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Biomedical subjects

C Weiler

Publications and source records attributed to C Weiler.

At least 19 recordsLinked to original sources
PubMed1992

Increased prostaglandin PGE2 and 6-keto-PGF1 alpha immunoactivity in incubates of gastric mucosa and forestomach of nephrectomized rats.

Prostaglandin E2 (PGE2)- and 6-keto-PGF1 alpha-like immunoactivity was measured in incubates of forestomach and gastric corpus mucosa in (a) unoperated rats, (b) rats with sham-operation of the kidneys and (c) rats with bilateral nephrectomy. In addition the mean ulcer area in the forestomach and gastric mucosa was assayed in all three groups of rats. The PGE2- and 6-keto-PGF1 alpha-like immunoactivity in gastric mucosa incubates and 6-keto-PGF1 alpha in the forestomach incubates was almost the same in unoperated and sham-operated rats. Increased 6-keto-PGF1 alpha in the forestomach and of PGE2 and 6-keto-PGF1 alpha in the gastric mucosa was found in rats with bilateral nephrectomy before gastric lesions were seen. A higher mean ulcer area occurred in the forestomach and gastric mucosa 24-48 h after bilateral nephrectomy. We conclude, that the increased PGE2- and 6-keto-PGF1 alpha production by the gastric mucosa and forestomach was associated with the loss of normal renal tissue function. Despite the protection of PGE2 and PGI2 by gastric tissue, gastric lesions nevertheless occur in acute uraemic rats.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Gastric mucosal PGE2 levels in gastric non-ulcer and ulcer patients with chronic renal failure or without renal diseases and in healthy subjects.

PGE2-like immunoactivity in mucosal specimens from gastric corpus and antrum was measured in individuals with chronic uremia or without renal diseases in absence or presence of gastric ulcerations and in healthy subjects. Regardless the group of patients, compared to normal mucosa, a significant decrease in PGE2-like immunoactivity (50-70%) was found in mucosa from atrophic, but not from superficial gastritis. Whenever patients of the control group or patients with renal diseases suffered from ulcers, PGE2-like immunoactivity, compared to nonulcer subjects, revealed a decrease of about 60-70% in the nonulcerated mucosa. Compared to nonulcerated mucosa, the tissue of the ulcer rim in all patients with gastric ulcer showed a relative increase in PGE2-like immunoactivity, eg, PGE2-like immunoactivity was twice as high in tissue from the ulcer rim. The output of PGE2-like immunoactivity into the gastric juice of subjects without renal diseases was comparable to that found in patients with chronic uremia in both basal and pentagastrin-stimulated conditions. We therefore conclude that gastric mucosal formation is probably not influenced by chronic uremia.

Adult↗
PubMed1990

Gastric mucosal prostaglandin E2 levels in cirrhosis and portal hypertension.

Prostaglandin E2 (PGE2) tissue levels were measured, using radioimmunoassay, in specimens from the gastric antral mucosa in (a) healthy subjects, (b) patients without liver diseases in the absence or presence of gastric ulcers, and (c) patients with alcoholic cirrhosis in the absence or presence of gastric ulcers. These groups were divided further into subgroups with or without portal hypertension. PGE2 tissue levels in subjects without liver diseases were not significantly different from those of cirrhotic patients without portal hypertension. However, in cirrhotic patients with portal hypertension, the PGE2 content was significantly lower, especially in the presence of congestion in the mucosa (about 70-80%). When a gastric antral ulcer was present, a further statistically significant decrease of the PGE2 levels was observed. It was concluded that a decrease in the PGE2 tissue levels in the gastric mucosa of cirrhotic patients is related to the presence of portal hypertension. Congestion in the mucosa, as a pathogenetically relevant factor for mucosal PGE2 deficiency, may play a role.

Adult↗
PubMed1990

Gastric mucosal prostaglandin E2 levels in gastric non-ulcer and ulcer patients with chronic renal failure or without renal disease, and in healthy subjects.

