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Biomedical subjects

M Gurwith

Publications and source records attributed to M Gurwith.

At least 19 recordsLinked to original sources
PubMed1999

Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles.

As a continuation of our structure-activity relationship studies, several new 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Selected compounds were further evaluated as cytotoxic agents using a clonogenic survival assay. The target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '-yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '-(benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target series, 19, 21, and 24 displayed significant growth inhibitory action against a panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the prototype drug etoposide (VP-16). Compound 21 was the most active analogue, being 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 21 was effective against (P388/0) leukemia but not against the growth of a (MCF7) mammary tumor.

Animals↗
PubMed1999

Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients.

Amphotericin B colloidal dispersion (ABCD, AMPHOTEC, AMPHOCIL), a lipid complex of amphotericin B, was developed to reduce the nephrotoxicity of amphotericin B while retaining its antifungal efficacy. In this retrospective review, the efficacy and safety of ABCD were evaluated in 220 BMT recipients (167 allogeneic; 53 autologous) with suspected or documented life-threatening fungal infections (primarily Candida or Aspergillus species). Patients were treated in five open-label clinical trials of ABCD therapy. ABCD was administered intravenously once daily, median dose of 4 mg/kg, for up to 409 days (mean 23 days, median 16 days). Successful therapeutic response to treatment (complete or partial) was reported in 52% of the 99 evaluable patients with proven infection, and in 40% of all 220 patients. In the evaluable population, the response and mortality rates were 51% and 73%, respectively, in the allogeneic BMT patients, compared to 52% and 48% in the autologous BMT patients. The response rate for evaluable patients with Candida spp was 65%, 38% for patients with Aspergillus spp, and 42 % for patients with other or multiple fungal infections. In this patient population at high risk of nephrotoxicity due to concomitant cyclosporine and/or other nephrotoxic agents, ABCD did not cause renal dysfunction. Although the majority of patients had pre-existing renal impairment (median baseline serum creatinine 1.8 mg/dl), there was no trend towards increasing serum creatinine. No unexpected toxicities were observed. In conclusion, ABCD appears to be safe and effective for the treatment of severe fungal infections in BMT patients.

Adolescent↗
PubMed1999

Clinical efficacy of amphotericin B colloidal dispersion against infections caused by Aspergillus spp.

Three published clinical trials of the efficacy of amphotericin B colloidal dispersion (ABCD) against infections caused by Aspergillus spp were reviewed. A total of 376 patients was treated. Systemic aspergillosis was identified in 67 evaluable patients. Overall, a complete or partial response was achieved in 47.8% of the evaluable patients, although there were substantial differences in the response rates between studies. Reasons for recruitment caused a marked difference in response rates. The overall response rate for ABCD in patients in which conventional amphotericin B (CAB) was contra-indicated or had previously failed was 34.3%, whereas the response rate in bone marrow transplant (BMT) or patients with renal impairment was 57.9 and 62.5% respectively. The efficacy of ABCD at doses of 4 mg/kg/day appears to be at least as good as in studies using CAB. The levels of renal toxicity were low at a dose of 4 mg/kg/day. Dose-limiting studies indicate that dosages can be safely increased to 7.5 mg/kg/day creating opportunity for improved efficacy.

Amphotericin B↗
PubMed1999

Renal sparing by amphotericin B colloidal dispersion: clinical experience in 572 patients.

Data from five clinical trials of amphotericin B colloidal dispersion (ABCD) in the treatment of invasive mycoses were pooled to analyze the renal sparing effects of ABCD. Serum creatinine levels at baseline and either during or at end of treatment were available for 499 of 572 patients (87.2%). The median cumulative dose of ABCD administered to the 499 evaluable patients was 4,050 (range: 30-74,250) mg, and the median duration of treatment was 18 (range: 1-407) days. For the entire group of evaluable patients, the median change in serum creatinine during treatment with ABCD was -0. 1 mg/dl; for the subgroups of patients enrolled in the trials because of amphotericin B toxicity or preexisting renal impairment, the median changes in serum creatinine were -0.3 and -0.2 mg/dl, respectively. There was no trend of increasing serum creatinine with increasing cumulative dose of ABCD (correlation coefficient = -0. 016). ABCD was prematurely discontinued in 19 of 572 patients (3.3%) because of elevated serum creatinine levels. Unlike conventional amphotericin B, ABCD is not associated with dose-dependent nephrotoxicity.

