Bystander tumoricidal effect and gap junctional communication in lung cancer cell lines

Calcium dobesilate, a vascular protective agent, was tested in vitro for its scavenging action against oxygen free radicals. Calcium dobesilate was as potent as rutin to scavenge hydroxyl radicals (IC50 = 1.1 vs 0.7 microM, respectively). It was also able to scavenge superoxide radicals, but with 23 times less potency than rutin (IC50 = 682 vs 30 microM, respectively). Calcium dobesilate significantly reduced platelet activating factor (PAF)-induced chemiluminescence in human PMN cells and lipid peroxidation by oxygen free radicals in human erythrocyte membranes, although these actions required calcium dobesilate concentrations > or = 50 microM. Finally, in cultured bovine aortic endothelial cells, magnesium dobesilate reduced the increase in cytosolic free calcium induced by hydrogen peroxide and inhibited phenazine methosulfate-induced cell potassium loss. In conclusion, calcium dobesilate was effective in scavenging hydroxyl radicals in vitro, at therapeutically relevant concentrations. Conversely, higher concentrations of the compound were required to scavenge superoxide radicals or to protect the cells against the deleterious effects of intracellular reactive oxygen species. Further studies in vivo are required to determine if these antioxidant properties of calcium dobesilate can play a role in its vascular protective mechanisms.     

Procainamide-induced agranulocytosis differs serologically and clinically from procainamide-induced lupus

Agranulocytosis is a well recognized but uncommon complication of procainamide (PA) therapy, whereas a lupus-like syndrome occurs in approximately 20% of patients treated chronically with PA. In order to gain insight into the immunopathogenic relationships among these conditions, we compared the humoral immune abnormalities in these patient groups as well as in asymptomatic PA-treated patients. A relatively uniform profile of IgM but not IgG autoantibody reactivity with a set of chromatin-related antigens was observed in eight elderly men who developed agranulocytosis after treatment with PA. In contrast PA-induced lupus patients had predominant reactivity with [(H2A-H2B)-DNA] in both IgM and IgG classes. Five of eight patients with agranulocytosis had elevated levels of neutrophil-reactive IgG which appeared to be due to immune complexes based on Fc gamma receptor blocking studies. However, 12 of 15 patients with PA-induced lupus, none of whom had neutropenia, had similar levels of neutrophil-reactive IgG, suggesting that this reactivity was not causally related to agranulocytosis. Agranulocytosis developed after less than 3 months treatment with PA in six of eight patients. This time course was similar to that seen in 77 PA-induced agranulocytosis patients reported in the literature plus 127 patients reported to the U.S. Food and Drug Administration in whom 90% developed agranulocytosis within 3 months of starting PA. In contrast, the mode duration of treatment with PA before lupus-like symptoms develop is 10-12 months. These findings, together with the different profiles of autoantibodies and clinical presentations, suggest that agranulocytosis arises from a different mechanism than that underlying PA-induced lupus.     

Protein annotation: detective work for function prediction

Agranulocytosis induced by metamizole is uncommon, with a frequency of less than one case per million treatments. We describe such a case in a patient requiring emergency surgery. An 85-year-old man with a history of infantile paralysis with mental retardation and Paget's disease and X-ray signs of the right femur came to the emergency room with a diaphysial fracture. He received 1 g metamizole i.v. every 8 hours for analgesia. Ten hours after admission a routine blood cell count showed a rapid fall in the number of leukocytes; at 24 hours the count was 600 x 10(9)/l. The diagnosis was agranulocytosis induced by metamizole. Postponement of surgery was advisable and treatment with granulocyte colony stimulating factor (GCSF) at a dose of 5 micrograms/kg/day. Agranulocytosis resolved after 3 days of treatment, after which time the bone was set with a straight femoral plate under subarachnoid anesthesia. Two packs of red blood cells were required during the immediate postoperative period. Twelve days after surgery the patient was released. We review the anesthetic approach to agranulocytosis and its treatment.     

Administration of filgrastim in two patients with drug-induced agranulocytosis

Two patients experienced agranulocytosis associated with either procainamide or trimethoprim-sulfamethoxazole. Both were treated with filgrastim in an attempt to decrease the duration of agranulocytosis. The first patient received 12 days and the second patient 4 days of filgrastim before white blood cell counts recovered. Published reports both support and refute the efficacy of filgrastim in this setting. The agent may be beneficial in certain cases of this disorder, but further investigation is necessary to determine if it has a definitive role.     