Investigations were carried out as to whether a disturbance in the formation of cytoprotective prostaglandin (PG) E2 in gastric mucosa is implicated in chronic renal failure. PGE2-like immunoactivity in gastric mucosal specimens was measured in individuals with chronic renal failure (creatine clearance less than 10 ml/min), in individuals without any renal disease, presenting either gastric ulceration or not, as well as in healthy subjects. Regardless of the group of patients, compared to normal mucosa a significant decrease in PGE2-like immunoactivity (about 50-70%) was found in mucosa from atrophic gastritis but not from superficial gastritis. Whenever patients of the control group or patients with kidney disease suffered from ulcers, PGE2-like immunoactivity showed a decrease of about 60-70% in the non-ulcerated mucosa compared to that of non-ulcer subjects. Moreover, ulcer patients showed the same frequency of gastritis and similar mucosal PGE2-like immunoactivity in their non-ulcerated mucosa. Furthermore, compared to the tissue from the ulcer edge, independent of the presence of renal disease, a relative deficiency of PGE2-like immunoactivity of about 50-60% was detected in the non-ulcerated mucosa of ulcer patients. We therefore conclude that chronic renal failure probably has no impact on PGE2 formation in the gastric mucosa. All told, relative mucosal PGE2 deficiency in gastric ulcer disease seems not to be correlated with chronic renal failure.

Adult↗
PubMed1989

Clinical trials of WR-2721 and cis-platinum.

WR-2721 is an aminothiol compound; in the animal model it protects against the nephrotoxicity, neurotoxicity, and hematologic toxicity of cis-platinum. We initiated Phase I trials of WR-2721 and cis-platinum to determine toxicity when WR-2721 was given prior to escalating doses of cis-platinum. With mannitol diuresis and WR-2721, transient nephrotoxicity occurred in 9 of 30 (27%) patients treated with cis-platinum 150 mg/m2 and 7% of patients given with cis-platinum 120 mg/m2. Bone marrow suppression was mild and infrequent. Mild to moderate peripheral neuropathies occurred in 26% of patients courses following a mean cumulative cis-platinum dose of 725 mg/m2. Objective partial responses were observed in 53 of 118 (45%) patients with measurable disease. Antitumor responses were observed in 25 of 53 patients with metastatic melanoma, 12 of 22 patients with locally recurrent or metastatic head and neck cancer, and 7 of 13 patients with metastatic breast cancer refractory to conventional chemotherapy. Controlled studies of WR-2721 and cis-platinum will be performed in the Eastern Cooperative Oncology Group in these disease sites to better define the activity of this regimen and its toxicity.

Adult↗
PubMed1988

Enhanced calcitonin secretion in the rat after parathyroidectomy and during chronic calcium deprivation.

The thyroidal content of calcitonin (CT) and the serum calcitonin responses to acute hypercalcaemia were studied in female rats during chronic hypocalcaemia induced by parathyroidectomy (PTX), a low calcium (Ca) diet, or both. The thyroidal CT content of the PTX animals 50 days after surgery was twice that of intact rats. An acute intraperitoneal (i.p.) calcium load on day 50 after PTX resulted in an increase in serum CT twice as large as that observed in control animals. Reversal of the chronic hypocalcaemia with 1,25(OH)2D3 resulted in a reduction in thyroidal CT as well as a depression of the calcium-induced CT response. In each case the values were similar to those observed in normocalcaemic controls. A low calcium diet increased the thyroidal CT content in intact rats and induced a further increase in PTX rats. The CT response to an acute Ca load was exaggerated by a low calcium diet in intact as well as in PTX rats. These results suggest that in the rat chronic hypocalcaemia enhances CT storage and secretion.

Animals↗
PubMed1988

Integration of full-dose adjuvant chemotherapy with definitive radiotherapy for primary breast cancer: four-year update.

Controversy exists over the effect of definitive radiotherapy on the ability to administer full doses of adjuvant chemotherapy in primary breast cancer. Ninety-six consecutive women with clinical stage I and II breast cancer were treated with radiotherapy plus chemotherapy. Three combinations of drugs were used: cyclophosphamide and 5-fluorouracil (CF); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); or cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP). Chemotherapy consisted of two cycles of CF (cyclophosphamide at a dosage of 100 mg/m2 orally on days 1-14+5-fluorouracil at 600 mg/m2 iv on days 1 and 8) during concurrent radiotherapy, followed by six cycles of CMFP (same CF dosages+methotrexate at 40 mg/m2 iv on days 1 and 8+prednisone at 40 mg/m2 orally on days 1-14). The study included 63 premenopausal and 33 postmenopausal patients; 72 had 1-3 positive nodes, had greater than or equal to 4 positive nodes, and 9 had negative nodes and negative estrogen receptors. The mean CF doses delivered during concurrent radiotherapy were 95% of the optimal doses, and the mean CMF doses administered during the six cycles after radiotherapy were 89%. The CMF was delivered at level I (greater than or equal to 85% of optimal doses) to 73% of the patients. With a median follow-up of 36 months, 16 relapses have been observed. Two of these patients had treatment failure only in the breast or axilla and are disease free after mastectomy. Of the 72 patients with 1-3 positive nodes, 10 relapsed in distant sites, while 4 of 15 patients with greater than or equal to 4 positive nodes have had distant failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma.

