Biomedical subjects

R S Benjamin

Publications and source records attributed to R S Benjamin.

At least 145 records · Page 8Linked to original sources

PubMed1983

Osteosarcoma: intra-arterial treatment of the primary tumor with cis-diammine-dichloroplatinum II (CDP). Angiographic, pathologic, and pharmacologic studies.

Intra-arterial CDP was utilized to treat the primary tumor in 11 pediatric patients with osteosarcoma and in one with malignant fibrous histiocytoma. The investigation commenced with a phase I-II pilot study in four osteosarcoma patients. A dose of 150 mg/m2 was found to be safe and effective in producing a clinical response. This was followed by a definitive study in the remaining seven osteosarcoma patients and in the one malignant fibrous histiocytoma patient. The results were assessed by specific clinical, pharmacologic, radiographic and pathologic criteria. The overall response in the definitive study was 50% with two patients exhibiting total tumor destruction. The success of intra-arterial CDP was attributed to its ability to achieve high local drug concentration and tumor penetration. This was demonstrated by pharmacologic studies.

Adolescent↗

PubMed1983

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986).

[14C]AZQ (2-4 mg/m2, 100-200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18-45% of the total radioactivity in tumor tissue and 30-56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/g vs. 31 ng/g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.

Adult↗

PubMed1983

A phase II trial of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU, NSC 95466) in recurrent malignant brain tumors.

Twenty-nine patients with recurrent primary malignant brain tumors were treated with 1-(2-chlorethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU) at an initial dose of 110 mg/m2 with subsequent doses determined by the degree of delayed toxicity. The interval between treatments was usually weeks. Eleven of 25 evaluable patients (44%) showed definite improvement and ten (40%) showed disease stability as determined by sequential CT scans and neurologic examination. The estimated median time to tumor progression for all 25 patients treated with PCNU was 28 weeks, 37 weeks for the responding patients but only 20 weeks for patients with stable disease. Toxicity consisted of delayed myelosuppression which was cumulative and occurred mainly with the platelets. Gastrointestinal toxicity occurred in a minority of the patients. PCNU has definite activity in primary malignant brain tumors which appears to be comparable to that reported for BCNU alone, but with less reported gastrointestinal side effects. Further clinical trials in patients with primary malignant brain tumors are indicated.

Adult↗

PubMed1983

Weekly Cisplatin during cranial irradiation for malignant melanoma metastatic to brain.

Because Cisplatin potentiates the effect of radiotherapy in animal tumor systems and because Cisplatin is capable of causing regressions of human malignant melanomas, a study was initiated in patients with malignant melanoma metastatic to brain to investigate the feasibility of administering Cisplatin once a week during cranial irradiation. Cisplatin 40 mg/m2/week (three doses) was given I.V. to 18 patients during whole brain irradiation, 3 000 rads in 12 fractions over 21/2 weeks. Eleven patients also received Cisplatin 120 mg/m2 every three weeks, starting three weeks after cranial irradiation. Median survival was ten weeks, and only one of 13 patients whose brain metastases had not been resected experienced neurological and CT scan improvement. Thirteen patients have died, and brain metastases were a major cause. No regression of extracerebral tumor was seen in 15 patients with evaluable extracerebral lesions. During weekly low-dose Cisplatin administration, nausea and vomiting were moderate to severe. No granulocytopenia was noted, although three courses were associated with mild thrombocytopenia. Mucositis, peri orbital swelling, vertigo, and headache were each noted in two of 51 courses of treatment and seizures, ototoxicity, pancreatitis, and hiccups were each noted in one course. Renal toxicity and ototoxicity each developed in three of the 11 patients receiving Cisplatin 120 mg/m2, and nausea and vomiting were severe.

Brain Neoplasms↗

PubMed1983

The pharmacologic fate of 2,5-diaziridinyl-3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ NSC-182986) by intracarotid or intravenous administration in beagles.

