HBsAg-positive chronic liver disease: inhibition of DNA polymerase activity by vidarabine.

Four patients who had chronic liver disease and were positive for hepatitis B surface antigen (HBsAg) were treated with vidarabine, a synthetic purine nucleoside that inhibits DNA polymerase activity in vitro and in vivo. Before treatment all had raised serum DNA polymerase concentrations. Three also had hepatitis B e (HBe) and were shown by electron microscopy to have hepatitis B virus (Dane) particles in their serum. In all patients 10 days'' treatment with vidarabine resulted in an immediate loss of DNA polymerase activity. In three patients the activity returned when treatment was stopped. In those three patients Dane particles and HBe antigen persisted during and after treatment; in the fourth patient, who remained negative for DNA polymerase, HBsAg titres fell. Although vidarabine inhibited virus replication, virus particles did not disappear from the blood in these patients, presumably because the particles were cleared only slowly. Similar results with interferon suggest that the virus disappears, and HBsAg titres fall, some weeks after the fall in DNA polymerase activity. Continued treatment may therefore have a sustained effect on viral replication. Whether vidarabine can permanently clear HBsAg and so arrest chronic liver disease remains to be seen, but at the very least it could reduce the spread of infection.     

Renal excretion of fluoride in renal failure and after renal transplantation.

We have compared the renal excretion of fluoride in a variety of patients with chronic renal failure maintained with and without protein restriction before and during regular dialysis treatment and after transplantation. The patients tended to continue to excrete normal dietary loads of fluoride quite well until renal function was seriously reduced. From a regression of function on excretion the mean level of creatinine clearance when a normal dietary load of fluoride 0.0526 plus or minus 0.019 mmol/2 h (1.0 plus or minus 0.36 mg/24h) has a 90% chance of being excreted lies around 16 ml/min, a level when most patients with renal failure will be symptomatic. Acute loading of such patients with additional fluoride in the form of sodium fluoride from 40 mg to 60 mg/day showed a twofold to threefold increase of serum fluoride concentrations, slight increases in urinary fluoride excretion, and heavy tissue absorption, suggesting that prior fluoride loading of the skeleton had not taken place. These effects contrasted with those in one patient with normal renal function and with those in one patient with skeletal saturation due to prolonged loading. After renal transplantation fluoride excretion increased but reached normal levels within three months of satisfactory function, suggesting that fluoride loading in renal failure and during regular dialysis therapy had not been excessive.     

Successful antimicrobial therapy of hepatic,intra-abdominal and intrapelvic abscesses.

Antimicrobial therapy without surgical drainage or therapeutic aspiration was effective in the management of four patients with deep abscesses ranging in diameter from 1.3 to 10.0 cm. Two of the patients had multiple hepatic abscesses, one had hepatic, intra-abdominal and intrapelvic abscesses, and one had an intrapelvic abscess alone. Anaerobic bacteria were isolated from the blood or abscesses in all four patients, and an aerobic-anaerobic infection was present in one patient. The patients were treated with metronidazole, alone or in combination with other antibiotics, for 3 to 6 weeks. Therefore, in selected patients with deep abscesses, a therapeutic trial of antimicrobial agents instead of surgery may be justified.     

Local infusion of urokinase and heparin into renal arteries in impending renal cortical necrosis.

Two patients with presumed impending cortical necrosis, after haemolytic uraemic syndrome in one and after concealed accidental haemorrhage in the other, were treated by local infusion of urokinase and heparin into the renal artery. Both recovered and one regained normal renal function. Local infusion of anticoagulants or thrombolytic drugs into one renal artery offers the possibility of a controlled examination of the efficacy of this treatment in preventing cortical necrosis.     

131I]metaiodobenzylguanidine therapy in carcinoid tumors.

Our experience with [131I]metaiodobenzylguanidine (131I-MIBG) therapy in two patients with carcinoid tumor is described. These patients were selected because of multiple areas of uptake on 131I-MIBG scan, consistent with the extent of the disease. Both patients presented diarrhea and liver metastases. Para-aortical lymphonodes and skeletal metastases were present in the first and the second patient, respectively. Previous treatment involved r-alpha-interferon, surgery or radiotherapy. In both cases 131I-MIGB therapy was started in December 1990 and is still continuing. No haematologic or hepatic side-effects have been observed. Mild hypotension (90/60 mmHg) occurred in one patient during the first course of therapy and was resolved by corticoid treatment. A stabilization of disease and a progressive reduction of diarrhea have been observed in both patients. In the second patient an initial decrease in liver metastases was confirmed by ultrasonography 7 months after the beginning of therapy.     

