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Biomedical subjects

D Glover

Publications and source records attributed to D Glover.

At least 55 records · Page 3Linked to original sources
PubMed1988

Myocardial kinetics of technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile.

To study the potential usefulness of technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile (Tc-MIBI) as a cardiac perfusion imaging agent, the left circumflex coronary arteries of 12 dogs were partially occluded. Eight additional control dogs had no coronary artery stenosis. Myocardial Tc-MIBI activities in the left circumflex and left anterior descending zones were continuously monitored by miniature implantable radiation detectors for 4 hr after administration of the isotope. The dogs were then killed. Serial gamma camera images were also acquired during the study. Heart rate, arterial blood pressure, pressure distal to the stenosis, and cardiac output did not change significantly during the experiment. Microsphere-determined regional myocardial blood flow was significantly reduced in the left circumflex distribution in the 12 dogs with coronary artery stenoses. In the 12 dogs with left circumflex coronary artery stenoses, the 4 hr fractional Tc-MIBI clearances from the normal and ischemic zones were minimal and equivalent (0.15 +/- 0.05 vs 0.15 +/- 0.07). In the eight control dogs, 4 hr fractional Tc-MIBI clearances from the left anterior descending and left circumflex artery zones were minimal and equivalent (0.11 +/- 0.06 vs 0.10 +/- 0.07). Four hour fractional Tc-MIBI clearance from the blood was 0.98 +/- 0.03 for the dogs with stenosis and 0.97 +/- 0.02 for the dogs without stenosis. One additional dog had complete occlusion of the left circumflex coronary artery followed by administration of Tc-MIBI and scandium-46-labeled microspheres. This heart was immediately sectioned and counted to determine the relationship of regional blood flow to Tc-MIBI distribution (r = .92).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of myocardial ischemia on regional function and stiffness in conscious dogs.

The extent to which cardiac nerves influence responses of regional ventricular function to acute myocardial ischemia was investigated in conscious dogs with intact cardiac innervation (N) and dogs with chronic cardiac denervation (D). Following coronary artery occlusion (CAO) left ventricular (LV) end-diastolic pressure increased more (P less than 0.01) in D (18 +/- 3.2 mmHg) than in N dogs (3.4 +/- 0.7 mmHg), whereas heart rate increased more in N (32 +/- 4.8 beats/min) than in D dogs (16 +/- 3.0 beats/min). In nonischemic zones of D dogs there were greater increases, P less than 0.05, in end-diastolic segment length, systolic segment shortening, and velocity of shortening than in N dogs. In ischemic zones, significantly greater increases in end-diastolic segment length were also observed in the D group, but similar reductions in segmental shortening occurred in both N (-116 +/- 2.8%) and D (-108 +/- 5.2%) dogs. The time constant of isovolumic relaxation was not different in the two groups. However, in ischemic zones of N dogs myocardial stiffness constant (k) increased by 109 +/- 24 from 33 +/- 4.9 and end-diastolic stiffness (Eed) rose by 1527 +/- 310 from 253 +/- 34 mmHg, whereas k increased significantly less (P less than 0.05) in D dogs. Eed of ischemic zones also rose significantly less (P less than 0.05) in D dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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

Phase II trial of misonidazole (MISO) and cyclophosphamide (CYC) in metastatic renal cell carcinoma.

In animal models pre-treatment with misonidazole, a hypoxic cell radiosensitizer, enhances the antineoplastic effects of alkylating agent chemotherapy. Laboratory data suggest that hypoxic tumor cells may be more resistant to chemotherapy because of suboptimal drug delivery, reduced rates of cell division, or because hypoxia confers relative drug resistance. The therapeutic potential depends on the tumor type, doses of radiosensitizer and alkylating agent, the time interval between drug administration, and the ratio of sensitization of normal and malignant tissues. A Phase II trial of misonidazole and cyclophosphamide was initiated by the Eastern Cooperative Oncology Group to determine the response rate and toxicity in patients with metastatic renal cell cancer. Patients received 5 gm/m2 of misonidazole intravenously two hr before 1200 mg/m2 of cyclophosphamide every 3 wk. Patients with prior chemotherapy or radiotherapy received 1000 mg/m2 of cyclophosphamide. Misonidazole was discontinued after a total dose of 15 gm/m2. The median total misonidazole dose was 23.5 gm (range 4.5-34.5 gm). The median number of cyclophosphamide cycles was 2 (range 1-12). Of the 30 patients evaluable for response, only one patient had an objective partial response. Twenty-nine patients had stable or progressive disease. One patient remains on cyclophosphamide after 9 mo. Estimated median survival is 4.8 mo. There have been no lethal toxicities; however, 9 patients (25%) experienced life-threatening leukopenia and an additional 42% experienced severe hematologic toxicity. Eight patients had WBC less than 1000 on days 7-14 of cycle 1. Thrombocytopenia and grade 3 anemia occurred in 1 and 2 patients, respectively. Moderate or severe nausea and vomiting occurred in 47% and 19% of patients, respectively. Only 3 patients experienced severe neurotoxicity. Four additional patients had moderate neurotoxicity. In summary, misonidazole in this dosing schedule does not enhance the antitumor activity of cyclophosphamide in renal cell carcinoma.

