0.60 +/- 0.42). Busulfan clearance rate normalized to surface area is twice as high in children (200 +/- 100 mL/min/m2) as it is in adults (95 +/- 54 mL/min/m2). Alterations in bioavailability (absorption or first pass elimination) or in actual volume of distribution may account for these differences in drug disposition. The observed differences suggest the need for separate phase I dose escalation studies in children with accompanying pharmacokinetic assessment.

Administration, Oral↗
PubMed1990

A phase II study of diaziquone in children with recurrent or progressive primary brain tumors: a report from the Childrens Cancer Study Group.

Seventy-five children with recurrent, progressive or metastatic primary brain tumors were treated with aziridinylbenzoquinone (AZQ; Diaziquone) at 9 mg/m2/day by 30-minute intravenous infusion for five days every three weeks. Sixty-six patients were evaluable for response by imaging studies. There were five partial responses and one complete response for a combined response rate of 9%. A complete response lasting for 35+ months occurred in one of twelve patients with metastatic or locally recurrent ependymoma. Objective responses were also seen in patients with primitive neuroectodermal tumors (PNET) (1/8), low-grade glioma (1/6), and primary central nervous system lymphoma (1/1). Stable disease of greater than six months duration was seen in patients with ependymoma, PNET and medulloblastoma. Profound and prolonged myelo-suppression was the significant toxicity observed. As administered in this study, AZQ has marginal activity and severe toxicity.

Adolescent↗
PubMed1990

Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission.

Between November 1976 and December 1987, 84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwent non T-cell depleted allogeneic bone marrow transplantation from Human Leukocyte Antigen-Mixed Lymphocyte Culture (HLA-MLC) matched sibling donors. The first 36 patients (November 1976-June 1983) were prepared with cyclophosphamide, 60 mg/kg/day, IV for 2 days and single fraction total body irradiation with 750 cGy at a dose rate of 26 cGy/minute (Group I). The next 48 patients (July 1983-December 1987) were prepared with similar chemotherapy, but received hyperfractionated total body irradiation with total 1320 cGy, 165 cGy twice a day at a dose rate of 10 cGy/minute (Group II). Patient characteristics between these two groups are similar except for the significantly older age distribution in Group II. Median follow-up of Groups I and II are 8 years and 11 months and 2 years and 3 months, respectively. The Kaplan-Meier relapse-free survival, survival, and relapse rates at 3 years are 56, 58, and 19% in Group I and 69 (p = 0.22), 77 (p = 0.07), and 10% (p = 0.37) in Group II. There is no difference in the incidence of interstitial pneumonitis, viral or idiopathic, engraftment rate, or incidence of graft versus host disease (GVHD) between these two groups. The fractionated total body irradiation treated group had significantly less nausea and vomiting. Multivariate analysis shows that total body irradiation regimen is not a significant factor in regard to relapse rate, relapse-free survival, and survival.

Adolescent↗
PubMed1989

A phase II study of cisplatin therapy in recurrent childhood brain tumors. A report from the Childrens Cancer Study Group.

Thirty-six children with brain tumors were treated with surgery, radiation and/or adjuvant chemotherapy. After tumor recurrence, cisplatin (60 mg/m2/day IV X 2) was given every three to four weeks. CT scans were used to measure drug response prior to the first, third and fifth courses. Complete and partial responses were demonstrated in nine of 31 evaluable patients. Dose limiting toxicities were renal and auditory. Seven patients developed the syndrome of inappropriate antidiuretic hormone secretion. This study confirms that cisplatin is active in a spectrum of brain tumors.

Adolescent↗
PubMed1989

Ocular changes in the mucopolysaccharidoses after bone marrow transplantation. A preliminary report.