Beagle dogs received either intravenous (I.V.) or intracarotid (I.C.) 14C ring labelled 2,5-diaziridinyl-3,6-bis-(carboethoxyamino) 1,4-benzoquinone (AZQ) at a dose of 2 mg/kg. Blood, urine and cerebrospinal fluid (CSF) samples were collected at intervals. At varying times, dogs from each group were sacrificed and histologic examination and drug determinations were performed on the major organs. By both routes of administration, the elimination of AZQ from plasma was biphasic with an initial half-life of 18 min and a terminal half-life of 26 hr. The apparent volume of distribution was 7.9 l/kg and the total clearance was 3.5 ml/kg/h. The 96 hr cumulative urinary excretion of total 14C was 41% of the administered dose, including 4% as the unchanged drug. At 1, 48, and 96 hr after I.C. AZQ, drug concentrations in the brain tissue were twice those by the I.V. route. High drug concentrations in the CSF were produced by both routes, although the CSF to plasma ratio was higher by I.C. than I.V. In extracranial organs, tissue concentrations of AZQ were at least twice as high by I.V. than by I.C. administration. No significant clinical or neurologic toxicity were noted when AZQ was given I.C. In the dog I.C. administration of AZQ seems to accelerate drug entry into the brain tissue.

Animals↗

PubMed1983

Human central nervous system pharmacology of pentamethylmelamine and its metabolites.

Pentamethylmelamine (PMM) 80 mg/m2 was administered I.V. to 8 patients during surgical resection of intracerebral tumors. PMM concentrations in tumors were generally much higher than concurrent plasma concentrations, ranging from undetectable (less than .01 micrograms/g) to as high as 4.47 micrograms/g and were much higher in malignant melanoma samples than in astrocytoma samples. PMM was barely detectable or undetectable in most samples of edematous brain tissue adjacent to intracerebral tumor and in temporalis muscle. The PMM metabolites tetramethylmelamine (TeMM), trimethylmelamine (TrMM), and dimethylmelamine (DMM) were each detectable in tumor samples from one or two patients. Monomethylmelamine (MMM) was present in tumor samples from all except one patient. MMM was noted in samples of edematous brain tissue adjacent to tumor from 4 of 8 patients. It was the only PMM metabolite found in brain. TrMM, DMM, and MMM but not PMM, and TeMM were found in tumor cyst fluid from a patient with an intracerebral malignant melanoma. Two patients receiving therapeutic doses of PMM had biopsies taken of subcutaneous malignant melanoma deposits. PMM was undetectable in samples from one patient but reached high concentrations in the other patient. In both patients, MMM was the major metabolite. There was no indication that PMM penetrated into extracerebral tumors more readily than into intracerebral tumors Cerebrospinal fluid (CSF) samples were obtained from one patient without neurological toxicity who received low doses of PMM and from 4 patients receiving high doses of PMM who had developed neurological toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Altretamine↗

PubMed1983

A pilot study of cis-diamminedichloroplatinum and radiation therapy in patients with high grade astrocytomas.

A pilot study was performed combining cis-diamminedichloroplatinum (CDDP) and radiation therapy to treat patients with high-grade astrocytomas. CDDP at a dose of 40 mg/m2/week intravenously was given during the course of cranial irradiation. Following irradiation, CDDP was given every three weeks on a schedule of 35-40 mg/m2/day for three days until toxicity became unacceptable or until tumor progression occurred. Radiation therapy consisted of 6 000 rads over a seven week period or 5 000 rads followed by an additional 1 500 rads to the tumor site. Patients were followed by computerized axial tomography (CT) scan and neurologic examination. Thirty patients were entered onto the study; 22 were considered evaluable. The median survival was 53 weeks and the median time to progression was 21 weeks. Toxicity was generally tolerable; however, ototoxicity may be enhanced by this treatment. CDDP combined with cranial irradiation is tolerable and feasible, although close follow-up is recommended in case CDDP has to be temporarily interrupted.

Adolescent↗

PubMed1983

Concentration of vinblastine in human intracerebral tumor and other tissues.

Uptake of vinblastine into human cerebrospinal fluid, intracerebral tumor and autopsy tissues was quantitated radiochemically after separating vinblastine from its metabolites by high pressure liquid chromatography. Only low concentrations of vinblastine were found in cerebrospinal fluid from a single patient. A second patient who received a tracer dose of radiolabelled vinblastine prior to surgical resection of an intracerebral tumor had slightly less radioactivity in tumor than in temporalis muscle, but more in tumor than in edematous brain surrounding the tumor. The radioactivity in tumor increased gradually and exceeded concurrent plasma radioactivity by 2 hr after drug administration. A third patient died 4 hr into a planned 24-hr infusion of radiolabeled vinblastine. Highest vinblastine concentrations were found in organs with high blood flow such as kidney and heart. Intermediate concentrations were found in liver and lung, and low concentrations were found in prostate, gastrointestinal tract, spleen, muscle, bladder, and hepatic and lymph node metastases. A fourth patient died one month after receiving radiolabeled vinblastine. Highest concentrations were in liver and next highest concentrations were in intracerebral tumor. Moderately high concentrations were found in pancreas, thyroid, lung, spleen, ovary, kidney, and kidney metastases. Lowest concentrations were found in omental metastases, heart, breast, and brain. Vinblastine concentration decreased with increasing distance into brain from the brain metastases. Thus, vinblastine was not selectively localized in tumors. The concentrations in tumor did not reflect the concentration in the organ in which the tumor was located. There was no indication that uptake into intracerebral tumor was impaired. Cerebrospinal fluid and brain concentrations of vinblastine did not give any indication of the concentration attainable in intracerebral tumor.

