Biomedical subjects
Publications and source records attributed to R Haas.
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BACKGROUND: Recombinant adenoviruses are highly efficient gene transfer vehicles but their administration to mammals is accompanied by a strong inflammatory response. The present study reports additional side effects observed during adenoviral gene transfer studies in rabbits. METHODS: Hematological and serological parameters, the course of viremia and the organ distribution were analyzed after in vivo administration of E1-deleted adenoviruses in rabbits. RESULTS: The systemic administration of a therapeutic dose of 5 x 10(11) infectious particles/kg (infusion time 20 min) led to an average reduction of 80-90% in the platelet count within 48 h. Full recovery took 10-14 days. Virus administration induced a strong but transient erythroblastosis (peaking 24 h after administration) which settled 48 h later. Normochromic anemia occurred over the next 10 days with hemoglobin levels dropping by about 40% to reach the lowest level 10 days after administration and taking two months for full recovery. Dose-dependent thrombocytopenia was also found in mice, but neither erythroblastosis nor anemia was observed (in equivalent doses). The hematological findings did not improve after local injection via the portal vein. Local and systemic administration led to a comparable course of viremia. Only minor differences were found in the biodistribution of viruses between local and systemic administration. Large amounts of viral DNA and transgene expression were found in the lungs, the kidneys and the ovaries, even after local administration via the portal vein. CONCLUSIONS: Local intravenous injection via the portal vein does not prevent systemic spread of viral vectors and the occurrence of vector-related side effects. The hematological changes observed in rabbits suggest the need for careful monitoring of hematological and rheological parameters in clinical trials.
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A pharmacokinetic study of 99mTc labelled JOMO-tech in rats (after intravenous administration of a dose of 20 microg/kg body weight) was conducted. JOMO-tech is a heterogeneous extract derived from Nocardia opaca cell walls. An excellent fitting of the three-compartmental disposition model was achieved. The first apparent elimination half-life was very short (t1/2alpha = 0.0572 +/- 0.01383 h) followed by longer second apparent elimination half-life (t1/2beta = 0.817 +/- 0.1922 h), whereas at late post-treatment time the third apparent elimination half-life (t1/2gamma = 21.7 +/- 2.1 h) proved to be long. The peak concentration in the blood extrapolated to t = 0 yielded 32.3 +/- 7.54 ngeq/ml, this being approximately 2-fold the amount of that measured in the 5th post-treatment minute (16.84 +/- 1.447 ngeq/ml). It was determined that the main route of excretion was renal. Up to the 48th post-treatment hour, 30.03 +/- 2.788% of the dose was excreted via the urine, and only 6.71 +/- 0.973% was excreted in the feces by the 7 rats evaluated. The amount of radioactivity detected in selected tissue samples (expressed in ngeq JOMO-tech/g wet tissue) decreased in the sequence liver > kidneys > lungs > blood > plasma. In the time period studied, the highest amount of the dose was found in the liver, whereas up to the 3rd post-treatment day a practically equivalent part of the dose was found in the excreta and in the liver.
If malignant growth is considered the result of abnormal gene expression, it is reasonable to use antisense nucleic acids for the treatment of malignant diseases. Antisense oligonucleotides can specifically down-regulate gene expression, and a number of first-generation antisense compounds have entered human clinical trials. In this review, some aspects relevant for the development of antisense-based drugs, such as the selection of appropriate target sequences, cellular delivery, and design of a clinical study, are described, using bcr-abl-oncogene-directed antisense oligonucleotides as an example. In addition, potential target genes for antisense inhibition in hematology and oncology, including oncogenes and adhesion molecules, are summarized. Down-regulation of such adhesion molecules as members of the immunoglobulin superfamily and integrins may provide new modalities for mobilization of CD34+ hematopoietic stem cells into the peripheral blood. The review closes with an overview of ongoing clinical trials in the treatment of malignant diseases by antisense oligonucleotides.