Metabolic correction and physiologic response were evaluated after bone marrow transplantation in mucopolysaccharidosis. Eleven patients were prospectively evaluated to determine the effect of bone marrow transplantation on the progressive ocular manifestations of these disorders. Follow-up of 0.6 to 2.8 years after successful donor stem cell engraftment showed that some patients had slow clearing of the corneal clouding, reduction of intracytoplasmic inclusions in the conjunctiva, resolution of optic nerve edema, and stabilized or improved retinal function as determined by electroretinography. These preliminary results suggest that early bone marrow transplantation may alter some of the progressive ophthalmic characteristics of the mucopolysaccharidoses. Long-term follow-up is necessary to determine if these early alterations in the ocular features are predictive of a prolonged functional improvement in the visual status.

Bone Marrow Transplantation↗
PubMed1988

Resolution of obstructive sleep apnea in Hurler syndrome after bone marrow transplantation.

Hurler syndrome, a lethal inborn error of lysosomal metabolism, results from the systemic accumulation of glycosaminoglycan. The progressive deposition of glycosaminoglycan in tissues of the upper aerodigestive tract has been suspected as the cause of airway obstruction, and many children have required tracheostomy. In a 3-year-old patient with Hurler syndrome, polysomnography confirmed the clinical impression of obstructive sleep apnea. Biopsy of an enlarged tonsil demonstrated that more than half the tissue volume resulted from abnormal lysosomal inclusions in macrophages. Three months after transplantation, repeat testing demonstrated resolution of airway obstruction, and 6 months after transplantation, tonsil biopsy showed complete absence of lysosomal inclusions. Bone marrow transplantation produces effective metabolic correction for Hurler syndrome and may be life-saving for patients with obstructive apnea.

Airway Obstruction↗
PubMed1988

Interferon-alpha n1 in children with recurrent acute lymphocytic leukemia: a phase I study of pharmacokinetics and tolerance.

Twelve children ages 3-15 years with relapsed acute lymphocyte leukemia (ALL) were treated over 25 days by intravenous or intramuscular administration of interferon-alpha n1 (IFN-alpha n1). Single doses ranged from 2.5 to 15 MU/m2, total doses from 60 to 200 MU/m2. Serum pharmacokinetics were determined following administration of two different doses. Calculation of area under serum concentration curve (AUC) values showed increased AUC with increased dose. Mean AUC (h x U/ml) ranged from 735 to 3986 at doses of 2.5 and 15 MU/m2, respectively, when given intramuscularly. AUC for i.v. and i.m. administration were similar. Side effects reported most commonly were fever and chills in 11 of 12 patients, nausea/vomiting in 7, mild lethargy in 3, and injection site pain in 4 of 9 treated i.m. Reversible hepatotoxicity occurred in the 3 patients receiving the highest doses, 10 then 15 MU/m2. Three patients had clinically significant bleeding associated with mildly increased coagulation studies and an additional three patients had increased coagulation parameters without bleeding. Four patients were considered to have stable disease; one treated at the highest dose level had clearance of peripheral blasts but remained in bone marrow relapse. IFN-alpha n1 as used in this study produced detectable blood levels with associated side effects. A Phase II intramuscular trial is recommended.

Adolescent↗
PubMed1988

A phase II study of diaziquone in childhood leukemia: a report from the Children's Cancer Study Group.

Diaziquone (aziridinylbenzoquinone, AZQ) was given by 30-min infusion at 25 mg/m2/day on a daily x 5 schedule to 16 children with acute lymphoblastic leukemia (ALL) in bone marrow relapse, 16 children with acute nonlymphocytic leukemia (ANLL) in bone marrow relapse, and 1 child with chronic myelocytic leukemia in blast crisis. None of the children achieved bone marrow remission. Five children (four with ALL and one with ANLL) were also evaluable for the response of central nervous system leukemia; all had a significant reduction in the cerebrospinal fluid blast count. Mild transient transaminase elevation was commonly seen. Grade 3 and 4 hyperbilirubinemia was seen in association with sepsis. AZQ was ineffective for induction of bone marrow remission as utilized in this study.