Adult↗

PubMed1983

Energy-dispersive X-ray fluorescence determination of platinum in plasma, urine, and cerebrospinal fluid of patients administered cis-dichlorodiammineplatinum(II).

A method involving the use of an energy-dispersive X-ray fluorescence spectrometer was developed for assaying total platinum concentrations in body fluids of patients treated with the antitumor drug cis-dichlorodiammineplatinum(II). Sample preparation by this procedure is simple, consisting in adding an internal standard (Zr) to 1 ml of biological fluid or tissue homogenate, pipetting 20 microliter of the sample onto a Mylar sample holder, and drying. This produces a thin-film sample, which effectively eliminates absorption enhancement effects due to other elements in the specimen. Standard addition studies were found to be linear in the concentration range of interest (0.1-10.0 micrograms/ml), with correlation coefficients exceeding 0.99. Minimum detection limits range from 0.10 to 0.25 micrograms Pt per ml, depending on the body fluid, which is adequate for routine patient monitoring after normal chemotherapeutic doses of cis-dichlorodiammineplatinum(II). In preliminary studies with mammalian liver, standard addition experiments were found to be linear and the minimum detection limit was found to be 1.4 micrograms/g dry weight.

Body Fluids↗

PubMed1983

Clinical pharmacology of the anticancer polypeptide neocarzinostatin.

The clinical pharmacology of the anticancer polypeptide neocarzinostatin was studied in 16 patients with disseminated neoplasia using a radioimmunoassay technique. Patients who received 2,400-3,600 U of the drug per square meter BSA by rapid IV infusion had triphasic plasma decay curves. For eight patients with normal hepatic and renal function, neocarzinostatin mean plasma half-lives were 0.14, 0.50, and 7.7 h. The mean plasma drug clearance was 32.4 ml/min/m2 and the apparent volume of distribution 19.3 l/m2. Two patients with liver dysfunction had shorter terminal plasma half-lives and greater drug clearance, while two with renal disease exhibited prolonged plasma half-lives and reduced drug clearances. The mean cumulative urinary excretion of neocarzinostatin was 69.1% of the administered dose at 72 h in three patients with normal hepatic and renal function. One patient with liver disease excreted 90.4%, while a patient with renal disease excreted only 58.1% of the dose in 24 h. In one patient with marked liver disease, biliary excretion accounted for 0.1% of the administered dose in 72 h. Cerebrospinal fluid concentrations of neocarzinostatin studied in two patients showed a CSF penetration of about 16% the plasma concentration at 1-5 h; concentrations persisted for 19 h in one patient with an Omayha reservoir. Neocarzinostatin was rapidly cleared from the plasma and eliminated in the urine. Dosage reductions of 50% are recommended for patients with impaired renal function, while no reduction or escalated doses could be tolerated by patients with liver disease. The pharmacologic data suggest a continuous IV infusion may be a more toxic but perhaps more effective schedule of administration.

Adult↗

PubMed1983

Clinical pharmacology of 2,5'-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ).

2,5'-Diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ) is an alkylating compound which has exhibited a broad spectrum of antitumor activity against a variety of experimental tumors, particularly those implanted intracranially. We have studied the clinical pharmacology of AZQ in 11 patients with various types of tumors. AZQ was administered at 1-12 mg/m2 daily for 5 days by i.v. infusion in 10-30 min. 14C-labelled AZQ was given on day 1 only. Blood and urine specimens were analyzed radiochemically and chromatographically. The plasma disappearance of unchanged AZQ was essentially biphasic, with an initial plasma t 1/2 of 1.4 +/- 0.4 hr and a terminal t 1/2 of 45.5 +/- 3.1 hr. The apparent volume of distribution was 14.2 +/- 3.0 l/kg. The cumulative urinary excretion of unchanged AZQ was 4.3% in 24 hr and 8.6% in 96 hr. The total clearance of the drug was 200 ml/kg/hr. Cerebrospinal fluid AZQ concentration peaked 45-90 min after drug administration, reaching about 70% of that in plasma, and then declined at nearly the same rate.

