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Biomedical subjects

G Sarna

Publications and source records attributed to G Sarna.

At least 19 recordsLinked to original sources
PubMed1994

A comparative study of intravenous versus intralymphatic interleukin-2, with assessment of effects of interleukin-2 on both peripheral blood and thoracic-duct lymph.

Recombinant human interleukin-2 (IL-2) was administered by the intravenous (i.v.) or intralymphatic (i.l.) route to 14 patients with advanced malignancy. IL-2 was given in doses of 600,000 IU/kg or 1,050,000 IU/kg daily x 5. Thoracic duct (TD) catheters were placed, and both TD lymphocytes (TDL) and peripheral blood lymphocytes (PBL) were studied. Five of eight patients at the 600,000 IU/kg dose experienced grade III toxicity as did five of six patients at the 1,050,000 IU/kg dose. Two episodes of grade IV toxicity were seen at the higher dose. The i.l. and i.v. routes had a similar toxicity profile excepting lymphangitis/pedal infection, seen only with i.l. administration. One partial response was seen in a patient with renal cell carcinoma. Lymphopenia was seen early in therapy, with lymphocytosis by day 6. Lymphoid yield of the TD catheter fell early in therapy, then increased over baseline by the end of treatment. Intralymphatic administration resulted in a prolonged serum t1/2 and lower serum levels than did i.v. administration, but resulted in higher TD levels. Antibodies against IL-2 were ubiquitous but had no clear effects. Lymphocyte trafficking studies suggested that IL-2 affected lymphocyte redistribution to liver, spleen, bone marrow, and lymph nodes. NK activity and phenotype and LAK activity increased in response to IL-2, with no advantage for TDL. Tumor necrosis factor-alpha and gamma-interferon levels increased sporadically with treatment. The i.l. route offered no advantage over the i.v. route, and TDL offered no advantage over PBL.

Adult↗
PubMed1992

Effect of milacemide on extracellular and tissue concentrations of dopamine and 5-hydroxytryptamine in rat frontal cortex.

1. Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5-hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2. Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400 mg kg-1, i.p.), peaking at 1 h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-1 milacemide). 3. Dialysate 5-HT was significantly increased only at 1.5 h after giving milacemide 400 mg kg-1. Dialysate 5-hydroxyindoleacetic acid (5-HIAA) concentration was not affected. 4. Milacemide (400 mg kg-1) at 1.5 h post-administration significantly increased frontal cortex tissue concentrations of dopamine and 5-HT; the percentage increase in dopamine being about four times that of 5-HT. Metabolite concentrations, including 5-HIAA, decreased. Changes in tissue and dialysate dopamine, DOPAC and HVA were approximately proportionate to each other. 5. The results are explicable in terms of an inhibition by milacemide of MAO-A.

Acetamides↗
PubMed1990

A pilot study of intralymphatic interleukin-2. II. Clinical and biological effects.

Interleukin-2 (recombinant methionyl human interleukin-2 alanine 125; IL-2) was administered intralymphatically to 12 patients with advanced cancer in a phase I trial. Doses were administered once a week for 6 weeks in a dosage escalation schedule; patients were entered in four groups at successively higher starting dosages. Toxicity occurred in a profile similar to that seen with intravenous IL-2. The maximum tolerated dose with this route/schedule was 275,000 units/kg, a figure not higher than expected with intravenous administration. T1/2 alpha was prolonged to 54 min from the 13 min figure we obtained with IL-2 given intravenously. Granulocytosis and eosinophilia were seen, along with lymphocytosis following initial lymphopenia. Anti-IL-2 antibodies were seen in 42% of patients (compared to 16% with this agent given intravenously), suggesting increased immunogenicity of this route/schedule. No clinical response was achieved. Immunologic effects will be reported separately but are summarized.

Adolescent↗
PubMed1988

Phase II study of human lymphoblastoid interferon in patients with multiple myeloma.