Cisplatin, alone or in combination with other chemotherapeutic agents, is relatively inactive against metastatic melanoma. Prior trials have demonstrated partial response (PR) rates of less than 10% with cisplatin alone. WR-2721 is an organic thiophosphate compound, which in the animal model, selectively protects normal tissues against the toxicity of cisplatin chemotherapy. During the course of a phase I trial of WR-2721 and cisplatin, objective PRs were noted in patients with far advanced metastatic melanoma. These observations led us to perform a phase II trial of WR-2721 and cisplatin. Thirty-six patients received 128 courses of WR-2721 before cisplatin (60 to 150 mg/m2). All patients had progressive disease before treatment. Objective PRs were observed in 19 of 36 evaluable patients (53%). Three additional patients had minor responses (MRs). PRs occurred in 53% of patients with prior chemotherapy (ten of 19). Sites of responding metastases were subcutaneous disease (15 of 19 patients), lymph nodes (16 of 21 patients), lung (four of ten patients), and liver (eight of 17 patients). The median duration of response was 4 months, with a mean of 4.5 months (range, 1 to 8 months). Transient nephrotoxicity was observed in less than 5% of courses. In all cases, renal function returned to normal within 1 to 2 weeks. Hematologic toxicity was mild and infrequent. Nine patients developed peripheral neuropathy following a median cisplatin dose of 670 mg/m2. Twenty patients experienced mild clinical hearing loss. These data suggest that WR-2721 may potentiate the antitumor activity of cisplatin in metastatic melanoma.

Adult↗
PubMed1986

[Catecholamine behavior, adrenoreceptor density of intact cells and sensitivity to catecholamines in a patient with orthostatic hypotension].

We evaluated sympathetic nervous system function in a patient with primary orthostatic hypotension. Plasma catecholamine levels--except for dopamine levels--and urinary catecholamine excretion were decreased, alpha-adrenoreceptor responsiveness to noradrenaline and beta-adrenoreceptor responsiveness to isoproterenol were increased according to increased beta-2-adrenoreceptor density on intact polymorphonuclear leukocytes. Alpha-2-adrenoreceptor density on intact platelets and adrenaline-induced platelet aggregation in vitro, however, were unchanged. We evolved a therapeutic regimen with fludrocortisone, propranolol, and dihydroergotamine that allowed the patient to resume nearly a regular degree of mobility.

Aged↗
PubMed1986

Human pharmacokinetics of WR-2721.

The pharmacokinetic properties of WR-2721 were investigated in 13 cancer patients given a 150 mg/M2 intravenous bolus dose of the drug. An average plasma clearance value of 2.17 L/min was obtained. Very little of the drug or the two metabolites, WR-1065 and WR-33278, were excreted in urine obtained after the blood collection schedule. Plasma concentrations of WR-2721 decreased by 94% within 6 minutes of drug administration. The mean value of 6.44 L obtained for the steady-state volume of distribution indicates that the extravascular space occupied by the drug is small. These observations suggest that in human cancer patients, WR-2721 is rapidly taken up by tissues and converted to metabolites.

Amifostine↗
PubMed1986

Phase I/II trials of WR-2721 and cis-platinum.

Renal dysfunction is a well-known dose-limiting toxicity of cis-platinum. Previous studies demonstrated a 32% incidence of nephrotoxicity following a 100 mg/M2 single dose of cis-platinum with mannitol diuresis. WR-2721 is an aminothiol which in the animal model improves renal tolerance to cis-platinum by factors of 1.3 to 1.7. Phase I trials were initiated to establish the toxicity when WR-2721 was given prior to escalating doses of cis-platinum. Fifty-two patients received 161 courses of WR-2721 prior to cis-platinum (60-150 mg/M2) with mannitol and hydration. Nephrotoxicity, measured by twice weekly serum creatinines and monthly creatinine clearances, occurred in only 10/97 (10%) courses with 120 mg/M2 of cis-platinum. No patient experienced a creatinine elevation after 135 mg/M2 of cis-platinum. With 150 mg/M2 of cis-platinum, 6/17 (35%) courses were associated with transient nephrotoxicity. Five patients who developed transient creatinine elevations following 150 gm/M2 of cis-platinum were subsequently retreated with WR-2721 and cis-platinum (100 mg/M2) without nephrotoxicity. Bone marrow suppression was mild and infrequent. Mild to moderate peripheral neuropathies were noted in seven patients following cumulative cis-platinum doses ranging from 460-1160 mg/M2. Objective partial responses were observed in 26/45 (58%) patients with measurable or evaluable disease. Thus, there is no evidence that WR-2721 protects against the antitumor efficacy of cis-platinum in man. Compared to retrospective series, our data suggest that WR-2721 may provide some protection against platinum-induced nephrotoxicity and neurotoxicity. Controlled trials will be required to define the potential clinical benefit of WR-2721 and cis-platinum.

