PubMed Health⌕ Search

Biomedical subjects

N I Nissen

Publications and source records attributed to N I Nissen.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of cyclosporin A and SDZ PSC833 as multidrug-resistance modulators in a daunorubicin-resistant Ehrlich ascites tumor.

Recent studies by Boesch et al. have demonstrated that a nonimmunosuppressive cyclosporin analog, SDZ PSC 833 (an analog of cyclosporin D), is an active multidrug-resistance modifier that is at least 10 times more potent than cyclosporin A. In vitro accumulation and cytotoxicity experiments using daunorubicin (DNR) and vincristine (VCR) under the influence of SDZ PSC 833 and cyclosporin A were performed in wild-type (EHR2) and the corresponding highly DNR-resistant (about 80-fold) Ehrlich ascites tumor cells (EHR2/DNR+). In accumulation experiments, both SDZ PSC 833 and cyclosporin A were found to reverse the multidrug-resistant (MDR) phenotype, but to the same degree at equimolar concentrations. Thus, in EHR2/DNR+ cells, both cyclosporins at 5 micrograms/ml enhanced DNR and VCR accumulation to sensitive levels, but only a negligible effect on DNR accumulation in the drug-sensitive cells was seen. In the clonogenic assay, the cytotoxicity of the two modulators was equal. The lethal dose for 50% of the cell population (LD50) was approx. 7 micrograms/ml for both compounds, and no toxicity was observed at concentrations below 2 micrograms/ml. At nontoxic doses, both cyclosporins effectively increased the cytotoxicity of DNR and VCR in a concentration-dependent manner. The dose-response curves were nearly identical and did not demonstrate differences in modulator potency. These data permit the conclusion that cyclosporin A and SDZ PSC 833 do raise the intracellular accumulation of DNR and VCR to the same levels and that SDZ PSC 833 does not potentiate cytotoxicity better than cyclosporin A in EHR2/DNR+ cells. However, since the new compound is nonimmunosuppressive and causes less organ toxicity, clinical studies of its MDR modulating effect seem highly relevant.

Animals↗
PubMed1992

Clinical pharmacokinetic studies of a human haemopoietic growth factor, GM-CSF.

The pharmacokinetics of glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was studied following intravenous (i.v.) and subcutaneous (s.c.) bolus injection of rhGM-CSF, 8 micrograms kg-1 employing a sensitive radioimmunoassay. After a single i.v. bolus injection, an initial high serum level of rhGM-CSF was observed, followed by a rapid decrease that occurred in two phases with a half-life (t1/2) alpha of 20.0 +/- 5 min and a t1/2 beta of 68.3 +/- 8 min. Following s.c. bolus injection the absorption was more prolonged. Peak serum concentrations did not occur until about 15-20 h, and were followed by a more protracted elimination than by the i.v. route. In all patients the single rhGM-CSF injection led to an increase in peripheral white blood cells (WBC), after a temporary drop of 2-5 h duration. The increase in WBC was of longer duration after s.c. than after i.v. bolus treatment. Since the subcutaneous administration leads to prolonged serum concentration of rhGM-CSF and prolonged increase in peripheral WBC, it seems preferable to i.v. bolus injection, and as effective as continuous i.v. infusion.

Adult↗
PubMed1992

In vivo kinetics of 111indium-labelled autologous granulocytes following i.v. administration of granulocyte-macrophage colony-stimulating factor (GM-CSF).

Administration of both glycosylated and non-glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) induces an immediate transient granulocytopenia of 1-3 hours' duration. In order to explore this phenomenon, granulocytes were labelled with 111Indium and the effect on the kinetics of granulocytes after administration of rhGM-CSF was studied in 10 previously untreated patients with malignant lymphoma. For both types and doses of rhGM-CSF, a significant and dramatic accumulation of the 111Indium-labelled granulocytes was observed in the lung within a few minutes after i.v. injection of rhGM-CSF. The accumulation of radioactivity coincided with the pronounced and transient granulocytopenia in peripheral blood. The 111Indium-labelled granulocytes later reappeared in the peripheral blood, indicating reversible pulmonary vascular margination of the granulocytes. Half-life of labelled granulocytes after reappearance was comparable to half-life values under normal conditions. The transient accumulation of granulocytes in the pulmonary vessels seems not to be of clinical importance in the management of patients, but it may to some degree explain previously described side-effects, such as transient hypoxemia ("first-dose" reaction) following administration of rhGM-CSF.

Agranulocytosis↗
PubMed1992

Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with Hodgkin's disease: a phase I/II study.