A Clinical Evaluation of Peritoneal Dialysis

A total of 18 peritoneal dialyses were performed on 14 patients at the Hamilton Civic Hospital over a period of 11 months. Nine of these patients were in uremia, four had non-nephrotoxic intoxication, and one had hepatic coma. Patients with chronic uremia may present with acute renal failure which may be treated by peritoneal dialysis with resultant significant prolongation of life. A decreased mortality rate might be expected in acute renal failure if dialysis is implemented before the classical picture of uremia develops. Many non-nephrotoxic intoxicating substances are readily dialysable. Considerable benefit to the patient and decreased time in hospital may result from the use of this procedure in cases of intoxication with such substances. Peritoneal dialysis may be of value in treatment of intractable congestive heart failure. This procedure may eventually provide another means of treating hepatic coma.     

Effects of piperine on antioxidant pathways in tissues from normal and streptozotocin-induced diabetic rats

Using diabetes mellitus as a model of oxidative damage, this study investigated whether subacute treatment (10 mg/kg/day, intraperitoneally for 14 days) with the compound piperine would protect against diabetes-induced oxidative stress in 30-day streptozotocin-induced diabetic Sprague-Dawley rats. Liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione (GSH and GSSG, respectively) content, and activities of the free-radical detoxifying enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. Piperine treatment of normal rats enhanced hepatic GSSG concentration by 100% and decreased renal GSH concentration by 35% and renal glutathione reductase activity by 25% when compared to normal controls. All tissues from diabetic animals exhibited disturbances in antioxidant defense when compared with normal controls. Treatment with piperine reversed the diabetic effects on GSSG concentration in brain, on renal glutathione peroxidase and superoxide dismutase activities, and on cardiac glutathione reductase activity and lipid peroxidation. Piperine treatment did not reverse the effects of diabetes on hepatic GSH concentrations, lipid peroxidation, or glutathione peroxidase or catalase activities; on renal superoxide dismutase activity; or on cardiac glutathione peroxidase or catalase activities. These data indicate that subacute treatment with piperine for 14 days is only partially effective as an antioxidant therapy in diabetes.     

Can elevated chromium induce somatopsychic responses?

The possible somatopsychological effects of chromium (Cr) was investigated in a population of patients, from a surgical ward of our hospital, who required total parenteral nutrition (TPN) solutions, and who became exposed to various amounts of this metal from this treatment. The study involved a questionnaire as well as biochemical tests which included serum Cr and other selected trace metals. The renal status for all eligible patients was within normal parameters. The patient population varied in age, pathology, surgical treatment, and duration on TPN. The results showed that every patient who received TPN had an increased serum Cr level; some increases were up to 50-fold above the normal reference level for serum Cr. Although statistical analysis failed to show any significant statistical relationship between an increased serum Cr and the investigated somatopsychological disturbances, this effect cannot be ruled out since one case did show all the dream disturbances: Considering these cases, the action of sedative medications that may suppress the effects of Cr, cannot be ruled out. As Cr(III) may be potentially genotoxic at high concentrations, infusion of this metal over long time periods should be avoided. Supplementation of Cr in TPN solutions appears to be unnecessary for short-term TPN because this metal is a known contaminant of these solutions. Efforts are required to find TPN nutrients with low or no Cr contamination.     

Renal function in patients receiving long-term lithium therapy.

Renal function was assessed in 42 stable outpatients who had been taking lithium for an average of 4 1/2 years. Impaired ability to concentrate the urine was found in 61% of the 41 patients who provided a urine sample for an osmolality measurement, and a moderate reduction in creatinine clearance was present in 12% of the entire group; 1 patient showed both defects. Urine microscopy revealed an excess of cells in 40%. It is suggested that lithium therapy produces a self-limiting lesion of the distal nephron that does not usually progress to chronic renal failure. The lesion is not dangerous, except that it may predispose to acute neurotoxic effects in the event of intercurrent illness or dehydration.     

Renal failure in otherwise uncomplicated acute viral hepatitis.