Interferon has been reported to have activity in the treatment of multiple myeloma. We studied 24 myeloma patients treated with human lymphoblastoid interferon (Wellferon) by intramuscular injection twice weekly at an initial dose of 3 MU/M2 (three patients) or 15 MU/M2 (21 patients). One of 17 evaluable patients achieved a partial remission, three others were stable over a 16-week period of treatment, and 13 others had progressive disease. Subjective toxicity was frequent and substantial, particularly at the 15 MU dose level. Hematologic toxicity was mild and reversible. Two patients experienced acute renal failure. The low rate of response (6%) and substantial level of toxicity fail to support further exploration of these schedules of interferon as a single agent in myeloma.

Adult↗
PubMed1987

Interferon in renal cell carcinoma. The UCLA experience.

Three sequential studies of alpha interferon were performed in a total of 84 evaluable patients with metastatic renal cell carcinoma. In Study I, conducted from 1981 to 1982, 43 patients received human leukocyte alpha interferon (IFN alpha) 3 X 10(6) U/day, 5 days per week for 12 weeks. In Study II, performed in 1983, vinblastine (0.1 mg/kg/week) was added to the same IFN alpha regimen in 22 subjects. Study III, held from 1984 to 1985, evaluated the effects of escalating doses of interferon alfa-2a (from 3 to 36 X 10(6) U/day) administered 5 days per week to 19 patients. Overall, complete (CR) and partial responses (PR) totaled 17% (14%, 14%, and 26% in Studies I-III, respectively). Median survival of all patients was 49 weeks. Median survival appeared to be superior in the third study, likely because of the patient mix (skewed toward a Karnofsky performance status of 10, disease-free interval longer than 1 year, and disease confined to the lung). Those prognostic factors were also found to correlate with improved median survival in the total group of 84 patients. Likewise, response to therapy was linked to prolonged survival; patients with CR, PR, or minimal responses had a median survival of 72 weeks. In all the favorable subgroups, responders had better outcomes than nonresponders, but it was not clear whether response to therapy merely selected out patients with better initial prognoses or actually led to improved survival.

Adult↗
PubMed1987

Immune interventions in disease.

Three therapeutic areas of clinical immunology that have seen active development recently are immunopharmacology of immunosuppressive drugs; clinical use of the alpha-, beta-, and gamma-interferons and interleukin-2; and monoclonal antibody applications in marrow transplantation and antitumor therapy. Understanding of the immune regulatory systems and of the soluble factors that convey information between immune and related cells (for example, lymphokines and cytokines and their receptors) has improved substantially. New information about established immunosuppressive drugs and the introduction of new drugs are providing new opportunities for effective treatment of autoimmune diseases and improved effectiveness of organ transplantation. Clinical trials are evaluating the use of interleukin-2 in immunodeficiency disorders and neoplastic disease. Monoclonal antibodies, which have been successfully applied to diagnostic procedures, have been shown to be useful for therapeutic applications in marrow transplantation and antitumor treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy.

To test the hypothesis that some of the neurologic sequelae of treatment for acute lymphoblastic leukemia (ALL) might be related to abnormalities in biopterin metabolism associated with methotrexate (MTX) therapy, total biopterin levels in cerebrospinal fluid (CSF) and plasma, and homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were measured in a cross-sectional study of 80 children with ALL. For comparison, biopterins were also measured in a group of children of similar age undergoing investigation for neurologic disease. In children with ALL studied before therapy, no significant difference was found between the means of plasma biopterin or CSF biopterin concentrations and the means in the control group. In children receiving MTX, plasma biopterin values were higher in the group given maintenance therapy than in children observed before treatment. CSF levels were significantly increased only in those patients who had completed 2 years of maintenance therapy. CSF concentrations of HVA and 5HIAA in patients with ALL who had received no treatment (median values 52 and 18 ng/ml, respectively) showed a wide scatter and were inversely related to age. In patients receiving MTX, concentrations of these metabolites were higher than in the untreated group, again reaching a peak in patients just completing 2 years of treatment (median HVA 110 ng/ml, 5HIAA 34 ng/ml). These results provide no support for the idea that neurotransmitter amine deficiency occurs in children with ALL receiving MTX, and indicate, rather, that amine and biopterin synthesis increases in such patients.