PURPOSE: As bone marrow toxicity is the major limitation of the optimal administration of chemotherapy, we investigated whether recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) could prevent myelotoxicity or accelerate hematopoietic recovery after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy. PATIENTS AND METHODS: Twenty-four previously untreated patients with Hodgkin's disease were included in a phase I/II study in which standard MOPP chemotherapy was followed by 5 days of GM-CSF at every other cycle. Patients were entered sequentially to receive one of four dosc levels (2, 4, 8, and 16 micrograms/kg of glycoprotein; 1.4, 2.8, 5.5, and 11.0 micrograms/kg of protein) and were randomly allocated to either 24-hour continuous intravenous (IV) infusion or twice daily subcutaneous (SC) injection of rhGM-CSF. RESULTS: WBC counts (mainly neutrophils, eosinophils, and monocytes) were significantly higher in cycles with rhGM-CSF than in cycles with MOPP alone. The total number of days of leukopenia (WBC count less than or equal to 2.0 x 10(9)/L) and neutropenia (absolute neutrophil count [ANC] less than or equal to 1.0 x 10(9)/L) was reduced in cycles with rhGM-CSF from 6.3 to 0.8 days and from 5.4 to 1.0 days, respectively. All dose levels of rhGM-CSF were effective in increasing the ANC, but only at the dose levels of 8 and 16 micrograms/kg did this significantly affect the scheduling of chemotherapy. Mild and reversible adverse reactions included low-grade fever, chest/bone pain, myalgias, erythemia, headache, fatigue, and periorbital edema. CONCLUSIONS: rhGM-CSF can be administered safely to patients with Hodgkin's disease and results in improved hematologic recovery after MOPP. Full-dose chemotherapy can be administered on time, resulting in an increase in the overall tolerated dose of myelosuppressive drugs when compared with historical controls. SC administration proved to be at least as effective as continuous IV infusion and should be preferred.

Adolescent↗
PubMed1992

Mitoxantrone in the treatment of chronic lymphocytic leukemia.

During the last few years it has been shown that intensive or continuing chemotherapy of patients with advanced chronic lymphocytic leukemia prolongs survival. In the search for new effective drugs with tolerable toxicity, mitoxantrone was evaluated in this phase 2 study. Seven of 11 previously untreated patients achieved complete or partial remission after single agent treatment with mitoxantrone, and 5 of .16 previously treated patients had the same degree of response. Only minor toxicity was observed. Therefore, it appears likely that mitoxantrone is as effective as chlorambucil, and it would seem justified to evaluate mitoxantrone in future combination chemotherapy regimens in patients with advanced chronic lymphocytic leukemia.

Adult↗
PubMed1992

A phase I/II study of dose and administration of non-glycosylated bacterially synthesized G-M CSF in chemotherapy-induced neutropenia in patients with non-Hodgkin's lymphomas.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) derived from E. coli was administered to 24 previously untreated patients with non-Hodgkin's lymphoma following the first cycle of CHOP chemotherapy. Four dose levels were examined, 1.5, 3.0, 5.5 and 11 micrograms/kg and patients were randomized to receive the drug either once or twice daily subcutaneously (s.c.). During rhGM-CSF treatment, the leucocyte counts increased up to 3-4 fold in 20/24 patients, reaching a peak 24-48 (mean 35) hours after initiation of rhGM-CSF. The leukopenic period in cycle one of the CHOP chemotherapy with rhGM-CSF, was shorter than after the course of chemotherapy without rhGM-CSF and also shorter when compared to cycle one of CHOP in the 127 historical controls (p < 0.05 and p < 0.001 respectively). Similar results were observed for neutrophil counts. No effect was seen on platelet counts at nadir but a significant, although moderate increase occurred in the recovery period on days 15 and 22 when compared to control cycles and historical controls. When dose levels were compared, there was only a trend to higher WBC counts at the higher dose groups (5.5 and 11 micrograms/kg) when compared to the two lower dose groups (1.5 and 3.0 micrograms/kg). In the overall evaluation there was no statistical significant difference in results between patients treated s.c. once daily versus twice daily. However when only the two highest dose levels (5.5 + 11 micrograms/kg) were compared, s.c. administration of rhGM-CSF twice daily led to higher leucocyte counts than once daily in the recovery period on day 15 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

[Malignant hematologic diseases. Diagnosis and treatment. A clearing report].