Helicobacter pylori is naturally competent for genetic transformation. The comB locus, consisting of the open reading frames orf2, comB1, comB2, and comB3, is involved in natural transformation competence. Homologies of the ComB proteins with components of the type IV secretion apparatus (VirB9 and VirB10) from the Ti plasmid of Agrobacterium tumefaciens, as well as proteins involved in conjugation of plasmids RP1 and RP4, suggest a similar organization of DNA import (transformation) in H. pylori with well-known DNA export systems.
Temperature elevation for a few degrees (degrees C) increases significantly the cytotoxicity of several antineoplastic drugs under experimental conditions. An isolated elevation of the tumour temperature, which is possible since a few years, might be able to improve local tumour control without increasing the systemic toxicity. This study was performed to examine the feasibility of regional hyperthermia with systemic chemotherapy in pediatric patients. The special interests were the level of temperatures that could be achieved as well as the degree of toxicity and undesired side effects. Furthermore there was some hope to attain local tumour control in cases with very poor prognosis. 34 patients up to 18 years were treated in Munich and Essen until the end of 1992. 21 suffered of local relapse, in 11 cases it was the 2nd up to the 7th relapse. In another 11 cases the indication for the combined treatment was tumour progress or non-response to previous therapy. 33 patients were pretreated by aggressive chemotherapy, 20 patients had received radiotherapy before. In 28 cases the tumour was located in the pelvis. The heating device that we use is commercially available. It is based on external electromagnetic radiation which induces heat by absorption within the tissue. Since the temperature distribution inside the tumours is very heterogeneous thermometry is necessary which can only be performed invasively. For this sake we use closed tip catheters which are inserted into the tumour by puncture or surgically. The catheters remain in place for the whole treatment duration of several weeks. Chemotherapy was performed in treatment cycles (3.4/patient) mainly using etoposide, ifosfamide, and carboplatin.(ABSTRACT TRUNCATED AT 250 WORDS)
Postoperative course is reported in 52 children with malignant tumors (neuroblastoma, Wilms-tumor, non-Hodgkin-lymphoma, osteosarcoma etc.) who were operated on between 1979 and 1987. 26 children received chemotherapy prior to surgery, whereas 26 children were operated on without preceding chemotherapy (control group). Most children were under six years of age. 15 Children (57.7%) with preoperative chemotherapy developed early postoperative complications, such as sepsis, pneumonia, suture dehiscence, woundhealing disturbances and ileus, whereas this was the case in only 5 children (19.2%) without preoperative chemotherapy (P 0.0005). Four of the children with preoperative chemotherapy (15.4%) sustained late complications, such as local recurrence or mechanical bowel obstruction, whereas none of the control children did so. Lethality rate from underlying disease did not differ in both groups during follow-up (5 = 19.2% vs. 5 = 19.2%). This demonstrates that the surgeon must carefully be aware of an increased possibility of early and late complications in children who have to undergo surgery for malignant tumors following preoperative chemotherapy.
Comparison of cytogenetic chimaerism was performed in two children after bone marrow transplantation (bmt) with resp. without T-cell depletion for ANLL. It showed a marked delay of full bone marrow function in the patient with a T-depleted graft. Host type bone marrow cells persisted over many months, whereas they disappeared quickly when undepleted marrow was transplanted. Donor-T-cells apparently interact with remaining host cells and thus they might more efficiently eliminate leukaemia. Therefore total removal of T-cells from the graft seems risky in bmt for leukaemia.
11 patients with refractory acute leukemia of childhood were treated with idarubicin per os. Bone marrow toxicity which was observed at a dose level of 60 mg/m2 p.o. (3 x 20 mg q 24 hrs p.o.) per 3 weeks was found to be the dose limiting factor. In contrast to the first phase I study of Tan et al. (16) the maximal tolerated dose in the present study was found to be lower at a level of 90 mg/m2 p.o. (3 x 30 mg/m2 p.o. q 24 hrs) per 3 weeks. Therefore, we recommend a dosage of 60 mg/m2 p.o. (3 x 20 mg/m2 p.o. q 24 hrs) per 3 weeks as a starting dose for phase II/III studies. 2 out of the 11 anthracycline pretreated patients (91-880 mg/m2) with acute leukemia reached a complete remission undergoing idarubicin p.o. as a single therapy.