Adolescent↗
PubMed1986

Phase I study of recombinant beta ser 17 interferon in the treatment of cancer.

Fifteen patients with advanced malignancy were treated with escalating doses of recombinant beta ser 17 interferon (IFN). Doses ranging from 0.006 to 500 X 10(6) units/m2 were administered according to a dosage escalation scheme by iv push twice weekly (starting 1 week after an initial dose) for a planned minimum of 5 weeks, to be continued as a function of response. Toxic effects were broad in scope but generally low in grade. They included fever, malaise, leukopenia, proteinuria, nausea/vomiting, diarrhea, and mild elevations of serum transaminases and creatinine. In one patient, transient hypotension with bradycardia ensued. Malaise and fever increased somewhat with increasing dose. Doses of up to 500 X 10(6) units/m2 were tolerated without severe toxicity. A maximum tolerated dose was not defined. IFN pharmacokinetics followed a biphasic decay curve, with a distribution phase alpha-half-life of 9 minutes and an elimination phase beta-half-life of 103 minutes. Anti-IFN antibodies by the ELISA technique were present in seven of 15 patients. Presence of antibody did not correlate with toxicity or response. 2',5'-Adenylate synthetase levels were increased 2 and 24 hours after the initial dose, with a trend toward higher increments with higher doses. Minimal anti-tumor responses were seen in two patients with melanoma.

2',5'-Oligoadenylate Synthetase↗
PubMed1985

Oral vinzolidine as therapy for Kaposi's sarcoma and carcinomas of lung, breast, and colon/rectum.

Vinzolidine, a semisynthetic vinca alkaloid, was studied as oral therapy in 30 patients with Kaposi's sarcoma, non-small cell lung cancer, colorectal cancer, and breast cancer. Substantial variations in morbidity were observed among the patients, some patients receiving doses up to 45 mg/m2 without toxicity while others had severe hematologic toxicity at doses as low as 25 mg/m2. Nausea/vomiting and diarrhea also occurred. Responses were seen in two of 11 patients with Kaposi's sarcoma but not in other patients. Unpredictable severe hematologic toxicity led to early closure of this study. The heterogeneity of patient tolerance may relate to variable oral drug bioavailability, and it is conceivable that vinzolidine could be administered more safely by the IV route.

Administration, Oral↗
PubMed1985

THC or Compazine for the cancer chemotherapy patient--the UCLA study. Part II: Patient drug preference.

Factors influencing preference for THC vs. Compazine (prochlorperazine) as an antiemetic agent during cancer chemotherapy were studied in 139 patients who received both medications in a double-blind randomized crossover design trial. Nausea reduction was the main determinant of preference. THC preference was associated with more, rather than fewer, drug-related side effects than Compazine, particularly sedation. Patients who reported being anxious or depressed did not experience accentuation of their mood states with either regime. Mood effects, nausea reduction, incidence of side effects, and drug preference were the same in patients under and over 50 years of age. Patients with a history of illicit drug use reported fewer side effects from THC, but reported no difference in drug preference or nausea reduction compared to those patients without a history of illicit use.

Adolescent↗
PubMed1985

Treatment of renal cell carcinoma with alpha (human leukocyte) interferon and vinblastine in combination: a phase I-II trial.