The malignant haematological disorders comprise the main groups leukemia, malignant lymphoma and multiple myeloma and the potentially malignant disorders: myelodysplastic syndrome, polycythaemia vera, myelofibrosis and M-component of uncertain significance. The common feature of all these disorders is monoclonality, i.e. they originate from one single cell. Around 2,000 new cases are diagnosed per year in Denmark. Because of the relative small number of patients, complex diagnosis and treatment (especially the possibility of cure on intensive treatment) a high degree of centralization is warranted to secure an evenly distributed high level of patient care and research. The present rules for referral of patients are unsatisfactory. A new referral system is proposed based on a common set of rules, agreed upon by five haematological centers in Denmark and the surrounding region, comprising diagnostic procedures, treatment, research and development for all haematological patients in the area. Based on these common rules (functional centralization) it is decided whether the individual patient can be treated in the primary hospital or should be referred to a center (geographical centralization). Recommendations about diagnosis, treatment and referral are made in this report. Detailed suggestions are given for diseases which may be treated locally whereas no detailed regimens are given for diseases and disease stages which should be centralized. In the latter cases, the main emphasis is placed on a presentation of treatment results.

Denmark↗
PubMed1991

Modulation of neutrophil and monocyte function by recombinant human granulocyte macrophage colony-stimulating factor in patients with lymphoma.

Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to inhibit the chemotaxis and enhance the oxidative burst response of human neutrophils in vitro. The present study describes the effect of recombinant GM-CSF on the neutrophil and monocyte function in patients with lymphoma undergoing GM-CSF treatment. Patients with either Hodgkin's or non-Hodgkin's lymphoma were treated with various dosages (2-16 micrograms kg-1 body weight per day for 5 days) of rhGM-CSF by intravenous or subcutaneous route. Prior to and on day 5 of rhGM-CSF treatment, neutrophil and monocyte chemotaxis and chemiluminescence responses to f-Met-Leu-Phe, zymosan activated serum (ZAS) and opsonized zymosan (OZ) were determined. It was observed that chemotactic response of neutrophils to f-Met-Leu-Phe and ZAS was reduced, whereas the chemiluminescence response of both cell types to f-Met-Leu-Phe and zymosan was enhanced by up to 43-fold. rhGM-CSF treatment did not affect degranulation of the neutrophils as measured by release of vitamin B12 binding protein. Degree of modulation of neutrophil and monocyte function by rhGM-CSF was independent of rhGM-CSF dosages administered. These data suggest that phagocytic defence system may be enhanced by GM-CSF treatment and that this cytokine may be a useful therapeutic adjunct in compromised patients.

Cell Degranulation↗
PubMed1991

Changes over the course of time in histological subclassification of Hodgkin's disease in Denmark.

Primary diagnostic lymph node biopsies from 317 patients with Hodgkin's disease pathologic stage (PS) I or II in the prospective randomised trial of the Danish National Hodgkin Study and from 174 patients with Hodgkin's disease stage III or IV examined and treated at the Finsen Institute, Copenhagen, Denmark, were reviewed. The original diagnosis of Hodgkin's disease was made during the period 1971-1983 and was a result of a consensus among three members of a panel of pathologists. In the current study, the histological material was re-examined in order to critically consider and exclude cases which are not histologically diagnostic but microscopically bear resemblance to Hodgkin's disease, to obtain a uniform subclassification in accordance with recent new points of the Rye classification, to examine possible changes in incidence over the course of time and to examine the NS subclassification according to the BNLI proposals. Two cases (0.4%) were reclassified as not being Hodgkin's disease, and 489 cases (99.6%) were reclassified as Hodgkin's disease in the subgroups: LP 7.5% (16.7%), NS 65.1% (54.7%), MC 21.9% (26.4%) and LD 1.2% (1.2%) (the numerals in brackets state the original subgroups). In 9.7% of the cases, the subclass could not be assessed, because the biopsies were too small for subclassification. The difference between the original and the present subclassification could be explained partly by a change in the criteria for the different subgroups and partly by interobserver disagreement. In the histologically reclassified material, the Rye classification lost its prognostic significance. It was not possible to demonstrate a gradual change over the course of time in the relative number of cases in each subgroup.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1990

Influence of age and duration of follow-up on lung function after combined chemotherapy for Hodgkin's disease.

Pulmonary function was studied in 48 patients 4-13 yrs after treatment for Hodgkin's disease with mantle-field irradiation followed by standard mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) chemotherapy. The patients were found to have a restrictive lung disease suggestive of pulmonary fibrosis. Low age at therapy (less than or equal to 30 yrs, median 24 yrs) was associated with a significantly more pronounced restrictive lung function impairment than older age (greater than 30 yrs, median 40 yrs) suggesting a higher susceptibility to the pulmonary side-effects of therapy. In addition younger smokers had a significantly greater reduction in diffusion capacity and forced expiratory volume in one second than older smokers, suggesting a higher susceptibility to the additional adverse effect of smoking. With longer follow-up nonsmokers had an increase in static lung volumes. It is suggested that this may be the result of more frequent pulmonary infections in such patients as compared with the general population. However, the duration of follow-up was not associated with changes in other indices of lung function.