Carcinoma, Renal Cell↗
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↗
PubMed1985

High-dose oral metoclopramide. An effective antiemetic agent.

Seventy-six patients receiving cisplatin and noncisplatin-containing cancer chemotherapy were treated with an outpatient phase II metoclopramide regimen. The program consisted of an outpatient intravenous loading dose of metoclopramide before chemotherapy, followed by oral metoclopramide at 1, 3, 5, and 8 hours after chemotherapy. Three oral dose levels were evaluated. Treatment with 2 mg/kg/dose or 100 mg/dose resulted in no vomiting in 53% of 65 evaluable patients, and 0-2 episodes of emesis in 74%. Oral doses of 50 mg/dose were less effective, preventing emesis in 18%. This trial demonstrated the antiemetic effectiveness of high-dose oral metoclopramide in a new schedule designed for the outpatient setting. The side effects included restlessness (51% of patients), dystonic reactions (9%), and gastrointestinal complaints (41%).

Adolescent↗
PubMed1985

Blood glucose homeostasis in rats with a deficiency of liver phosphorylase kinase.

The glycogen storage disorder (gsd/gsd) rat has little or no phosphorylase kinase activity in the liver and is unable to break down liver glycogen on fasting. Nevertheless, gsd/gsd rats do not become hypoglycaemic on fasting. Gsd/gsd rats showed a decreased rate of glucose turnover measured with [6-3H]glucose. Perfused livers from gsd/gsd rats showed decreased rates of gluconeogenesis from lactate and alanine when the results were expressed per gram of liver, but the total glucose produced per liver was normal. Measurement of gluconeogenesis in vivo using [14C]-bicarbonate showed that gsd/gsd rats had a decreased rate of glucose production from substrates that enter the gluconeogenic pathway before pyruvate. We conclude that gsd/gsd rats have adapted to unavailability of liver glycogen by decreasing peripheral uptake of glucose and not by increasing gluconeogenesis.

Animals↗
PubMed1984

BIOLOG - a DNA sequence analysis system in PROLOG.

BIOLOG contains facilities for the analysis of nucleic acid sequences. These facilities are available through queries and commands of the underlying implementation language PROLOG. Familiarity with PROLOG is gained by using the built-in BIOLOG functions. This experience should enable the user to extend the current system and define new facilities.

Amino Acid Sequence↗
PubMed1984

Alterations in oxygen transport following WR-2721.

The toxicity of radiation and alkylating agent chemotherapy is in part related to free radical formation in DNA and associated proteins, which is enhanced by oxygen and other electron affinic compounds. During the Phase I clinical trials of WR-2721 and alkylating agent chemotherapy, venous blood samples were obtained prior to and immediately following the WR-2721 infusion. We have observed a marked increase in the oxygen saturation of venous blood following WR-2721 (430-910 mg/m2 at a rate of 15 mg/m2/minute). The mean venous PO2 (PvO2) rose from a baseline of 34.0 +/- 13.54 torr to a mean value of 54.60 +/- 12.47 torr (p less than 0.001). The percent venous oxygen saturation increased from 54.52 +/- 21.38% to 82.73 +/- 7.66%. The highest values generally occurred within the first 2 hours after the completion of the WR-2721 infusion. No significant differences were found between the pre and post WR-2721 values for either the venous pH, CO2, or bicarbonate levels. Despite increased PvO2, the patients' heart rates, blood pressures, or respiratory rates did not change pre and post WR-2721. No apparent differences were noted in the effects of WR-2721 or PvO2 when given at doses of 740 or 910 mg/m2. However, when WR-2721 (418-1100 mg/m2) was administered over 15 minutes, the PvO2 increased in only 8/13 courses. We postulated that the marked increase in venous blood oxygen concentration was secondary to one of the following mechanisms: 1) Increased affinity of hemoglobin for oxygen, 2) microcirculatory shunting, or 3) decreased tissue requirements for oxygen. In 12 patients oxygen-hemoglobin dissociation curves and intracellular red cell pH's were obtained before and after 740-910 mg/m2 of WR-2721. Despite the significant increase in oxygenation of venous blood after WR-2721, there were no changes in either oxygen-hemoglobin dissociation or intracellular red cell pH to account for this increase. The oxygen consumption of peripheral blood granulocytes was measured prior to and following 15 courses of WR-2721. A marked decrease in granulocyte oxygen consumption was observed in 6/8 patients who had a significant increase in PvO2 and only 1/7 patients who had either a decrease or no change in PvO2 after WR-2721. Our preliminary investigations suggest that the increased venous blood oxygen content may be secondary to a reduction in normal tissue oxygen consumption. WR-2721 may afford protection by both decreasing oxygen consumption and delivery to normal tissues and increasing intracellular sulfhydryls.