Twelve patients with otherwise uncomplicated acute viral hepatitis (two were HBsAg-positive) developed renal failure. Apart from dehydration due to repeated vomiting in one patient, no factor responsible for precipitating renal failure could be identified. The clinical course was characterised by renal failure with plasma urea concentrations reaching maximum values of 26-69 mmol/l (175-416 mg/100 ml). Ten patients needed dialysis for up to two weeks. Seven patients recovered completely, while the other five died from sepsis. The types of renal failure were similar to those described in fulminant hepatic failure and cirrhosis--namely, functional renal failure in five patients and acute tubular necrosis in seven. Two of the patients with functional renal failure later developed tubular necrosis. The mechanism responsible for renal failure in acute viral hepatitis is uncertain, though endotoxaemia may contribute.     

Late treatment of paracetamol poisoning with mercaptamine.

Forty patients who had taken overdoses of paracetamol were treated with mercaptamine. Twenty-three patients given mercaptamine within 10 hours of poisoning had normal liver function tests at follow-up, and one could not be traced. In 16 patients mecraptamine was begun more than 10 hours after ingestion of paracetamol ("late" mercaptamine). Eight of these patients developed severe liver damage, which in six was moderate or severe before mercaptamine administration. Acute renal failure occurred in two patients; in one other renal function was temporarily severely impaired. At follow-up two patients were not available, and one admitted moribund had died soon after admission. The remaining 13 all had normal liver function tests. It is concluded that late mercaptamine is not dangerous and may prevent further liver damage.     

Cyclophosphamide Therapy in the Nephrotic Syndrome in Childhood

Forty-six children with the nephrotic syndrome whose renal biopsy specimens showed minimal changes and whose response to corticosteroid therapy was unsatisfactory were treated with cyclophosphamide. Three patients were completely steroid-resistant from the outset and the remainder were steroid-dependent. In several patients steroids controlled the condition less effectively with time. Most patients showed signs of steroid toxicity, and growth retardation was striking.A moderate leucopenia was induced with cyclophosphamide, and treatment was maintained for three to four months in the majority of cases. Thirty-eight children (83%) have remained in complete remission off all treatment for periods of 3 to 23 months, 33 after one course of cyclophosphamide and five after a second course. Two other patients who remitted but relapsed later are still on treatment. In only six patients was full remission not obtained, and three of these were steroid-resistant from the start. Two died from pneumonia and adrenal failure and four continued to have proteinuria, though in one an impressive reduction occurred.The results indicate that cyclophosphamide therapy is an effective alternative for nephrotic children with normal glomeruli on light microscopy who develop steroid dependence or resistance, and who exhibit toxic effects of steroid therapy.     

Phase I evaluation of coumarin (1,2-benzopyrone) and cimetidine in patients with advanced malignancies.

Fifty-four patients with advanced malignancies were treated on this phase I trial of coumarin and cimetidine. The dose of coumarin was escalated, with three patients treated at each dose level, while the cimetidine dose was held constant at 300 mg four times daily. Patients received coumarin alone as a single daily oral dose for 14 days; on day 15, cimetidine was added and both drugs were continued until progression of disease. This trial was initiated with patients receiving coumarin at 400 mg daily and closed at 7 g daily with four of five patients on this dose experiencing nausea and vomiting. Treatment was generally well tolerated over a wide range of coumarin doses. Symptomatic side effects were few, mild, and usually self limited. Side effects included insomnia, nausea, vomiting, diarrhea, and dizziness. Two patients withdrew from therapy because of daily nausea and vomiting. Typically, nausea, vomiting, and dizziness occurred 2.5-3 hours after a dose of coumarin. In most patients, these side effects abated spontaneously with continuation of therapy. There was no significant hematologic or renal toxicity. Hepatotoxicity occurred in only one patient and was manifested by asymptomatic abnormal elevations of serum hepatic transaminases. This toxicity was reversible upon interruption of therapy. Objective tumor regressions were observed in six patients with renal cell carcinoma. Responses occurred at coumarin doses ranging from 600 mg to 5 g daily. Coumarin is a relatively nontoxic, oral, outpatient therapy that warrants further investigations for the treatment of human malignancies. Because of its low toxicity, there is potential for combining coumarin with chemotherapeutic and/or biological agents in an attempt to improve on efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of quercetin on antioxidant defense in streptozotocin-induced diabetic rats.

