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Biomedical subjects

D Hartmann

Publications and source records attributed to D Hartmann.

At least 145 records · Page 8Linked to original sources
PubMed1987

Toxicity of polyinosinic-polycytidylic acid admixed with poly-L-lysine and solubilized with carboxymethylcellulose in mice.

Polyinosinic-polycytidylic acid [poly(I,C)] is a double-stranded RNA that is a potent interferon (IFN) inducer in rodents and, when suitably complexed with poly-L-lysine and carboxymethylcellulose [poly(I,C)-LC], also in primates and humans. In addition, poly(I,C)-LC has shown significant therapeutic activity in a number of preclinical tumor models and significant toxicity in both the preclinical and clinical settings. To better understand the toxicity of this agent, particularly in light of the previously reported bell-shaped dose response curve for immunomodulation and therapeutic activity, we undertook a pharmacological/toxicological study of poly(I,C)-LC. These experiments revealed that the injection of toxic doses of poly(I,C)-LC significantly reduced the body weight of animals and induced serological and histological abnormalities. We found that poly(I,C) is the toxic moiety of poly(I,C)-LC and that both agents induced pulmonary thrombosis as well as hepatic necrosis. The hepatic necrosis was reflected in serum enzyme levels, with significant increases in ornithine carbonyl transferase, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase levels. In addition, reduced platelet counts indicated a significant increase in platelet consumption in agreement with the thrombosis. There were, however, only minor changes in prothrombin and activated prothrombin times. It was of interest that coincubating poly(I,C)-LC and peritoneal macrophages in vitro resulted in the production of tumor necrosis factor, which has a similar pattern of toxicity; this finding suggests that poly(I,C)-LC's pattern of toxicity may be associated with the induction of TNF and/or IFN.

Animals↗
PubMed1987

[Histo-immunolocalization of human and murine type I and III collagens in human cancers grafted to congenital athymic mice].

Seven human carcinomas and five sarcomas are microsurgically grafted to the nude mouse. We demonstrate with antibodies to human and murin Type I and III collagens that the capsule of the grafted human tumors and the intratumoral perivascular collagen are always of murin origin. Mouse Type I and III collagens take progressively the place of their human counterparts in the extracellular matrix of carcinoma. In contrast the intratumoral collagens of sarcomas are ever of human nature. The murin collagen, probably induced by the tumors, is perhaps one of the factors which prevents in the nude mouse the metastasis of the human grafted tumors.

Animals↗
PubMed1987

Lack of influence of etretinate on the intestinal absorption of D-xylose and of phytomenadione (vitamin K1) as representatives of hydrophilic and lipophilic compounds.

The possible influence of the aromatic retinoid etretinate (Tigason ) on the intestinal absorption of D-xylose and phytomenadione (vitamin K1) has been studied in 7 healthy male volunteers between 22 and 25 years of age. D-xylose and phytomenadione were selected as being representative of water-soluble and fat-soluble test compounds, respectively. Following an oral dose of 25 g D-xylose the plasma levels and urinary excretion pattern of the compound were followed over 6 h. The plasma concentrations of phytomenadione after an oral dose of 20 mg of the vitamin were measured over 14 h. These absorption tests were performed before (baseline) and at the end of a 3-week treatment period with 25 mg b.i.d. etretinate. In addition some parameters on the serum lipid status pre and post etretinate treatment were monitored. The pharmacokinetic and biochemical determinants after treatment with etretinate were referenced to the pretreatment values and nonparametric confidence intervals (a less than 0.05) for these ratios were calculated. With respect to the area, AUC, under the D-xylose plasma concentration--time curve (0.79 less than or equal to RAUC = 1.00 less than or equal to 1.17) as well as to the cumulative amount excreted into urine over 6 h (0.90 less than or equal to RSUM = 1.04 less than or equal to 1.28) and to renal clearance (0.91 less than or equal to Rcl = 1.05 less than or equal to 1.25), no effect of etretinate on absorption and/or renal handling of D-xylose was discernible.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Study on the possible interaction between tenoxicam and furosemide.