Antineoplastic Agents↗

PubMed1983

Leiomyosarcoma of the penis.

We report a case of an aggressive leiomyosarcoma of the penis treated with radical surgery, radiotherapy and chemotherapy. The patient died 7 months after diagnosis.

Humans↗

PubMed1983

A randomized study of continuous infusion vindesine versus vinblastine in adults with refractory metastatic sarcomas.

A randomized study was conducted in 33 adult patients with refractory metastatic sarcomas to compare the therapeutic efficacy of continuous vindesine versus continuous vinblastine. Of 30 evaluable patients, 15 patients received vindesine as a continuous 5-day infusion at 1.2 mg/m2 repeated every 3 weeks, and 15 patients received vinblastine at 1.5 mg/m2/day every 3 weeks. Ten patients had stable disease, while 20 patients showed progressive disease. No objective responses were observed. There was adequate myelosuppression and both drugs were well tolerated with few catheter-related problems. It does not appear that vindesine or vinblastine, given by continuous 5-day infusion, is active in the treatment of metastatic sarcomas in adults.

Adult↗

PubMed1983

Tumor penetration of AMSA in man.

4'-(9-Acridinylamino)-methanesulfon-m-anisidide (AMSA) has shown significant antitumor activity against several murine tumors and leukemias. During its Phase I and II clinical trial, we were able to obtain tumors, plasma, and CSF specimens from patients who received varying doses of AMSA, as well as patients who received high doses and had autologous bone marrow rescue. The drug was analyzed chromatographically. The tumor to plasma drug concentration ratios ranged from 200% to 486%, apparently independent of dose and sampling time. Because AMSA was not detected in the CSF, the drug may not be effective in the treatment of meningeal metastasis. High-dose AMSA therapy with bone marrow rescue did not result in significantly higher AMSA concentrations in the tumor, nor did it elicit favorable response.

Aged↗

PubMed1983

Clinical pharmacology of intraarterial cis-diamminedichloroplatinum(II).

After intraarterial (30 patients) or i.v. (seven patients) administration of cis-diamminedichloroplatinum, X-ray fluorescence spectrometry was used to measure platinum concentrations in plasma and urine. Arteries infused included hepatic (seven patients), carotid (six patients), iliac (ten patients), brachial (three patients), and femoral (four patients). All patients received i.v. mannitol. Pharmacokinetic parameters after intraarterial administration were similar to those after i.v. administration, although differences existed for different intraarterial routes of administration. Mean for all patients combined were: Co, 2.67 +/- 0.97 (S.D.) microgram/ml; t1/2 beta, 71.1 +/- 26.6 hr; clearance, 0.72 +/- 0.25 liters/hr/sq m; total volume of distribution, 45.2 +/- 17.0 liters/sq m; C x t, 167 +/- 72 mg/hr/liter; and 24-hr urinary excretion, 20 +/- 10% of the administered dose. Intrahepatic infusion of the drug was associated with a significantly lower Co (1.88 +/- 0.50 g/ml) and C x t (140 +/- 25 mg hr/liter) and significantly higher clearance (0.91 +/- 0.24 liters/hr/sq m) and volume of distribution (67.6 +/- 4.6 liters/sq m) than administration by other routes, suggesting first pass extraction of drug by liver. In addition, an apparent minor late rise in serum platinum concentration may suggest enterohepatic recirculation of drug. High fluid intake was associated with a low Co and a high volume of distribution, consistent with expansion of the central compartment by fluids. Low serum albumin (less than 3.5 g/dl) was associated with significant shortening of the t1/2 beta (50.5 +/- 21.6 hr), suggesting that the amount of unbound filterable drug may possibly be higher in patients with low serum albumin concentrations. Plasma from veins draining an infused area has a higher Co and C x t during infusion than concurrent plasma from peripheral veins. Thus, intraarterial administration of cis-diamminedichloroplatinum results in increased drug exposure of tumor in the infused area without substantially decreasing exposure of systemic tumor.

Cisplatin↗

PubMed1983

Human pharmacokinetics of a new acridine derivative, 4'-(9-acridinylamino)methanesulfon-m-anisidide (NSC 249992).