Twenty-four patients with measurable metastatic renal cell carcinoma were treated in a phase I-II trial with alpha (human leukocyte) interferon (alpha IFN) and vinblastine (VBL) in combination. Patients received 3 X 10(6) IU/day of alpha IFN im 5 days/week and VBL iv weekly (at a starting dose of 0.15 mg/kg), with doses modified for toxicity. All patients were evaluable for toxicity; 23 patients were evaluable for response. An objective response rate of 13% was observed (three partial responses). An additional 22% of patients had minimal responses (five patients). The occurrence of nausea, vomiting, thrombocytopenia, hepatic dysfunction, and fever was comparable to that seen in previous studies of alpha IFN alone. Granulocytopenia, neurotoxicity, and malaise, however, occurred with increased frequency and severity. alpha IFN and VBL administered in combination in this dose schedule demonstrated activity similar to but toxicity greater than that seen in previous trials of alpha IFN alone.

Adult↗
PubMed1985

Human alpha-lymphoblastoid interferon. A phase I study including pharmacokinetics and effects on hematologic stem cells (CFU-GMs).

Human alpha lymphoblastoid interferon (Wellferon) was administered to 33 patients in a phase I study. Patients received Wellferon intramuscularly every 12 hours for 14 doses in nine dosage levels ranging from 0.75 X 10(6) units to 50.0 X 10(6) units. Toxicity tended to be dose dependent and included fever/chills, malaise, hematologic toxicity, and digestive tract toxicity. Thirty X 10(6) u q 12 h was felt to be the maximum tolerated dose. Three partial responses (renal cell carcinoma, diffuse histiocytic lymphoma, Hodgkin's disease) were achieved. Interferon rapidly (2 to 3 hours after the initial injection) reached peak serum levels which varied generally with dose and exceeded 500 u/ml at the 30 and 50 X 10(6) u dosages. Multiple doses of interferon resulted in cumulative peak levels substantially higher than first dose levels (greater than 500 u/ml at dosages greater than 3 X 10(6) u/ml and greater than 1,500 u/ml at dosages greater than or equal to 18 X 10(6) u). Interferon given at high dosages persisted up to 10 days beyond the final injection. Despite hematologic toxicity, inhibition of CFU-GM was not seen.

Dose-Response Relationship, Drug↗
PubMed1984

Clinical thermochemotherapy. A controlled trial in advanced cancer patients.

In vitro and in vivo animal studies and some clinical trials have shown apparent benefit from thermochemotherapy; however, this treatment modality has not been adequately tested in humans. This investigation evaluated response to and toxicity of secondary thermochemotherapy, using each patient as his own control. Patients with advanced cancer who had documented disease progression while receiving chemotherapy alone were subsequently treated with the same drug, by the same dose and route, combined with localized hyperthermia. Thirty-four patients whose diseases included metastatic colon carcinoma, melanoma, sarcoma and hepatoma in viscera (29) or surface tissues (5) were treated with combination thermochemotherapy for 1 hour daily for 5 days/month. Effective heating from 41 to 45 degrees C minimum tumor temperature was possible in 17/19 (89%) tumors in which temperatures could be measured safely. The authors observed 5 (15%) tumor regressions for 1 to 5 months (median, 2 months), and 19 (56%) tumor stabilizations (growth arrest of previously progressive disease) for 1 to 9 months (median, 4 months). Subjective improvement in activity and/or pain control occurred in 6 (18%) patients and 20 (59%) had no progression of symptoms during treatment. Moreover, there was no detectable morbidity from localized hyperthermia, and no evidence of increased chemotherapy toxicity. While the mechanism(s) of response is poorly understood, the documented disease regressions and stabilizations of previously progressive disease in 24 (71%) patients during secondary combination thermochemotherapy indicates that the addition of hyperthermia may have useful anticancer activity. Expanded trials are warranted.

Adult↗
PubMed1984

A technique for repeated sampling of cerebrospinal fluid in freely moving rats and its uses.