Amifostine↗
PubMed1984

Phase I controlled trials of WR-2721 and cyclophosphamide.

WR-2721 is an organic thiophosphate compound which in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Controlled Phase I trials of WR-2721 and cyclophosphamide were initiated to determine if WR-2721 protected against cyclophosphamide's hematologic toxicity. Fifteen patients received WR-2721 (450-1100 mg/m2) prior to cyclophosphamide (1200-1800 mg/m2) and were subsequently retreated 4 weeks later with the same cyclophosphamide dose alone. With WR-2721 pretreatment, 11/15 (73%) patients had improved WBC counts. The mean WBC increased from 1800/mm3 on cyclophosphamide alone to 2700/mm3 with WR-2721 + cyclophosphamide (p = 0.008). In 11 patients who had nadir differential counts performed, 7 (64%) demonstrated improved nadir granulocyte counts with WR-2721. The mean granulocyte count increased from 765/mm3 on cyclophosphamide to 1274/mm3 with WR-2721 + cyclophosphamide (p = 0.05). In the second trial, 25 patients received the reverse sequence: an initial dose of cyclophosphamide (1200-1800 mg/m2) alone, followed 4 weeks later by WR-2721 (450-1100 mg/m2) prior to the same dose of cyclophosphamide. With WR-2721 pretreatment, 12/25 (48%) patients had improved nadir WBC counts. The mean WBC increased from 1550/mm3 on cyclophosphamide alone to 1850/mm3 with WR-2721 + cyclophosphamide (p = 0.02), while the nadir granulocyte count increased from 449/mm3 to 844/mm3 (p = 0.001). No patient developed microscopic or gross hematuria or inappropriate antidiuretic hormone secretion. One patient developed mild thrombocytopenia. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced granulocytopenia, but the dose modification factors and degree of clinical benefit remain to be established. The current recommended WR-2721 dose for Phase II trials is 740 mg/m2 administered over 15 minutes.

Adult↗
PubMed1984

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

WR-2721 is a sulfhydryl compound which in the animal model improves renal tolerance to cis-platinum (DDP) by factors of 1.3 to 1.7. Phase I trials were initiated to establish the toxicity and dose modification factors when WR-2721 was given prior to escalating doses of DDP. Nineteen patients received 27 courses of WR-2721 (450-910 mg/m2) 20 minutes prior to DDP (50-120 mg/m2). Patients were prehydrated, but no mannitol or other diuretics were administered. Mild, transient nephrotoxicity was observed in only 2 of 15 courses of DDP 80-100 mg/m2 when WR-2721 was given prior to DDP. Although 5 of 9 patients treated with WR-2721 prior to 120 mg/m2 of DDP developed transient nephrotoxicity, their serum creatinines returned to normal baseline values within 1 to 2 weeks. Subsequently, the protocol was modified to include mannitol diuresis. Thirty-four courses of WR-2721 (740 mg/m2) prior to DDP 120-150 mg/m2 with mannitol diuresis were administered. Biweekly serum creatinine and monthly creatinine clearances have remained normal in all patients treated with 120 mg/m2 of platinum and WR-2721. Four of 10 patients treated with 150 mg/m2 of cis-platinum experienced transient nephrotoxicity 5-7 days after treatment. Mild ototoxicity was noted in 4 patients following 150 mg/m2 of DDP. WR-2721 does not appear to protect against the antitumor efficacy of DDP, as 57% of all patients achieved objective partial responses, lasting 1+ to 7+ months. Partial responses occurred in 3/4 (75%) of patients with melanoma and 7/10 (70%) patients with cancer of the head and neck. Compared to retrospective series, our data suggest that WR-2721 may provide some protection against platinum-induced nephrotoxicity, but the dose modification factors remain to be established.

Amifostine↗
PubMed1983

Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent).