A possible interaction between furosemide and the non-steroidal antiinflammatory drug (NSAID) tenoxicam was investigated in 12 patients (6 males, 6 females) with mild heart insufficiency and with a need for antiinflammatory treatment. The patients received once daily doses of 40 mg furosemide over 15 days. From day 6 onwards until day 13 tenoxicam was concurrently administered: 20 mg b.i.d. on days 6 and 7 and 20 mg once a day on days 8 through 13. On days 0 (pre-check), 1, 3, 5, 9, 12 and 15 vital parameters were measured and urine quantitatively collected to assess the elimination of a series of biochemical determinants. The urinary excretion profiles of furosemide and trough plasma levels of tenoxicam were measured on days 5, 9, 12 and 15. Vital parameters (blood pressure, heart rate, ECG and body weight) were not affected by tenoxicam. The urinary excretion of sodium and chloride tended to decrease during treatment with tenoxicam, but this effect was not significant. Tenoxicam caused a significant drop of prostaglandin E2 (PGE2) in 12-h urine of both gender: from 601 +/- 397 ng on day 5 to 264 +/- 117 ng on day 9 for men and from 128 +/- 78 ng on day 5 to 67 +/- 55 ng on day 9 for women. Creatinine clearance, beta 2-microglobulin clearance and urinary excretion of N-acetyl-glucosaminidase did not reveal evidence for acute renal impairment. The urinary excretion profile of furosemide was not significantly changed by concurrent dosing of tenoxicam. The drop in PGE2 excretion was likely a direct effect of tenoxicam on the synthesis of renal prostaglandins.

Acute Kidney Injury↗
PubMed1986

Dissociation of therapeutic and toxic effects of polyinosinic-polycytidylic acid admixed with poly-L-lysine and solubilized with carboxymethyl cellulose in tumor-bearing mice.

In this paper, we describe a study of the therapeutic parameters (dose and schedule) and immunomodulatory activity (macrophage, natural killer cell, and T-cell number and function) of polyinosinic-polycytidylic acid admixed with poly-L-lysine and solubilized with carboxymethyl cellulose [poly(I,C)-LC] in the treatment of MBL-2 tumor ascites. Tumor-bearing mice received an optimal therapeutic protocol [100 micrograms poly(I,C)-LC administered twice a wk], a maximum tolerated dose [50 micrograms poly(I,C)-LC administered daily], or the optimal immunomodulatory protocol for normal mice [10 micrograms poly(I,C)-LC administered daily]. The percentage of tumor-associated macrophages and their cytotoxic activity correlated with host survival. In addition, splenic T-cell activity correlated with host survival, and splenic natural killer cell function had a near significant correlation with host survival. These results indicate that the optimal dose and schedule of poly(I,C)-LC for immunomodulation in tumor-bearing animals are also the optimal therapeutic protocol but have less toxicity than the maximum tolerated dose.

Animals↗
PubMed1985

Unaltered immunocompetence in patients with non-disseminated breast cancer at the time of diagnosis.

Immunologic parameters were examined preoperatively in 104 patients with breast cancer, staged according to the TNM classification and in 95 age-matched healthy women. The immunologic evaluation in the peripheral blood included lymphocyte and monocyte counts, determination of E-rosette-forming T-lymphocytes (SER+) and B-lymphocytes (MER+), T-lymphocyte subsets defined with monoclonal antibodies (Leu-1, Leu-2a, Leu-3a) and with lectin fractionation (soybean agglutinin), lymphocyte transformation test with phytohemagglutinin (PHA) and concanavalin A (ConA), and colony formation of T-lymphocytes in agar (T-lymphocyte colony-forming cells, [TL-CFC]). Two age groups (Group A: 30-50 years; Group B: 51-70 years) and the different tumor stages (Stage I-IV) were analyzed. Patients and controls did not differ in the absolute numbers of lymphocytes, T- and B-cells. In patients of Group B, the absolute number of monocytes was increased slightly in Stage II and III and significantly in Stage IV (P less than 0.05). Similarly, the lymphocyte response to PHA was significantly reduced in Stage IV Group B only (P less than 0.05). ConA-induced lymphocyte proliferation and TL-CFC capacity were not different in patients and controls. In the small number of patients and age-matched controls in whom T-lymphocyte subsets were determined, the absolute numbers of T-cells with helper or suppressor phenotype as defined with Leu-3a, Leu-2a, or lectin fractionation with soybean agglutinin were similar. This study demonstrates that in patients with early breast cancer (Stage I-III), immunocompetence as defined by either functional in vitro studies or surface marker analysis is not significantly altered at the time of diagnosis. In contrast, patients with advanced disease (Stage IV) show a significant increase in the absolute number of monocytes and a depressed PHA responsiveness of mononuclear cells.

Adult↗
PubMed1985

Optimization of an immunotherapeutic protocol with poly(I,C)-LC.