Amphotericin B↗
PubMed1998

Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia.

We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after > or = 3 days of empirical antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized to receive therapy with ABCD (4 mg/[kg.d]) or amphotericin B (0.8 mg/[kg.d]) for < or = 14 days. A total of 213 patients were enrolled, of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B-treated patients had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients (P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD treatment than with amphotericin B treatment.

Adolescent↗
PubMed1998

Amphotericin B colloidal dispersion for treatment of candidemia in immunocompromised patients.

The efficacy and safety of amphotericin B colloidal dispersion (ABCD; Amphotec, Sequus Pharmaceuticals, Menlo Park, CA), a lipid complex of amphotericin B, were evaluated in immunocompromised patients with candidemia. These patients were recruited from five open-label clinical trials of ABCD therapy for fungal infections subsequent to bone marrow transplantation, hematologic malignancies, solid tumors, solid-organ transplantation, or other severe underlying disorders. ABCD was given intravenously in a median daily dose of 3.9 mg/kg for < or =72 days. Response rates were as follows: 53% overall (n = 88), 66% for patients with candidemia alone (n = 67), and 14% for patients with disseminated candidemia (n = 21). Nephrotoxicity occurred in 16% of patients, with either doubling of the baseline serum creatinine level or an increase of > or =1 mg/dL or a > or =50% decrease in calculated creatinine clearance. On average, there were no significant changes in the levels of serum creatinine or bilirubin from baseline to the end of treatment. In conclusion, ABCD was safe and effective for treating immunocompromised patients with candidemia.

Adolescent↗
PubMed1997

Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis.

To assess the efficacy and safety of amphotericin B colloidal dispersion (ABCD), 82 patients with proven or probable aspergillosis who were treated in clinical trials with ABCD were compared retrospectively with 261 patients with aspergillosis who were treated with amphotericin B at six cancer or transplant centers from January 1990 to June 1994. The groups were balanced in terms of underlying disease; ABCD recipients were younger and more likely to have preexisting renal insufficiency than were amphotericin B recipients (40.7% vs. 8.7%, respectively), and amphotericin B recipients were more likely to be neutropenic at baseline than were ABCD recipients (42.5% vs. 15.9%, respectively). Response rates (48.8%) and survival rates (50%) among ABCD-treated patients were higher than those (23.4% and 28.4%, respectively) among amphotericin B-treated patients (P < .001 for both comparisons). Renal dysfunction developed less frequently in ABCD recipients than in amphotericin B recipients (8.2% vs. 43.1%, respectively; P < .001). Multivariate analysis revealed that treatment group was the best predictor of response, mortality, and nephrotoxicity (ABCD: relative risk [RR] = 3.00, P = .002; RR = 0.35, P < .001; and RR = 0.13, P = .001; respectively). This retrospective study suggests that in the treatment of aspergillosis ABCD causes fewer nephrotoxic effects than amphotericin B and the efficacy of ABCD is at least comparable with that of amphotericin B.

Adolescent↗
PubMed1991

Protective and restorative role of AS101 in combination with chemotherapy.