Since the introduction of combined immunosuppressive therapy (IST) into management of aplastic anemia (AA) in childhood response and probability of survival improved. In contrast to bone marrow transplantation (BMT), however, patients after IST are not considered cured as high rates of relapse and development of clonal disease demonstrate. From 11/93 to 9/97 114 children (65 m, 49 f; median age 9.5 y.) from 37 centers in Germany and Austria were registered in the SAA 94 study. 86 patients lacking a matched sibling donor received IST. Most of the patients suffered from very severe (VSAA: PMN < 200/microliter) or severe AA (SAA: PMN < 500/microliter). All patients were treated with combined IST consisting of ALG and Cyclosporin A (CSA). VSAA and SAA patients were additionally treated with G-CSF. Therapy response was evaluated at day 112, after 6, 12 and 18 months. 8/86 patients died, the probability of survival being 87% after 4 years. At d 112 61% of evaluable patients became independent of transfusions (IST response: CR + PR), 13% with normal blood counts (CR). After 6 months 33% showed CR. At 12 and 18 months response improved to 74% resp. 80%, 39% resp. 55% CR. The best response was achieved in the subgroup of VSAA with 90% (PR + CR) and 65% CR after 18 months. 4 patients developed AML 3-19 months after the beginning of IST. In 2/4 pts. an aberrant clone (-7; 5q-) could be detected retrospectively in BM at diagnosis of AA. 3 nonresponders developed chromosomal aberrations (+19; -7, +12; +8) after 4, 12 and 16 months without morphological signs of AML or MDS. Overall 11 relapses occurred at a median time of 12 months (range 5-27 months) after the beginning of IST. 2 of them relapsed under CSA therapy, 2 under tapering of CSA and 7 after cessation of CSA. 7 patients responded again to CSA monotherapy. Overall response rate is 77% with a probability of event free survival (EFS) of 54% after 4 years regarding all complications mentioned as events.
In two double-blind studies 66 insulin-dependent diabetic subjects pretreated with pork insulin were changed to human insulin (recombinant DNA) or a purified pork insulin preparation (regular and NPH insulin). Sixty-five patients previously pretreated with beef insulin were transferred, in a randomized, double-blind fashion, to human insulin and purified beef insulin of the same preparations (regular and NPH insulin). Patients' metabolic control, as demonstrated by fasting and 1-h postprandial blood glucose, HbA1c, and daily insulin dosage, over 4 mo was unchanged in our four groups compared with the values before changing insulin preparation. No severe hypoglycemic attacks or skin reactions were reported.
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This clinical study reports on the results of a new method in the treatment of peri-implantitis. The surfaces of 24 plasma flame-sprayed cylindric implants in 17 patients who were diagnosed with peri-implantitis were decontaminated with a combination of toluidine blue (100 micrograms/mL) and laser irradiation at a wavelength of 906 nm. Bone defects were filled with autogenous bone using e-PTFE membranes for retention of the grafting material. Premature membrane exposure occurred in all patients after an average of 3 weeks (+/- 10 days), which required immediate removal of the exposed membrane in 1 patient. Since the soft tissue showed minimal signs of inflammation, the membranes were left in situ for another 6 weeks in all other patients. The mean radiographic peri-implant bone gain was 2 mm +/- 1.90 mm after 9.5 months (maxilla 2.5 mm +/- 2.38 mm; mandible 1.9 mm +/- 1.87 mm). Two implants around which the initial bone defect had already reached the basket had to be removed after 10 months and 35 months, respectively, despite radiographic evidence of improvement of the peri-implant defect. The longer the membrane stayed in situ, the more bone was gained, as long as the membrane was covered by soft tissue (P = .01). However, the longer an exposed membrane was left in place, the smaller the resultant bone gain (P = .0001). Therefore, despite the absence of clinical signs of inflammation, exposed membranes should be removed immediately. The short-term results of this study corroborate the efficacy of the applied treatment method in prolonging the service time of dental implants involved with peri-implantitis.