Adolescent↗
PubMed1988

Contribution of monocyte-macrophage system to serum alpha 1-antitrypsin.

The major serum antiprotease is alpha 1-antitrypsin (A1AT). Deficiency of A1AT can result in infantile cirrhosis and premature emphysema, both of which have a high degree of morbidity and significant mortality. Although synthesized primarily by the liver, A1AT has been histochemically localized in monocytes and macrophages in vitro and has been shown to be produced in tissue culture of monocyte-macrophage origin. This study was planned to quantitatively and qualitatively assess the in vivo monocyte-macrophage system contribution to serum A1AT. We used bone marrow transplantation (BMT) as an experimental method because there is commanding evidence that after engraftment, the monocyte-macrophage system of the recipient is replaced by that of donor origin. Protease inhibitor (Pi) typing was done on 150 potential BMT recipients and on their potential donors before transplantation. From these initial recipients, 92 eventually underwent transplantation, and 11 recipient-donor pairs, in which each donor's Pi type contained a band not in the recipient's Pi type, were chosen for the study. Six recipients survived beyond 100 days after BMT, and in these cases the donor contained either an S or an M2 band in his or her Pi type not present in the recipient. Using a silver stain method on diluted serum of known M1M2 and MS types, we were able to detect a 2% dilution of the S band and a 25% dilution of the M2 band. When the same method was applied to gels used in typing recipient Pi after BMT, we were unable to detect any contribution to serum A1AT by the donor monocyte-macrophage system.

Bone Marrow Transplantation↗
PubMed1987

A nonpathologic allele (IW) for low alpha-L-iduronidase enzyme activity vis-a-vis prenatal diagnosis of Hurler syndrome.

We identified a phenotypically normal obligate heterozygote for Hurler syndrome with exceedingly low levels of alpha-L-iduronidase enzyme activity. Subsequent investigation determined that low alpha-L-iduronidase activity was systemic, also characteristic of the subject's leukocytes and cultured skin fibroblasts. Residual alpha-L-iduronidase activity of cultured fibroblasts was found to have reduced catalytic activity (Vmax) against the 4-methylumbelliferone substrate, but normal substrate affinity (KM). Additional studies further characterized the residual enzyme activity in this woman who is an apparent compound heterozygote for Hurler syndrome, and for an allele with low alpha-L-iduronidase activity lacking pathologic manifestation. Such low activity "pseudodeficiency" alleles will complicate attempts at prenatal diagnosis of Hurler syndrome and related disorders in rare families.

Adult↗
PubMed1987

Determination of urinary homovanillic and vanillylmandelic acids from dried filter paper samples: assessment of potential methods for neuroblastoma screening.

Urinary homovanillic (HVA) and vanillylmandelic (VMA) acids were analyzed on 200 random urine samples from patients with neuroblastoma and controls, after the samples had been dried onto absorbent filter paper. The acids were determined quantitatively by gas chromatography (GC) and qualitatively by thin layer chromatography (TLC). The results were analyzed for correlation between liquid urine samples and urine dried on filter paper and between TLC and GC methods. A high overall correlation for HVA and VMA (99%) was found between liquid and dried filter samples analyzed by GC. The correlations were more significant for samples with elevated levels of these acids than for those with normal levels. Normalization of the results to the urinary creatinine concentration (UCr) is indicated due to variations in urine concentration. Results from TLC analysis showed a false positive rate of 3.5% and a false negative rate of 0.5% compared to GC analysis. This work suggests that a combination of a sensitive TLC method with a rapid quantitative GC method would be suitable for mass neuroblastoma screening in infants.

Adolescent↗
PubMed1987

Prevention of deterioration in metachromatic leukodystrophy by bone marrow transplantation.