Subcutaneous fat necrosis following traumatic pancreatitis

Agranulocytosis and septicaemia developing in a patient with rheumatoid arthritis after 3 years' intermittent treatment with diclofenac, cimetidine and flucloxacillin for staphylococcal osteomyelitis is described. Treatment with recombinant granulocyte-colony-stimulating factor and high-dose methylprednisolone had no effect on the neutropenia which resolved on stopping all drug therapy. Relapse of agranulocytosis followed reintroduction of flucloxacillin and cimetidine 3 months later.     

Immunocytologic detection of isolated tumor cells in bone marrow of patients with squamous cell carcinomas of the head and neck region

Methimazole 5 mg three times daily was prescribed in 1994 spring to a woman, aged 53 years, with relapsed hyperthyroidism. The drug was discontinued six weeks after initiation because of leukopenia. Two weeks still later, the patient developed chills, high fever, and a sore throat. The leukocyte count was 1,100/mm3 with 23% granulocytes, 76% lymphocytes and 1% monocytes. The granulocyte count stopped decreasing only three weeks after the drug was discontinued when the recombinant human granulocyte colony-stimulating factor (rhG-CSF) was given; the patient recovered uneventfully. Thus we recommend that the peripheral leukocyte count of patients who receive methimazole therapy must be carefully monitored during the first three months. Furthermore, the use of rhG-CSF for methimazole-induced agranulocytosis abbreviates the period required for marrow recovery after cessation of this offensive drug.     

Is there an answer to the medical review policy nightmare?

Two cases are reported of patients who developed agranulocytosis after treatment with typical and atypical antipsychotics. The patients were successfully treated with olanzapine. We suggest the consideration of olanzapine as a safer treatment in patients who require immediate continuation of antipsychotic medication and have a prior history of classic and atypical neuroleptic-induced agranulocytosis.     

Maternal cocaine alters eupneic ventilation but not gasping of neonatal rats

Lithium administration was used in a patient with a clozapine-induced neutropenia and in another with complete agranulocytosis to assess whether lithium could stimulate neutrophil production. In both cases, following lithium administration, the neutrophil count was increased to the normal range within 6 days. In the patient who had presented a neutropenia, clozapine treatment was then reinstated in the presence of lithium and continued without the neutrophil count dropping into the yellow-alert range thereafter.     

Agranulocytosis as a complication of acute infectious mononucleosis

INTRODUCTION: Acute infections mononucleosis is the most common clinical manifestation of primary Epstein-Barr virus (EBV) infection occurring during adolescence. It is a benign lymphoproliferative, usually self-limiting disease. Complications are relatively rare, but they may occur, especially hematological. Most common are autoimmune hematolytic anemia and thrombocytopenia, and they respond to corticoid therapy. Deuteration of white blood cells is rather rare, whereas mild neutropenia is a normal finding during the course of acute disease. On the other hand, agranulocytosis is extremely rate, and almost every case has been reported in the literature. Filgrastim--the recombinant human granulocyte colony-stimulating factor (G-CSF) stimulates the activation, proliferation and maturation of progenitor granulocyte cells. This drug is usually applied in treatment of iatrogenic neutropenia, during chemotherapy of malignancies and in some idiopathic and cyclic neutopenias. CASE REPORT: A female patient, 18 years of age, has been hospitalized at the Clinic of Infectious Diseases in Novi Sad on two occasions. First because of severe acute infectious mononucleosis with acute hepatitis and jaundice 10 days after onset of symptoms. Physical examination revealed severe intoxication, dehydration, icteric skin, mucosis and massive hepatosplenomegaly. The diagnosis was confirmed by ELISA IgM, EBV VCA positive and ELISA IgG EBV VCA and IgG EBVNA negative results. The patient was discharged from hospital after 24 days without complaints and with normal physical and laboratory findings. For several days she felt well, but gradually severe fatigue and malaise occurred and she became febrile again. That was the reason why she was hospitalized again, two weeks later. This time she was febrile, extremely intoxicated with general lymphadenopathy, catarrhal gingivostomatitis and massive splenomegaly. The first laboratory findings showed severe neutropenia (absolute count of granulocytes was 0.156 x 10/l, with only 12% segmented neutrophils). Mild anemia--3.05 x 10/l was also registered, while the platelet count was normal. Other biochemical analyses were normal, the Coombs' test negative, while the serological response was also normal. Bone marrow puncture was performed and normocellular bone marrow was registered, somewhere hypercellular due to hyperplasia of granulocyte progenitor cells from promyelocytes to normal maturated cells. Anemia showed megaloblastoid proliferation, while megakaryocytes were normal. High doses of corticosteroids were applied (dexamethasone 160 mg daily) and filgrastim 5 micrograms every other day. From the very beginning of therapy the patient felt better, whereas granulocytes responded with elevation as soon as 48 hours after initiation of therapy. On the sixth day the treatment was stopped because the level of granulocytes was normal and the patient has completely recovered. She was discharged from hospital 4 weeks later with mild meteorism, but normal physical and laboratory findings and mild splenomegaly registered only by ultrasonography. DISCUSSION: During the last 10 years only several cases of severe leukopenia with acute infectious mononucleosis had been reported in literature. In all cases it was associated with some other hematological complications and it occurred in young adults without previously registered immunodeficiency. We have no knowledge about application of filgrastim in treatment of EBV-induced agranulocytosis, but the International Association for Studying Agranulocytosis and Aplastic Anemia reported that in 4% of patients Epstein-Barr virus can cause agranulocytosis even a year after the occurrence of acute disease.     