The CSF plays an important role in removing transmitter amine metabolites from the brain and their measurement therein has frequently been used to study transmitter amine metabolism in the human brain during life. Much data, albeit largely qualitative, indicates that brain transmitter metabolism is reflected in the CSF. There is however remarkably little quantitative data available as human CSF and brain material are rarely concurrently available from the same patient. Conversely, until recently we have had much direct information on transmitter metabolism in the rat brain but CSF studies have been few, largely because of technical difficulties in measuring the metabolites. Therefore we have had little quantitative data on brain--CSF relationships for transmitter amine metabolism in any one species. Such evidence is important not only because it sheds light on the relevance of human CSF findings to brain chemistry but also because it may be used to study transmitter metabolism in the brain of the living rat and provides quantitative data on the role of the CSF in the removal of the metabolites from the brain. We will be reporting findings on these topics. These were obtained by the withdrawal of small volumes of cisternal CSF from conscious freely moving rats via an indwelling catheter and determining dopamine and 5-hydroxytryptamine metabolites by HPLC in both CSF and brain with and without administration of various drugs.

Animals↗
PubMed1983

The treatment of renal cell carcinoma with human leukocyte alpha-interferon.

An extended phase II trial of human leukocyte (alpha) interferon was done in 48 patients with measurable metastatic renal cell carcinoma, 43 of whom were evaluable. Of these patients 1 (2.5 per cent) had a complete response that was maintained after 19 months, 6 (14 per cent) had a partial response and an additional 23 per cent had either a minimal response or stabilization of previously growing metastases for greater than 3 months. Toxicity caused termination of treatment in only 1 patient and generally was tolerable. Major toxicity consisted of fever (80 per cent), fatigue (80 per cent) and hematologic toxicity (42 per cent), which was severe in only 2 patients. Characteristics of patients responding to therapy were good performance status, previous nephrectomy and metastases limited to the lungs. The results achieved with human leukocyte interferon were superior to those achieved by immunotherapy or chemotherapy at this and other institutions, and further trials are warranted.

Adenocarcinoma↗
PubMed1983

Alpha(human leukocyte)-interferon as treatment for non-small cell carcinoma of the lung: a phase II trial.

Thirty-eight patients with advanced measurable non-small cell carcinoma of the lung (20 adenocarcinoma, 13 epidermoid carcinoma, 5 large cell anaplastic carcinoma) were treated with alpha(leukocyte)-interferon. Patients received 3 X 10(6) units intramuscularly 5 days out of 7. Patients were treated for 12 weeks or as modified for disease progression or positive response to therapy. In 37 patients evaluable for response, one partial response was observed (adenocarcinoma). Toxicity included fever and malaise, leukopenia, thrombocytopenia, nausea-vomiting, and hepatic toxicity. One additional patient with previous cardiac and pulmonary disease had a cardiorespiratory arrest several hours after his first interferon injection. The relationship between those events is not clear. As administered, alpha-interferon showed no meaningful activity as therapy for non-small cell carcinoma of the lung.

Adenocarcinoma↗
PubMed1983

Phase I study of Wellferon (human lymphoblastoid alpha-interferon) as cancer therapy: clinical results.

Thirty-three patients with advanced malignancy were treated with Wellferon. Doses ranging from 0.75 X 10(6) to 50 X 10(6) U were administered intramuscularly every 12 h for a 7-day course of therapy. Courses were repeated every 4 weeks as a function of tumor response. Toxicity resulted in fever, chills, malaise, leukopenia, thrombocytopenia, nausea and/or vomiting, diarrhea, hepatocellular damage, and, in a single case, gastrointestinal bleeding (which was a possible cause of patient death). Toxicity tended to increase with increasing dose, and 30 X 10(6) units every 12 h for 7 days was considered to be the maximally tolerated dose. Partial responses were seen in three patients with diagnoses of renal cell carcinoma, diffuse histocytic lymphoma, and Hodgkin's disease. Minimal responses were seen in four patients with diagnoses of chronic lymphocytic leukemia, multiple myeloma (two patients), and breast cancer. Positive response to therapy did not correlate with dose level.

Cell Survival↗