The clinical pharmacology of 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine) was studied, utilizing [9-14C]amsacrine i.v. in 19 patients with disseminated neoplasms. The mean terminal plasma half-life for total 14C ranged from 34 hr in patients with normal organ function to 46 hr in patients with severe liver disease. For unchanged amsacrine, the mean values of plasma half-life were 7.4 and 17.2 hr for patients with normal and abnormal liver function, respectively. The plasma half-lives of 14C were prolonged, while those for unchanged amsacrine appeared to be normal in patients with renal dysfunction. The mean 72-hr cumulative urinary excretion of total 14C varied from 35% in normal patients to 49% in patients with severe liver disease, while patients with renal disease excreted only 2 to 16%. In comparison, the urinary excretion of unchanged amsacrine was 12, 20 and 2% of the administered dose, respectively, in these same patients. Amsacrine biliary excretion studied in two patients showed about 8 and 36% of the administered radioactivity excreted in the bile in 72 hr, with less than 2% as unchanged amsacrine. Cerebrospinal fluid concentrations of amsacrine were below 2% of the simultaneous plasma levels in three patients. Impaired amsacrine drug clearance was frequently associated with liver dysfunction. Patients with impaired amsacrine drug clearance experienced the most severe clinical toxicity. Hepatic metabolism and biliary excretion appear the most important routes for amsacrine elimination. Renal elimination, although less important, is significant in patients with severe kidney dysfunction. To avoid excessive clinical toxicity, initial dose reductions of 30 to 40% are recommended for patients with severe liver or renal disease or for those who have pharmacologically documented impaired drug clearance.

Aminoacridines↗

PubMed1983

Combination chemotherapy for advanced sarcomas of bone and mesothelioma utilizing rubidazone and DTIC: a Southwest Oncology Group Study.

Twenty-three patients with disseminated bony sarcoma and 23 patients with malignant mesothelioma were evaluable in a Southwest Oncology Group (SWOG) clinical trial utilizing rubidazone and DTIC. One partial remission (PR) was observed in a previously untreated patient with metastatic Ewing's sarcoma. One patient with giant cell tumor of bone had an improvement, short of PR. Thirteen patients with osteogenic sarcoma and 23 with malignant mesothelioma had no response to this combination of drugs. The major toxic effects of therapy included nausea, vomiting, and myelosuppression, especially leukopenia; no cardiac toxicity was noted. We conclude that the combination of rubidazone and DTIC is inactive in bony sarcoma and mesothelioma.

Adult↗

PubMed1982

The natural history of resectable metastatic melanoma (Stage IVA melanoma).

One-hundred-two patients with malignant melanoma who had distant metastases surgically resected and were judged to be clinically free of disease (M. D. Anderson Stage IVA melanoma) were studied. The median survival for all the patients from time of diagnosis of stage IVA disease was 18 months. The site of the resected metastases did not appear to influence survival, being approximately the same for the brain (15 months), lung (16 months), intraabdominal (18 months), and skin and/or lymph nodes (23 months). The site of the resected metastases also did not influence the median disease-free interval. Patients who had metastases resected from several organs at the same time had a median survival of 15 months, which was similar to that of patients with one resected site. Patients who were rendered Stage IVA on several occasions by surgical excisions had a median survival of 36 months. Thirty-five patients received surgery only and 67 patients received adjuvant chemotherapy, immunotherapy, or combined chemoimmunotherapy after surgery. For the group treated with surgery only, the median disease-free interval and survival from diagnosis of stage IVA disease were 6 months and 16 months, respectively, and for the adjuvant group 6 months and 21 months, respectively. Specifically, by the type of adjuvant therapy, the median disease-free interval and survival from stage IVA for 23 patients receiving Corynebacterium parvum were 6.9 and 19 months; for 39 patients receiving BCG, eight months and 26 months; for 24 patients receiving BCG + DTIC, eight and 17.4 months; and for all 51 DTIC treated patients 6.3 and 17.8 months, respectively. Patients receiving BCG had a median survival superior to the surgery only group (P = 0.02). An increase in survival was seen predominantly in patients who achieved IVA status more than once and received BCG. Patients with recurrent soft-tissue metastases appeared to benefit most from BCG in prolonging the disease-free interval. Only 1/10 treated by surgery alone had a disease-free interval longer than 1 year, compared with 9/16 who received BCG (P = 0.01). Stage IVA melanoma appears to be distinctly different in prognosis from Stage IVB melanoma and should be classified separately. Patients with recurrent soft-tissue disease may benefit significantly from treatment with BCG.

Adolescent↗