The immunomodulator AS101 has been found previously by us to stimulate the secretion of high levels of interleukin 1 and colony stimulating factor (CSF) in vitro, as well as the production of CSF in vivo in mice models. These cytokines are known to induce proliferation and differentiation of hematopoietic progenitor cells from the spleen and bone marrow (BM) and to protect mice from DNA-damaging agents. The present studies were designed to evaluate the effects of prolonged treatment with AS101 on myelopoiesis, BM cellularity, and CSF secretion in mice treated with a sublethal dose of cyclophosphamide (CYP) and on the survival of mice undergoing treatment with lethal doses of this compound. In this model, the hematopoietic progenitors were suppressed during the overbound phase of myelopoiesis resulting from the cytotoxic effects of CYP. This allowed the detection of a significant proliferative effect of AS101 in vivo on BM colony-forming units granulocyte-macrophage progenitor cells, BM cellularity, and the secretion of CSF. Moreover, AS101 protected these animals from the lethal effects of high doses of CYP. These protective effects were demonstrable only when AS101 was administered to mice prior to CYP treatment. The only exception was CSF secretion by spleen cells that had been reconstituted when AS101 was administered both prior to and following CYP treatment. AS101 was found to have a synergistic effect with CYP in the treatment of tumor-bearing mice, suggesting that the combination of these two modalities provides a more effective treatment of their tumors. These results strongly suggest an immunoregulatory role for AS101 in counteracting the chemotherapy-induced hematopoietic suppression as well as usefulness as adjunct treatment of cancer when used in combination with CYP.

Adjuvants, Immunologic↗
PubMed1991

Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis.

Perorally administered acyclovir was evaluated in the therapy of acute infectious mononucleosis in a multicentered, randomized, double-blind, placebo-controlled trial. A total of 120 patients received 600 mg of acyclovir or placebo five times daily for 10 days. All patients were entered into the study within 7 days of symptom onset and had a positive Monospot test. Analysis of mean values and time to resolution of fever, lymphadenopathy, weight change, hepatomegaly, splenomegaly, liver function tests, atypical lymphocytes, hours of bed rest, sense of well-being, and return to normal activities revealed no significant differences. There was a trend toward suppression of Epstein-Barr virus excretion in the oropharynx in acyclovir recipients. No toxicity was detected in patients treated with acyclovir. Under the conditions of the study, there was no evidence that treatment with perorally administered acyclovir affected the course of infectious mononucleosis.

Acyclovir↗
PubMed1990

Radioprotective effects of the immunomodulator AS101.

Ammonium trichloro(dioxyethylene-O-O')tellurate (AS101) is a new synthetic compound previously described by us as having immunomodulating properties and minimal toxicity. Clinical trials are currently in progress with AS101 on AIDS and cancer patients. We found that AS101 was capable of inducing spleen cells and peritoneal exudate cells to secrete high quantities of CSF and IL-1. Because IL-1 has been previously described as a radioprotector and CSF may induce in vivo the proliferation of hemopoietic cells, we designed the present study in order to evaluate the effects of prolonged in vivo injections of AS101 on protection against lethal doses of irradiation, on the recovery pattern of precursor cells, and on the functioning of bone marrow (BM) and spleen cells of mice undergoing sublethal doses of treatment. We demonstrate that pretreatment with AS101 protects mice from lethal effects of ionizing radiation. AS101 was also found to significantly increase the number of BM and spleen cells, the absolute number of granulocyte macrophage-CFU and the secretion of CSF by BM cells. All were tested 9 days after sublethal dose of irradiation was administered. AS101 was found to have all of these radioprotective effects only when administered to mice before irradiation treatment. Moreover, the compound was found to enhance the proportion of CFU-S that enters the S phase of the cell cycle. These findings indicate that AS101 may be a promising agent to be used in reducing the time needed for reconstitution of hemopoietic cells after irradiation treatment.

Adjuvants, Immunologic↗
PubMed1990

Immunologic effects of AS101 in the treatment of cancer patients.

AS101 [ammonium trichloro(O,O'-dioxyethylene)tellurate] is a new immunomodulator previously shown to stimulate the production of different cytokines in vitro and in vivo. We report here our results of a phase I clinical trial conducted on 47 cancer patients with advanced malignancies. AS101 was administered intravenously at escalating doses from 1 to 10 mg/m2, twice or thrice a week. The maximal tolerated dose has not yet been determined. However, significant immunologic responses were noted at dose levels of 1-3 mg/m2 administered three times a week. At these doses statistically significant rises in gamma-interferon, natural killer cell activity, tumor necrosis factor and interleukin-2 (IL-2) levels as well as the expression of IL-2 receptors were noted. In most of the immunologic parameters the maximal response was seen at 3 mg/m2. Throughout the study toxicity was minimal. In view of these results phase II studies are currently being initiated.