Adult↗
PubMed1979

A comparative study of a BCNU containing 4-drug program versus MOPP versus 3-drug combinations in advanced Hodgkin's disease: a cooperative study by the Cancer and Leukemia Group B.

A prospective randomized trial by CALGB examined the relative value of four chemotherapy regimens in 537 patients with stage III B and IV Hodgkin's disease. A new combination BOPP, derived by substitution of BCNU for nitrogen mustard in the MOPP regimen, was compared to MOPP and to two 3-drug regimens, derived by removing the procarbazine in BOPP (BOP) or removing the alkylating agent (OPP). The 4-drug programs gave significantly higher frequency of complete remissions (BOPP 67%, MOPP 63%) than the 3-drug regimens (BOP 40%, OPP 42%), and significantly longer duration of remission and survival. BOPP had a therapeutic activity equal to MOPP, and was accompanied by less toxicity. After 6 cycles of induction chemotherapy, responding patients, both CR and PR, were continued on maintenance chemotherapy for 3 years. No significant difference in relapse rate was demonstrated following maintenance treatment with either vinblastine, chlorambucil, or chlorambucil plus monthly vincristine + prednisone doses. Nor could a reinforcement phase late in the maintenance program be shown to influence the relapse rate. The median survival for all patients entered on the 4-drug programs was 5 years, while the median has not yet been reached at 6 years for those patients, who obtained CR.

Adult↗
PubMed1979

Long term follow-up of combination chemotherapy-radiotherapy of stage III Hodgkin's disease: a Cancer and Acute Leukemia Group B study.

The Cancer and Acute Leukemia Group B studied the effect of combination chemotherapy-radiotherapy on Stage III Hodgkin's disease. Chemotherapy consisting of 4 weekly doses of vinblastine and one dose of mechlorethamine hydrochloride was followed by no therapy (CT), radiation to involved fields (CTIF) or total nodal radiation (CTTN). Two other treatment arms included total nodal radiation alone (TN) or total nodal radiation followed by chemotherapy (TNCT). Maximum follow-up is ten years. Complete remission percentages were 36 (8/22) for CT, 71 (17/24) for CTIF, 100 (21/21) for CTTN, 86 (19/22) for TNCT and 89 (16/18) for TN. Disease-free survival in patients receiving radiation +/- chemotherapy is 23% (19/73) at 5 years, but even after 9 years relapses were observed in two patients. Forty-one percent of all patients are alive and 32% have survived for five years. Ability to administer adequate therapy was the main determined for response duration and survival. Factors influencing the outcome of the disease include histology, age, splenectomy, initial white blood cell count and performance status, whereas symptomatology, initial absolute lymphocyte count and sex played no role on survival.

Adult↗
PubMed1979

Combination chemotherapy for non-Hodgkin lymphomas: a ten year follow-up study.

In 1968 the Cancer and Acute Leukemia Group B (CALGB) demonstrated optimal control of disseminated non-Hodgkin lymphomas (NHL) with vincristine-prednisone induction followed by cyclophosphamide maintenance. A study was then begun to determine whether four drugs in combination or sequence could achieve greater control. NHL patients at each participating CALGB institution were randomly assigned to one of three regimens:I) Cyclic vincristine-streptonigrin alternating every 2 weeks with cyclophosphamide-prednisone up to 155 days; II) Sequential treatment with the same 4 drugs taken singly up to 182 days; and III) Vincristine-prednisone induction for 6 weeks followed by cyclophosphamide maintenance. Results are now reported after a 10 year follow-up period. The 203 evaluable patients are those on whom Rappaport histopathologic classification was available. Frequency of complete-response did not differ significantly among the three regimens: I) 38%; II) 30%; and III) 45%. Remission durations were significantly longer among patients receiving maintenance therapy. After ten years, two patients from Regimen I, one from Regimen II, and five from Regimen III remain alive and well. It was concluded that neither of the four-drug regimens conferred a significant advantage in terms of response rate or survival time over the standard treatment.

Antineoplastic Agents↗
PubMed1979

Phase I trial of a new form of an oral administration of VP-16-213.

A new oral form of VP-16-213 consisting of a hydrophilic soft gelatin capsule containing a VP-16-213 solution was tested for toxicity in 26 patients. The drug was administered at four different dose levels, 350, 500, 650, and 750 mg/m2, in 5-day courses every 21-28 days. A dose-dependent effect was observed with regard to hematologic toxicity and alopecia. It is concluded that the drinking ampules of VP-16-213 can be replaced with the new oral capsules with a recommended initial dose of 100-130 mg/m2 given in 5-day courses every 21-28 days.

Administration, Oral↗