The first girl in a family was affected with late infantile metachromatic leukodystrophy (MLD) and had the expected characteristic central nervous system progressive deterioration, which resulted in decerebration and death. The second girl (propositus) demonstrated similar symptoms and signs at the same age. Both girls had characteristically low arylsulfatase A levels. The propositus underwent allogeneic bone marrow transplantation (BMT) from a normal histocompatible sibling. Two and a half years later, the propositus has not developed the intellectual and neurologic impairment demonstrated by the first sibling, although nerve conduction has continued to worsen. These results suggest that the induction of normal enzyme levels by BMT may be retarding or inhibiting CNS deterioration. These results, confirming earlier results of others, are sufficiently promising to warrant a larger scale critical trial of BMT early in the course of MLD.

Arylsulfatases↗
PubMed1987

Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation.

At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.

Actuarial Analysis↗
PubMed1987

Natural history of primary autoimmune neutropenia in infancy.

Five patients with primary autoimmune neutropenia were evaluated during their first 2 years of life. Their illness resolved spontaneously after 6 to 41 months (median 13 months), and the patients were subsequently followed for 13 to 73 months (median 28 months). None required immunosuppressive therapy to induce remission, and routine antibiotic therapy adequately controlled all infectious episodes. An increased rate of infection, particularly otitis media and upper respiratory tract infection, occurred during the neutropenic period. No other noninfectious illnesses, particularly no other autoimmune diseases, were reported in any of these patients at any time. In each case, resolution of neutropenia paralleled the disappearance of neutrophil autoantibodies which were specific for the NA1 antigen. This report describes the clinical and laboratory findings and the long-term history of primary autoimmune neutropenia in these five patients.

Agranulocytosis↗
PubMed1987

Pediatric phase I trial of carboplatin: a Childrens Cancer Study Group report.

Carboplatin is one of a series of cisplatin analogs now undergoing clinical investigation. Phase I and II trials in adults demonstrate activity in a number of human cancers and less toxicity than might be expected with the parent compound. This phase I trial was undertaken to establish the maximum tolerated dose and the recommended phase II dose in children treated by a 1-hour iv infusion every 4 weeks. Twenty-nine patients with recurrent or progressive tumor were entered in this study at the Children's Hospital of Los Angeles and Children's Memorial Hospital in Chicago between April 12, 1983, and November 27, 1984. Beginning with a dose of 350 mg/m2 (about 80% of the adult phase II dose), we escalated the dose in groups of patients to 670 mg/m2; dose-limiting myelosuppression was encountered at this dose. Fifty-seven infusions are at least partially evaluable for toxicity. Asymptomatic hypomagnesemia, hypocalcemia, and ototoxicity were observed infrequently, and nausea and vomiting were mild. One patient with a mixed glioma of the posterior fossa achieved a good partial response lasting 9 months. Stable disease for greater than or equal to 6 months was observed in three patients: one each with ependymoma, brain stem glioma, and spinal cord astrocytoma. The recommended pediatric phase II dose is 560 mg/m2 given as a 1-hour iv infusion every 4 weeks.

Adolescent↗
PubMed1987

Three years of experience with random urinary homovanillic and vanillylmandelic acid levels in the diagnosis of neuroblastoma.

During the last 3 years, random urine samples from 408 patients were tested for elevated homovanillic acid (HVA) and vanillylmandelic acid (VMA) levels to rule out the diagnosis of neuroblastoma. Thirty-seven of these patients had elevated HVA and/or VMA levels, and neuroblastoma was subsequently diagnosed. In three additional patients with negative test results (normal HVA and VMA levels), tumors were subsequently diagnosed (false-negative rate of 7.5%). Ten percent of the patients with neuroblastoma had normal HVA and 27.5% had normal VMA levels at the time of diagnosis. Only one patient (2.5%) with neuroblastoma had elevated VMA levels in the presence of normal HVA levels. More than 60% of the patients with neuroblastoma had urinary HVA and/or VMA levels higher than twice the upper limit of normal. No false-positive results were encountered. Age and stage distributions of the patients are shown, and the significance of the results is discussed.

Child, Preschool↗