Adjuvants, Immunologic↗
PubMed1988

Randomized clinical trial of rifampin-trimethoprim and sulfamethoxazole-trimethoprim in the treatment of localized urinary tract infections.

To investigate whether 10 days of rifampin-trimethoprim (RIF-TMP) or 6 weeks of sulfamethoxazole-trimethoprim (SMX-TMP) would decrease the relapse rate in patients with acute uncomplicated upper urinary tract infections in comparison with 10 days of SMX-TMP, we randomized 189 patients to receive RIF-TMP or SMX-TMP in a ratio of 1:2. After the site of infection was established by the antibody-coated bacterium (ACB) test, patients with upper-tract infections who received SMX-TMP were again randomized and received either a total of 6 weeks or 10 days of therapy. All patients who received RIF-TMP were treated for 10 days. Clinical and microbiological evaluations were repeated at 2 and 6 weeks posttreatment. Eighty-five patients (54 ACB positive) received 10 days of RIF-TMP, 71 patients (45 ACB positive) received 10 days of SMX-TMP, and 18 patients (18 ACB positive) received 6 weeks of SMX-TMP. The overall recurrence rates in patients who received 10 days of therapy were 32% for RIF-TMP and 23% for SMX-TMP (P = 0.13). There were 12 (14%) relapses in the RIF-TMP group compared with 2 (3%) relapses in the SMX-TMP group (P = 0.01). In patients with upper-tract infections, the relapse rates were not statistically significantly different (P = 0.13). There were two (11%) recurrences (one relapse and one reinfection) in the 6-week treatment group. This 6% relapse rate was not different from the 4% relapse rate observed in patients with upper-tract infections who received 10 days of SMX-TMP. The number of patients who discontinued treatment because of an adverse effect in the 6-week SMX-TMP treatment group was significantly greater than those in the 10-day SMX-TMP treatment group (P=0.003) and the RIF-TMP treatment group (P=0.05). Ten days of SMX-TMP was as effective as 6 weeks of SMP-TMP or 10 days of RIF-TMP in the treatment of uncomplicated upper urinary tract infections and caused the fewest untoward effects.

Adult↗
PubMed1987

Clinical and serologic responses to acellular pertussis vaccine in infants and young children.

We administered diphtheria, tetanus, and pertussis (DTP) vaccine containing acellular (lymphocytosis promoting factor and filamentous hemagglutinin) pertussis vaccine to three groups of 20 children each (4 to 6 years, 17 to 21 months, and 5 to 9 months of age). All the children tolerated the vaccine well; no reactions occurred that contraindicated further immunization. Older children had significantly more local (redness or swelling) and systemic (fever or fretfulness) reactions than younger children. Eighty percent to 90% of the children in the two older age groups had fourfold or greater increases in antibody titers to DTP antigens one month after vaccination. The postvaccine concentrations of antibody to tetanus and diphtheria were greater than 0.01 IU/mL in all children. Serologic responses to lymphocytosis promoting factor and filamentous hemagglutinin varied with age; significantly more older children than younger children had four-fold or greater increases. Acellular pertussis DTP vaccine was antigenic in young children and was less reactogenic than standard whole cell DTP vaccine according to rates reported in previous studies.

Antibodies↗
PubMed1987

IgE and IgG antibodies to beta-propiolactone and human serum albumin associated with urticarial reactions to rabies vaccine.

We examined the antibody response to a rabies vaccine doubly inactivated with 0.025% beta-propiolactone and 0.1% tri(n)butyl phosphate and stabilized with 2.5% human serum albumin. Antibodies were measured by using the following four antigen preparations: complete doubly inactivated rabies vaccine, rabies vaccine inactivated only with tri(n)butyl phosphate, beta-propiolactone and human serum albumin, and human serum albumin alone. The fluid phase of the preparation of beta-propiolactone and human serum albumin completely inhibited IgE binding to solid-phase vaccine. Of 21 subjects with urticarial reactions to a booster, 19 had IgE to doubly inactivated vaccine and to beta-propiolactone and human serum albumin. None of 27 immunized subjects without urticaria had detectable IgE. In paired pre- and postimmunization sera, IgE appeared in six of seven of the subjects with urticaria and in one of seven nonreactors. These sera did not contain a significant level of IgE to singly inactivated vaccine or to human serum albumin alone.