Agranulocytosis induced by vancomycin or ticarcillin/clavulanate

OBJECTIVE: To reacquaint clinicians with a reportedly rare adverse event of agranulocytosis occurring after long-term administration of vancomycin and ticarcillin/clavulanate, with a subsequent review of other reported cases in the literature. CASE SUMMARY: A 45-year-old white woman with spina bifida developed agranulocytosis (2.7 x 10(3)/mm3 white blood cells with only 3% polymorphonuclear leukocytes and no reported eosinophils or basophils) after long-term administration of vancomycin and ticarcillin/clavulanate for decubitus ulcers and chronic osteomyelitis. Consequently, the cell counts rebounded rapidly on discontinuation of both medications and returned to normal within 1 week. DISCUSSION: The incidence of vancomycin-associated neutropenia is presumably rare, but the increased use of vancomycin may disclose a more frequent occurrence. It is suggested that the mechanism for the reaction is immunologically mediated, yet this remains unclear. Although it is difficult to determine the causative agent in this case, vancomycin was most suspect clinically. Ticarcillin/clavulanate is less likely because our patient has since been readmitted and treated with oxacillin, imipenem/cilastatin, and amoxicillin/clavulanate without affecting the white blood cell count. In that regard, it could be reasoned that an immunologic reaction to ticarcillin would have resulted in a similar outcome with other penicillins. CONCLUSIONS: This case serves as a reminder to clinicians that patients receiving long-term treatment with vancomycin should have their white blood cell count monitored at least weekly.     

Resolution of metastatic calcification in the paws of a cat with successful dietary management of renal hyperparathyroidism

BACKGROUND: Clozapine is an atypical antipsychotic drug indicated for patients with schizophrenia in whom traditional antipsychotic drugs (such as haloperidol or the phenothiazines) are ineffective, or in those who experience intolerable adverse effects. Clozapine treatment may be complicated by the development of life-threatening agranulocytosis, so regular haematological monitoring is required. OBJECTIVES: To determine the incidence of clozapine-induced agranulocytosis in Australia and the importance of monitoring white blood cell counts in patients treated with clozapine. DESIGN: Review of haematological monitoring for the first three years (June 1993-July 1996) of operation of the Australian Clozaril (clozapine; Novartis Australia) Patient Monitoring System (CPMS) central database. RESULTS: In the 4061 patients prospectively monitored by the CPMS, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6% (n = 104); the incidence of agranulocytosis was 0.9% (n = 37). So far there have been no deaths in Australia from the complications of clozapine-induced agranulocytosis. CONCLUSION: The incidence of agranulocytosis and neutropenia associated with clozapine use in Australia is similar to that in the rest of the world. Monitoring the white blood cell counts of patients being treated with clozapine ensures minimal risk to patients who develop agranulocytosis.     

Role of clozapine in the occurrence of chromosomal abnormalities in human bone-marrow cells in vivo and in cultured lymphocytes in vitro

Bone-marrow chromosomes were examined from 38 mentally and physically retarded and two psychiatric patients who were being treated with a variety of neuropharmacologic drugs. Twenty of these patients used clozapine (Leponex). The clastogenic effects of clozapine in vitro were studied in the lymphocyte cultures of three patients--one free of hematologic disease and two who 6 months earlier had had agranulocytosis attributed to the use of clozapine. The mean frequency of cytogenetic abnormalities in the bone-marrow cells of patients who used clozapine was significantly increased (P less than 0.05). The two patients who had had agranulocytosis had a greater frequency of cytogenetic abnormalities in their cultured lymphocytes in vivo and in vitro than the patient free of hematologic disease. A clone with a 13/14 chromosome translocation was detected in one of the patients. As all patients received a number of drugs during the in vivo and in vitro studies no definite conclusions could be drawn regarding the role played by clozapine in the occurrence of chromosomal abnormalities.     