In light of evidence that some complications of diabetes mellitus may be caused or exacerbated by oxidative damage, we investigated the effects of subacute treatment with the antioxidant quercetin on tissue antioxidant defense systems in streptozotocin-induced diabetic Sprague-Dawley rats (30 days after streptozotocin induction). Quercetin, 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one, was administered at a dose of 10mg/kg/day, ip for 14 days, after which liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione content, and activities of the free-radical detoxifying enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. Treatment of normal rats with quercetin increased serum AST and increased hepatic concentration of oxidized glutathione. All tissues from diabetic animals exhibited disturbances in antioxidant defense when compared with normal controls. Quercetin treatment of diabetic rats reversed only the diabetic effects on brain oxidized glutathione concentration and on hepatic glutathione peroxidase activity. By contrast, a 20% increase in hepatic lipid peroxidation, a 40% decline in hepatic glutathione concentration, an increase in renal (23%) and cardiac (40%) glutathione peroxidase activities, and a 65% increase in cardiac catalase activity reflect intensified diabetic effects after treatment with quercetin. These results call into question the ability of therapy with the antioxidant quercetin to reverse diabetic oxidative stress in an overall sense.     

Drug dosing guidelines in patients with renal failure.

The metabolism and excretion of many drugs and their pharmacologically active metabolites depend on normal renal function. Accumulation and toxicity can develop rapidly if dosages are not adjusted in patients with impaired renal function. In addition, many drugs that are not dependent on the kidneys for elimination may exert untoward effects in the uremic milieu of advanced renal disease. A familiarity with basic pharmacologic principles and a systematic approach are necessary when adjusting drug dosages in patients with abnormal kidney function. The distinct steps involve calculating the patient''s glomerular filtration rate, choosing and administering a loading dose, determining a maintenance dose, and a decision regarding monitoring of drug concentrations. If done properly, therapy in renal patients should achieve the desired pharmacologic effects while avoiding drug toxicity. Physicians must not oversimplify the pharmacologic complexities presented by patients with renal failure by relying excessively on nomograms and "cookbook" equations. In addition to a reduced glomerular filtration rate, patients with renal disease often have alterations in pharmacokinetics such as bioavailability, protein binding, hepatic biotransformation, and volume of distribution. An awareness of biologically active or toxic metabolites of parent compounds that accumulate when the glomerular filtration rate is reduced is also necessary to avoid toxicity. The effects of dialysis on drug elimination and the need for supplemental dosing are additional considerations in patients undergoing renal replacement therapy.     

Absence of Nafcillin-Associated Nephritis: A Prospective Analysis of 210 Patients

In a prospective study of 210 consecutively seen patients receiving nafcillin, no patient''s therapy was discontinued because of clinically manifested or suspected nephritis. Administration of nafcillin was discontinued because of an adverse reaction in only two patients, one with a rash and one with neutropenia. In seven of the ten patients in whom renal dysfunction developed during treatment, renal function improved while the patients continued to receive nafcillin. In the remaining three patients, renal failure was attributed to other factors including rhabdomyolysis and myoglobinuria, gastrointestinal hemorrhage and hypotension, and what appeared to be aminoglycoside toxicity.No renal biopsy studies were done because none were clinically indicated. Although the results of this study do not rule out the possibility that nafcillin may induce nephritis, if it does occur it appears in such a mild form—manifested solely as urinary sediment abnormalities—or so infrequently that it was not detected in this group of patients.In four patients, leukopenia could not be explained on any basis other than nafcillin administration.     

Safety of treatment for subclinical osteomalacia in the elderly.

Forty one elderly patients admitted to hospital for acute illnesses were also found to have subclinical osteomalacia. Immediately before discharge, therefore, all were randomised to receive either vitamin D2 25 micrograms daily, alfacalcidol 0.5 micrograms daily, or placebo. Treatment was given for at least three months, those allocated to placebo then being switched to an active drug. Within the first three months of treatment with either of the active drugs most patients had exhibited a fall to normal in osteoid values. In only four treatment periods was there a mild increase in serum calcium concentration, and in no patient was this accompanied by deterioration in renal function. Any increase in serum creatinine concentration was invariably attributable to the underlying disease for which the patient had been admitted in the first place. Subclinical osteomalacia in the elderly may be corrected by relatively low doses of alfacalcidol (0.5 micrograms daily) or vitamin D2 (25 micrograms daily) given for three months. Such treatment is safe and not accompanied by a serious risk of hypercalcaemia or renal impairment.     