Antibodies, Viral↗
PubMed1986

Single-dose tioconazole compared with 3-day clotrimazole treatment in vulvovaginal candidiasis.

A total of 80 patients were equally randomized to receive a single dose of 6.5% tioconazole ointment or a 3-day course of 100-mg clotrimazole vaginal tablets for the treatment of vulvovaginal candidiasis. Of the 32 evaluable patients treated with tioconazole, 27 (84%) remained asymptomatic 4 weeks posttreatment, compared with 28 of 33 patients (85%) treated with clotrimazole. A total of 34 patients in each group could be evaluated for mycological response based on culture results 1 and 4 weeks after treatment. Twenty patients (59%) who received tioconazole and twenty-one patients (62%) who received clotrimazole remained culture negative 4 weeks after therapy. Of 40 patients who received tioconazole, 12 (30%) experienced local irritation or itching, compared with 2 of 40 patients (5%) treated with clotrimazole (P less than 0.01). Single-dose tioconazole ointment was as effective as a 3-day course of clotrimazole tablets, but significantly more patients in the tioconazole-treated group experienced local side effects.

Adolescent↗
PubMed1985

An open study evaluating the reactogenicity and immunogenicity of a DTP vaccine containing an acellular pertussis component in four to six year old children.

Acellular pertussis vaccines have been used for mass immunization of children in Japan since the fall of 1981, but until recently they have not been evaluated in the United States. We report a trial with a DTP vaccine containing an acellular pertussis component in 36 four to six year old children who had previously received four doses of United States DTP licensed vaccine with a whole cell pertussis vaccine component. The study vaccine contained diphtheria and tetanus toxoids and 300 HA units of Takeda acellular pertussis component. The principle immunizing antigens in the pertussis component of the vaccine were lymphocytosis promoting factor (LPF) and filamentous hemagglutinin (FHA). Local and systemic reactions were monitored during the first 48 hours after vaccination, and pre-immunization and one month post-immunization serum specimens were obtained for antibody assay. The following reaction rates were noted: redness 50%, tenderness 50%, swelling 41%, fever (greater than or equal to 38 degrees C) 3%, drowsiness 17%, fretfulness 14%, anorexia 11%, and vomiting 6%. Pertussis antibody values (preimmunization/postimmunization) were as follows: agglutinin GMT, 1:21/1:100; FHA mean ELISA u, 28 +/- 6/greater than or equal to 229 +/- 47; LPF mean ELISA u, 176 +/- 59/1732 +/- 280. The pertussis component of the study vaccine would appear to be less reactogenic than United States whole cell pertussis vaccines but still immunogenic when given as a booster immunization to four to six year old children. Further studies are needed to assess reactions and immunogenicity in younger and previously unimmunized children.

Anorexia↗
PubMed1983

Diarrhea among infants and young children in Canada: a longitudinal study in three northern communities.

Diarrhea among neonates and their siblings was studied in 98 families living in Winnipeg, Manitoba, and in 31 native Indian families and in 15 Inuit (Eskimo) families living in isolated settlements in northern Canada. The rate of infection due to rotavirus in neonates was significantly higher and infection occurred more often in the first six months of life in the northern communities (range, 0.36 in Winnipeg to 1.07 in Eskimo Point). No protective effect of breast-feeding was discerned, since infection due to rotavirus occurred more frequently and earliest in neonatal life in Eskimo Point, the community with the highest rate of breast-feeding. In contrast, infection due to Norwalk virus was most common among the neonates of Berens River (0.15 infections per child per year), the only community with relatively unsafe water supplies. Infection due to rotavirus appears to be more frequent in the far North, whereas infection due to Norwalk virus appears to be related more to inadequate sanitation.

Child↗