Videolaparoscopic access in the surgical treatment of colorectal cancer: critical analysis]

Clozapine was approved by the U.S. Food and Drug Administration in 1989 for treatment of severely ill schizophrenic patients. It has activity against both the positive and negative symptoms of schizophrenia, which has made it an alternative to traditional antipsychotic medications such as haloperidol. However, clozapine must be used cautiously due to its side effect profile. These side effects include agranulocytosis, seizures, and cardiorespiratory symptoms. We report the case of a patient who developed polyserositis (pericardial effusion, pleural effusion, and pericarditis) after being started on clozapine, and whose symptoms remitted upon discontinuation of clozapine. The literature is reviewed and the treatment implications are discussed.     

Structural features associated with reactive metabolite formation in clozapine analogues

Clozapine is associated with a high incidence of agranulocytosis. We had previously found that it is oxidized by granulocytes, or simply HOCl, to a reactive metabolite that irreversibly binds to the cells, and we proposed that this reactive metabolite is responsible for clozapine-induced agranulocytosis. The reactive metabolite appeared to be a nitrenium ion formed by chlorination of the nitrogen bridge between the two aromatic rings. If this is correct, analogs that contain this structural feature should also be oxidized to a reactive intermediate while those not possessing this feature would, at least, not form the same type of reactive intermediate and, therefore, may not induce agranulocytosis. We tested the first part of this hypothesis with three clozapine analogs that do contain a nitrogen bridge and three that do not. Consistent with the hypothesis, the three analogs that do contain the nitrogen bridge formed reactive intermediates that could be trapped with glutathione when oxidized by HOCl, myeloperoxidase or activated neutrophils. In contrast, we found no evidence of a reactive intermediate on oxidation of analogs that contained an oxygen or sulfur bridge rather than a nitrogen bridge. If such reactive metabolites are responsible for drug-induced agranulocytosis, it should be possible to use such a simple screening method to test drugs at an early stage in their development for the potential to induce agranulocytosis.     

Effect of porcine calcitonin in primary hyperparathyroidism (author's transl)

In order to investigate the effect of calcitonin (CT) on calcium and phosphorus metabolism in primary hyperparathyroidism (PHP), porcine calcitonin (80 MRC units) was injected intramuscularly at 9:00 a.m. and 5:00 p.m. for 10-14 days in 7 patients with parathyroid adenoma. Fasting blood specimens were drawn at 8:00 a.m. every other day and 24 hour urine samples were collected through out control and test days. To examine the acute effect of CT, blood and urine were checked several times until 8 hours after the first injection. A fall in the fasting serum calcium level observed in 5 patients during the repeated administrations of CT, as well as that observed in 6 patients within 6 hours after the first injection, showed a significant correlation with the initial serum calcium level. Serum phosphorus concentration decreased in all patients 6 hours after the first injection, while fasting levels seemed to remain unchanged. During the repeated administrations, urinary excretion of calcium and phosphrus decreased correspondingly with the fall in serum calcium levels, although no definite tendancy was observed within 8 hours after the first injection. Fasting serum PTH levels during the repeated administrations were measured in 2 patients. In a patient whose serum calcium returned to the initial level on the 7th day of administration, a gradual rise of PTH was observed, while in another patient whose serum calcium was kept lower than the initial level, PTH remained almost unchanged. These results indicate that, under such a condition where there is marked increase of bone resorption as PHP, repeated administrations of CT bring about not only a hypocalcemic effect but also the reduction of calcium and phosphorus excretion through a decreased filtered load. In addition, it was suggested that, in some cases of PHP, the hypocalcemic effect of CT may be abolished by an increase of PTH secretion from the parathyroid glands during long-term administration.     