Amifostine↗
PubMed1986

WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial.

WR-2721 S-2-(3-aminopropylamino) ethyl phosphorothioic acid, is an organic thiophosphate compound that in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Preliminary data from our controlled phase I trial of WR-2721 and cyclophosphamide suggested that WR-2721 protected against cyclophosphamide-induced granulocytopenia. Since variable drug doses and infusion rates were used in these early studies, we initiated a controlled phase II trial using constant drug doses to establish more precisely WR-2721's level of protection. Initially, 21 patients received 1,500 mg/m2 of cyclophosphamide alone and were retreated 4 weeks later after hematologic recovery was complete with 740 mg/m2 of WR-2721 before the same dose of cyclophosphamide. With WR-2721 pretreatment, 19 of 21 (90%) patients had improved WBC and granulocyte counts. The mean WBC increased from 1,760/mL with cyclophosphamide alone to 2,500/mL with WR-2721 pretreatment (P less than .0005). The mean granulocyte count increased from 541/mL on cyclophosphamide to 1,247/mL with WR-2721 and cyclophosphamide (P less than .0005). Following cyclophosphamide administration alone, neutropenic fevers developed in three patients. No patient experienced a febrile episode following WR-2721 and cyclophosphamide administration. Platelet nadirs below 100,000/mL were only noted in two patients treated with cyclophosphamide alone. Objective partial responses were observed in four of 19 (21%) patients with measurable or evaluable disease. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced hematologic toxicity.

Aged↗
PubMed1986

Final report of the phase I trial of single-dose WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid].

Two hundred one patients were entered in a single-dose phase I trial of WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid]. Major toxic effects included emesis and hypotension. The observed minor toxic effects were somnolence and sneezing. Two infusion schedules were tested: long-infusion time, which fixed the rate, but varied total time; and short-infusion time, which varied the rate, but fixed the time to 15 minutes. Emesis was significantly influenced by infusion time; the long schedule caused a 57% incidence whereas the short schedule caused only a 28% incidence. Within the long-infusion group, higher-dose patients and women were more likely to vomit. Although only 15% of the entire group had hypotension, the long-infusion schedule had a hypotension incidence of 23%; the short schedule had an incidence of only 3% (P less than 0.0005). Within the long-infusion group, dose and tumor site significantly influenced the incidence of hypotension. No factors were associated with these toxic effects in the short-infusion schedule. However, certain toxic effects were too infrequent to detect significant differences. For future trials we recommend 740 mg/m2 infused in 15 minutes. With this schedule, vomiting was seen in 25% of infusions and hypotension was seen in only one of 68 infusions. To date, no delayed toxic effects have been detected in any organ system, and the trial resulted in no toxic deaths.

Adult↗
PubMed1985

Treatment of hypercalcemia in parathyroid cancer with WR-2721, S-2-(3-aminopropylamino)ethyl-phosphorothioic acid.

The chemoprotective and hypocalcemic agent WR-2721, S-2-(3-aminopropylamino) ethyl-phosphorothioic acid, inhibits parathyroid hormone secretion in vivo and in vitro. We report the first clinical use of WR-2721 in refractory hypercalcemia secondary to parathyroid cancer. After several days of saline diuresis the patient received WR-2721, 740 mg/m2 over 15 minutes, resulting in a fall in serum calcium from 11.76 to 9.06 mg/dL within 24 hours. Serum parathyroid hormone levels decreased from 675 to 140 microLeq/mL 2 hours after the infusion was complete. When hypercalcemia recurred the patient was retreated with differing doses and infusion rates to determine the optimal method of drug administration to provide a satisfactory hypocalcemic response without adverse effects. In this patient, WR-2721 in intravenous boluses of 150 mg/m2 was effective without adverse effects. Using high-pressure liquid chromatography with electrochemical detection, plasma pharmacokinetic studies showed that WR-2721's distribution half-life is 0.55 minutes.

Adenoma↗