Decreased natural killer activity in thalassemia major: a possible consequence of iron overload

We have investigated the natural killer (NK) activity of both fractionated (Percoll density gradient) and unfractionated mononuclear cells from patients with beta-thalassemia major who are iron overloaded as a consequence of chronic transfusion therapy. These patients were found to have significantly decreased NK activity against K562 targets at all effector:target ratios tested (p less than 0.001). Both splenectomized and nonsplenectomized patients had normal proportions of Leu-11b-staining (NK) cells. Since they had normal to elevated absolute white cell and lymphocyte counts, a change in the absolute number of NK cells could not account for the decreased killing. We also found that the decrease in NK activity was transfusion related (r = -0.603, p less than 0.005). To determine whether or not this decrease in NK activity could be related to iron overload, we preincubated patient effector cells with desferrioxamine (DFO) or 2,3-dihydroxybenzoic acid (DHB) for 6 hr before addition of K562 targets. Both of these iron-chelating agents consistently increased the NK activity of cells from thalassemia patients. DHB had the greater effect, being able to increase patient NK activity to virtually normal levels. On the other hand, preincubation of cells from normal controls with DHB caused only a slight increase in NK activity, while similar treatment with DFO had little or no effect. When target cells were preincubated with the chelating agents before addition of either normal or patient effector cells, no change in cytotoxicity was seen, demonstrating that the chelating agents act at the effector cell level. Furthermore, if the chelating agents were saturated with iron prior to preincubation with the effectors, no increase in the cytotoxicity of thalassemic NK cells was observed. These results indicate that thalassemia patients have a reversible, transfusion-related decrease in NK function which may arise as a consequence of iron overload.     

Influence of treatment of diabetic rats with combinations of pycnogenol, beta-carotene, and alpha-lipoic acid on parameters of oxidative stress

Treatment with antioxidants may act more effectively to alter markers of free radical damage in combinations than singly. This study has determined whether treatment with combinations of pycnogenol, beta-carotene, and alpha-lipoic acid was more effective at reducing oxidative stress in diabetic rats than treatment with these antioxidants alone. It is not feasible, based on this study, to assume that there are interactive effects that make combinations of these antioxidants more effective than any one alone to combat oxidative stress. Female Sprague-Dawley rats, normal and streptozotocin-induced diabetic, were treated (10 mg/kg/day ip for 14 days) with pycnogenol, beta-carotene, pycnogenol + beta-carotene, or pycnogenol + beta-carotene + alpha-lipoic acid; controls were untreated. Concentrations of thiobarbituric acid reactive substances, glutathione and glutathione disulfide, and activities of glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase were measured in liver, kidney, and heart. Four types of effects were observed: (1) treatment with beta-carotene alone either reversed (cardiac glutathione disulfide) or elevated (cardiac glutathione, hepatic glutathione peroxidase activity) levels seen in diabetic animals; (2) beta-carotene alone produced no effect, but pycnogenol both alone and in combinations elevated (renal glutathione peroxidase and glutathione reductase activities, hepatic glutathione reductase activity and glutathione disulfide) or depressed (cardiac glutathione disulfide) levels seen in untreated diabetic animals; (3) all treatments with antioxidants, either alone or in combination, either normalized (lipid peroxidation in all tissues), elevated (hepatic GSH, cardiac glutathione peroxidase activity), or had no effect on (activities of hepatic catalase and superoxide dismutase in all tissues) levels seen in diabetic animals; (4) in only one case (cardiac glutathione reductase activity) levels in diabetic animals treated with combinations of antioxidants were normal, but elevated in animals treated with either antioxidant alone. Antioxidant effects seem to be dependent on the nature of the antioxidant used and not on combination effects.     

Continuous ambulatory peritoneal dialysis: experience with 22 unselected patients with renal failure.

The present study describes our experience with CAPD in an unselected group of patients presenting with endstage renal failure. Twenty-three consecutive patients were offered CAPD, in-center, and home hemodialysis. Twenty-two patients selected CAPD, including 14 patients more than 60 years of age, four patients with diabetes, and one with multiple myeloma. CAPD training was performed in an out-of-hospital office facility. One patient returned to hemodialysis following the development of resistant Pseudomonas peritonitis, two patients died of a myocardial infarction, and one patient died with a GI bleed. The other 18 patients are doing well. Assessment of 17 patients maintained on therapy for four months or more revealed that the patients are less depressed, less organic, and have fewer physical symptoms than previously reported for a comparable group of patients maintained on hemodialysis for a similar period of time. In conclusion, CAPD can be successfully employed, at least for the initial months of therapy, to treat the vast majority of patients with endstage renal disease. CAPD training and follow-up care can be provided in an out-of-hospital office facility.