Apoptosis of neurons in the vestibular nuclei of adult mice results from prolonged change in the external environment

Five patients with non-cytotoxic drug-induced agranulocytosis were treated with recombinant human granulocyte-colony-stimulating factor (rh-G-CSF). The drugs involved were dipyrone, captopril, clozapine and carbimazole. Bone marrow examination revealed a depleted granulopoiesis with normal erythro- and megakaryocytopoiesis. After discontinuation of the suspected drug, rh-G-CSF was administered daily at 5 microg/kg subcutaneously. The neutrophil counts were recovered between day 6 and 12 and patients were discharged from hospital shortly afterwards. Compared to data from the literature, the neutrophil recovery appeared to be faster than expected without the use of haematopoietic growth factors. In conclusion, rh-G-CSF at a standard dose of 5 microg/kg seems to be an effective treatment for drug-induced agranulocytosis.     

Techniques for induction of neutropenia and granulocytosis in rats

After a single administration of vinblastine, rats develop profound neutropenia. The agranulocytosis lasts 3 days, and it is observed on the third, fourth and fifth day after vinblastine administration. The granulocytosis that develops on days 7-14 after vinblastine administration was significantly increased when androgenic steroids were administered. Deca-Durabolin induced greater granulocytosis than testosterone. The peak values were observed 10 and 12 days, respectively, after drug administration. All values of WBC's, granulocytes and hematocrit ratios were obtained in unanesthetized, unrestrained rats from an aortic cannula implanted at least 10 days prior to the experiment.     

Surgical and medical management of patients with pulmonary metastasis from parathyroid carcinoma

BACKGROUND: The aim of this study was to characterize patients with pulmonary metastasis of parathyroid carcinoma and to evaluate the long-term effect of surgical and medical therapy. METHODS: Seven patients with pulmonary metastasis of parathyroid carcinoma were treated between 1980 and 1992. Six patients underwent resection of pulmonary metastases, and one patient has had long-term bisphosphonate therapy alone. Bisphosphonate was also given before or after operation to three patients. RESULTS: Two patients underwent a unilateral thoracotomy for a single pulmonary lesion, and four other patients with multiple lesions underwent staged bilateral thoracotomies. The postoperative serum calcium level returned to normal after each thoracotomy in three patients who were alive and well 3, 8, and 12 years after the first thoracotomy. Hypercalcemia persisted in the other three patients. In two of the patients, bisphosphonate therapy was also unable to control hypercalcemia. In one patient the serum calcium level has been maintained in the 13 mg/dl range by bimonthly bisphosphonate therapy alone for 3 years. CONCLUSIONS: The aggressive surgical approach to pulmonary metastasis of parathyroid carcinoma was shown to be effective for palliation in selected patients. Bisphosphonate therapy is an alternative to resection but has only a temporary calcium-lowering effect.     

A method for performing a calcium balance study in man and the interpretation of results

Methods for the measurement of calcium in the diet, urine and faeces for the performance of a calcium balance study was described, along with experiments on analytical procedures including recovery values. A means of calculating the inherent "technical error" in such a balance is given, and a method for determining the significance of any change in a patient's balance is described. These are illustrated by worked examples of data from a patient suffering from Paget's disease and one with osteoporosis before and after treatment with calcitonin.     

The levels of granulocyte colony-stimulating factor in the plasma of the bone marrow aspirate in various hematological disorders

We developed a sensitive method of measurement of granulocyte colony-stimulating factor (G-CSF) by an enzyme-linked immunosorbent assay, which we applied in the plasma of the bone marrow aspirate in 70 patients with various hematological disorders. The lowest limit of detection by this method is 2 pg/ml. G-CSF was detected in all but two of the patients. Compared to the G-CSF level in normal healthy controls, those in non-Hodgkin's malignant lymphoma, aplastic anemia, agranulocytosis and multiple myeloma were significantly higher, while the level in refractory anemia was not different. The G-CSF level in acute myelogenous leukemia patients was either elevated or decreased regardless of the French-American-British subgroup. The level in acute lymphoblastic leukemia was not different from the normal value, as was that in refractory anemia with an excess of blasts, and that in chronic lymphocytic leukemia. A patient with chronic myelomonocytic leukemia showed initial elevation of G-CSF with normalization after entering complete remission. The G-CSF level in chronic myelogenous leukemia was significantly decreased, although one patient in hematological remission who was under alpha-interferon therapy showed normal levels. The level in polycythemia vera was not significantly different from the normal value. The G-CSF level for the entire group showed an inverse, although not statistically significant, correlation with the percentages of myeloid cells of the bone marrow (r = -0.174, p = 0.1703, n = 80). These results are thought to reflect the regulatory mechanism of granulopoiesis in the bone marrow in various hematological disorders, and it is concluded that this method may be of clinical use in the treatment of patients with these disorders and in the selection of candidates likely to benefit from G-CSF administration.