The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2'-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short- lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2'-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.     

Protective effects of R 56 865 against ischemic damage in the isolated rabbit heart.

We examined the role of calcium in the pathogenesis of ischemic cardiac cell death in the isolated working rabbit heart subjected to normothermic global ischemia followed by reperfusion. Apart from measurements of cardiodynamic function and ultrastructural examination, we also used a cytochemical procedure to localize exchangeable calcium pools at the ultrastructural level. The effects of verapamil (1.5 x 10(-8) M, 3 x 10(-8) M) (high affinity for L-type calcium channels) were compared with those of R 56 865 (4 x 10(-7) M) (Ca2+ overload blocker with low affinity for the L-type calcium channels). A severe depression of cardiac function was observed after solvent or verapamil pretreatment and 25 min of ischemia followed by reperfusion. R 56 865 treatment resulted in a significantly improved postischemic recovery when compared to solvent and verapamil treatment groups. The ultrastructural and cytochemical results corroborated the hemodynamic findings. In solvent and verapamil-treated hearts, irreversible damage was observed mainly in mid- and endocardial areas. Ultrastructural changes were accompanied by shifts in calcium localization: i.e. loss of sarcolemmal calcium binding capacity, accumulation of calcium precipitate in the mitochondria. In the R 56 865 treatment group, damage was limited to some cells scattered in the midcardial areas. In conclusion, R 56 865, which has little affinity for the slow channels was highly effective in protecting against ischemic damage, indicating that, in this experimental set-up, the calcium responsible for cellular Ca2+ overload is not entering via L-type calcium channels.     

Iatrogene Trachealverletzung bei intraoperativer Bauchlagerung

Two patients 16 and 21 years old developed tracheal rupture during elective surgery following trouble-free orotracheal intubation and intraoperative ventral positioning. The injuries remained undetected in both patients for more than 12 h. Diagnostic investigation after the onset of first symptoms indicated in each a tear in the posterior tracheal wall. Early operation prevented the development of serious complications in both patients. The casuistics indicate that tracheal injuries can emerge in minor elective surgery that may be carried out on an outpatient basis, and ventral positioning for surgery may represent a risk factor for their occurrence. Clinical symptoms, diagnostic procedure, findings, and therapy are discussed.     

Prostaglandins and angioplasty. An experimental study in canine arteries

To prevent platelet aggregation following percutaneous transluminal angioplasty (PTA), cyclooxygenase inhibitors such as acetylsalicylic acid (ASA) and indomethacin are recommended. However, ASA blocks both the proaggregating effects of thromboxane (TXA2) and the antiaggregating and vasodilating effects of prostacyclin (PGI2). The authors measured the contractile response of dilated canine carotid arteries in situ and in vitro using an isometric force transducer. Following PTA, contraction of the arterial wall was significantly reduced (p less than 0.01). By blocking cyclooxygenase with indomethacin (3 micrograms/ml), contraction was greatly improved (p less than 0.001). These results suggest that PTA may result in marked release of prostacyclin by the damaged arterial wall, which could account for the decreased responsiveness of the artery to exogenous norepinephrine.     

Denovo urothelial carcinoma of the upper and lower urinary tract in kidney — transplant patients with end-stage analgesic nephropathy

Summary Patients with end-stage analgesic nephropathy bear a higher risk for urothelial cancer than do patients with other renal diseases. In a retrospective study in patients with analgesic nephropathy and kidney transplants we analyzed the prevalence and clinical course of de novo urothelial cancer. Diagnosis of analgesic nephropathy was based on the patients' history and clinical data. Only patients under cyclosporine treatment were included. Between 1968 and 1993, 2,371 kidney transplants were performed on 2,072 patients in the Department of Abdominal and Transplant Surgery. The prevalence of analgesic nephropathy was 3.1%. Of 65 patients with analgesic nephropathy and kidney transplants, 10 (15.4%) developed urothelial carcinoma; 10.8%, bladder cancer; and 9.1%, renal pelvic cancer. The mean age at diagnosis was 56.1 years. Urothelial cancer occurred on average at 33.6 months posttransplantation. On average, 6 of 10 patients with urothelial cancer died of the disease at 16.9 months after the diagnosis. All patients with urothelial bladder cancer had a muscle-infiltrating tumor of moderate or high grade. Since urothelial renal pelvic cancer occurred in 9.1% of our patients with analgesic nephropathy and urological screening is insufficient in patients on dialysis, we suggest that prophylactic nephroureterectomy be performed on one side before transplantation and on the contralateral side at 3–6 months after transplantation. An aggressive approach is indicated in patients with urothelial cancer of the bladder.     

St. Thomas Cardioplegia Versus Topical Cooling: Ultrastructural and Biochemical Studies in Humans

Transmural left ventricular biopsies were studied from 28 patients undergoing cardiopulmonary bypass with anoxic cardiac arrest. The myocardium was protected by topical cooling (20° C) (Group 1, 15 patients) or by cardioplegia with St. Thomas' solution (Group 2, 13 patients). Biopsies were taken at the start of bypass and 3 to 5 minutes after unclamping of the aorta. Mean cross-clamp time was not significantly different between the groups (50 minutes for Group 1 and 53 minutes for Group 2; p > 0.05).The ultrastructural changes induced by ischemia and subsequent reperfusion were almost exclusively related to the mitochondria. The degree of mitochondrial damage was evaluated by a semiquantitative analysis based on mitochondrial fine structure. The frequency of severe postischemic mitochondrial damage was significantly higher in Group 1 (20.1% verus 2.7% in Group 2; p < 0.05).Biochemical analysis of the biopsies indicates that the myocardial concentration of creatine phosphate decreases by about 50% after topical cooling (p < 0.05). With St. Thomas cardioplegia, no significant change in the tissue level of this high-energy phosphate takes place. The results show evidence of the superiority of the St. Thomas cardioplegia to topical cooling alone.     

Segmental unilateral priapism--a case report

A case of segmental priapism in a 24-year-old man with congenital spherocytosis is presented. Preoperative cavernosography and computer tomography clearly revealed thrombosis of the left proximal corpus cavernosum. Because the lesion had already been in existence for 5 weeks irrigation to flush out the thrombosis was no longer possible.