The development of successful immunotherapeutic protocols requires new therapeutic strategies as well as the development of clinically predictive tumor models and protocols. A bell-shaped response curve is observed with many biological response modifiers (BRMs), not only for immunomodulation, but also for therapeutic activity. Although most BRMs, including poly(I,C)-LC, are toxic at high doses, the administration of nontoxic doses by an optimal protocol and route of injection results in significant therapeutic benefit and increased immunomodulation in tumor-bearing animals compared to the administration of a maximum tolerated dose (MTD). We suggest that Phase II clinical trials using an optimal immunomodulatory protocol may result in increased therapeutic activity compared to protocols based on the MTD.

Animals↗
PubMed1984

Human B-like lymphoblastoid cell lines obtained by long-term culture of normal spleen leukocytes.

B-like lymphoblastoid cell lines were obtained by long-term culture of human spleen leukocytes in RPMI 1640 medium containing human plasma fraction instead of whole foetal calf serum. These cell lines, which did not form E-rosettes had membrane immunoglobulins, and expressed Epstein-Barr virus antigens. Most synthesized intracytoplasmic immunoglobulins and were shown to be diploid and to remain so after subcultures. All produced interferon upon induction with Sendai virus.

B-Lymphocytes↗
PubMed1983

[Intact cellular immune response in patients with locally metastasizing breast carcinoma at the time of diagnosis].

Reduced cellular immune response is well documented in patients with advanced breast cancer. To investigate immunocompetence at the time of diagnosis, 104 patients with breast cancer staged according to the TNM classification were studied preoperatively and compared with 95 age matched healthy women. Tests of blood mononuclear leukocytes included lymphocyte and monocyte counts, determination of rosette forming T (SER +) and B (MER +) lymphocytes, T lymphocyte subsets defined with monoclonal antibodies (Leu-1, Leu-2a, Leu-3a) and with lectin fractionation (soybean agglutinin, SBA), lymphocyte transformation tests with PHA and ConA and colony formation of T cells in agar (TL-CFC). Two age groups (A: 30-50, B: 51-70 years) and the different tumor stages (I-IV) were analyzed. Patients and controls did not differ in absolute numbers of lymphocytes, T and B cells. In patients of group B the absolute number of monocytes was slightly increased in stages II and III and significantly in stage IV (p less than 0.025). Similarly, the lymphocyte response to PHA was significantly reduced in stage IV group B only (p less than 0.05). ConA induced lymphocyte proliferation and TL-CFC capacity were not different in patients and controls. In the small number of patients and age matched controls, in whom T lymphocyte subsets were determined, the relative numbers of T cells with helper or suppressor phenotype as defined with Leu-3a, Leu-2a, or SBA were similar. In conclusion, in breast cancer, at the time of diagnosis, blood T lymphocyte populations and functions are not altered except in elderly patients with disseminated disease. The monocytosis and reduced PHA responsiveness observed in the latter group may be related phenomena.

Adult↗
PubMed1983

[Fibrotic interstitial pneumopathies. Collagenolytic activity of the alveolar fluid].

Collagenolytic enzyme release in alveolar structures is probably one of the initial events leading to impaired balance between collagen synthesis and degradation in the connective matrix of the lung, resulting in pulmonary fibrosis. The collagenolytic activity was determined in the bronchoalveolar fluid of 40 normal subjects or patients with miscellaneous pulmonary diseases and was found to be present in seventeen, viz.: 7/7 patients with interstitial fibrosis, irrespective of its origin: 4/4 patients with radiation pneumonitis; 4/15 patients with sarcoidosis and 2/2 patients with transient eosinophilic pneumopathy. There was no evidence of fibrosis in the 23 patients who showed no collagenolytic activity. Thus, collagenolytic enzymes are present in the alveolar structures of patients with interstitial pulmonary diseases of diverse origin capable of leading to fibrosis. Monitoring the release of this enzyme by bronchoalveolar lavage could be useful to evaluate the risk of fibrosis in such patients.

Collagen↗
PubMed1983

The role of the penetrating wound in the development of sympathetic ophthalmia experimental observations.

Clinical observations have established that sympathetic ophthalmia (SO) develops after a penetrating wound but not subsequent to often more severe intraocular disturbances such as extensive photocoagulation. A feature of the penetrating wound that appears important in the pathogenesis of SO is the access it provides for intraocular antigens to reach regional lymph nodes. The intraocular compartment has no lymphatic drainage and appears to function like a number of alymphatic biologic sites. In an experimental model of SO, subconjunctival injection of retinal S antigen in one eye induced a bilateral sympathetic uveitis, whereas intraocular injection in one eye was ineffective in inducing sympathetic disease.

Animals↗