We investigated the causes of the hypocalcemia associated with WR-2721, an investigational drug that protects normal tissues against the toxic effects of radiation and chemotherapy. Sixteen patients with advanced cancers had serial measurements of serum calcium and other studies of blood chemistry before and after taking the compound. In all 16 patients (18 courses) the mean serum calcium level fell from 2.33 to 1.90 mmol per liter (9.33 to 7.62 mg per deciliter, P less than 0.001) after WR-2721, and in all 8 patients from whom data were obtained, serum calcium levels remained depressed at 24 hours. In 12 patients, ionized calcium levels dropped from 0.98 to 0.80 mmol per liter (P less than 0.01). Serum magnesium values fell from 0.96 to 0.74 mmol per liter (1.91 to 1.48 mg per deciliter, P less than 0.001). There were no changes in arterial pH or serum phosphate concentrations. In nine patients urinary calcium excretion rose from 3.96 to 10.68 mumol per minute (P less than 0.01) after WR-2721. Despite hypocalcemia, parathyroid hormone levels fell in all subjects. WR-2721 also inhibited the release of parathyroid hormone from bovine parathyroid cells incubated in vitro in low (0.5 mM) concentrations of calcium. We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia.

Amifostine↗
PubMed1982

Adrenaline 1% combined with guanethidine 1% versus adrenaline 1%: a randomised prospective double-blind cross-over study.

The hypotensive effect of a combination of guanethidine 1% with adrenaline 1% was compared with adrenaline 1% alone on the eyes of 20 patients with ocular hypertension in a randomised double-blind cross-over trial. The patients received 8 weeks of treatment with each preparation. A significant increase in the hypotensive effect was found by adding guanethidine 1% to adrenaline 1%. This hypotensive effect was maintained over the 8-week period of the trial.

Clinical Trials as Topic↗
PubMed1981

Low-dose combined guanethedine 1% and adrenaline 0.5% in the treatment of chronic simple glaucoma: a prospective study.

This paper reports on the results of a prospective double-blind crossover study, comparing adrenaline 1% with adrenaline 0.5% combined with guanethedine 1% over an 8-week period with each formulation. The guanethedine/adrenaline formulation was found to be the more effective hypotensive agent of the two. This study confirms the potentiating effect of adding guanethedine to adrenaline, and suggests that this combination would be a useful alternative treatment when adrenaline 1% or adrenaline 0.25% with guanethedine 1% is insufficient.

Aged↗
PubMed1981

Phase I trials of WR2721 in combination with radiation therapy and with the alkylating agents cyclophosphamide and cis-platinum.

Three phase I trials of the radioprotector S-2-(3-aminopropylamino) ethylphosphorothioic acid (WR2721) have accessed 60 patients. Study 1 is devised to determine the maximum tolerated dose (MTD) of a single dose of the protector 15 to 30 minutes before a single radiation treatment of a size used routinely in palliative management. Study 2 plans to determine the MTD for up to 15 daily doses of the drug over 3 weeks during palliative radiotherapy. Also, the multipe-dose study will establish the MTD before palliative irradiation for fewer than five fractions a week. Study 3 uses the existing single-dose MTD determined in Study 1 as pretreatment 15 to 30 minutes before cyclophosphamide or cis-platinum. Toxic symptoms include emesis, hypotension, hypertension, somnolence, and sneezing. Only one serious episode of hypotension, considered idiosyncratic, and one instance of moderate to severe vomiting have occurred. Forty-one patients have been entered in Study 1 and a dose of 600 mg/m2 has been reached. The next step is to proceed to the planned highest level of 740 mg/m2. Of five patients in the multiple-dose study, one has been given, without toxicity, WR2721 at the level of 100 mg/m2 for 15 fractions over 3 weeks. Fourteen patients are accessed to the alkylating agent study. Using protector doses of 450 mg/m2, a cyclophosphamide level of 1500 mg/m2 has been accomplished. However, two of three patients who received 450 mg/m2 of WR2721 before 120 mg/m2 of cis-platinum have shown moderate elevation of the serum creatinine, both of which returned to normal.

Amifostine↗
PubMed1981

Cytogenetic evidence for the clonal nature of Richter's syndrome.

Sequential chromosome studies were done on a patient who developed diffuse histiocytic lymphoma (DHL) after a long history of untreated chronic T-cell leukemia. During the indolent phase of her disease, a pseudodiploid lymphocyte population with 3q+ and 14q+ chromosome markers gradually replaced the originally diploid tumor cells. The karyotype of the lymphoma was hypertriploid (70--74 chromosomes) with the same 3q+ and 14q+ markers. The findings indicate that DHL in this patient evolved from the leukemic T-cell clone.

Clone Cells↗