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Biomedical subjects

J Kuhn

Publications and source records attributed to J Kuhn.

At least 91 records · Page 5Linked to original sources
PubMed1994

Phase I trial of dacarbazine with cyclophosphamide, carmustine, etoposide, and autologous stem-cell transplantation in patients with lymphoma and multiple myeloma.

PURPOSE: We investigated the feasibility of escalating doses of dacarbazine (DTIC) in combination with high-dose cyclophosphamide, carmustine, and etoposide (CBV) given with autologous stem-cell transplantation in 33 patients with relapsed or refractory lymphoma or multiple myeloma. PATIENTS AND METHODS: Eligible patients were treated in this phase I study with cyclophosphamide (7.2 g/m2), carmustine (BCNU) (600 mg/m2), etoposide (2.4 g/m2), and escalating doses of DTIC (3,000 to 6,591 mg/m2) administered either as a 2- (in 23 patients) or a 6- (in 10 patients) hour infusion to determine the maximum-tolerated dose (MTD) of DTIC and the toxicity profile of this combination. RESULTS: The MTD of DTIC infused over 2 hours and given with the CBV regimen was 3,900 mg/m2, with the dose-limiting toxicity being hypotension. Seven patients experienced transient acute hypocalcemia in association with the DTIC infusion. Prolonging the DTIC infusion to 6 hours or administration of supplemental calcium did not allow further dose escalation of DTIC to occur. Other non-hematologic toxicities observed with this regimen have been reported with CBV alone. Of 25 patients assessable for tumor response at first evaluation posttransplant, 13 (52%) were in complete remission (CR), four (16%) were in partial remission (PR), five (20%) had stable disease (SD), and three (12%) had progressive disease (PROG). Of 31 patients assessable for relapse-free survival, 22 are alive with 13 in CR, one in PR, two with SD, and six with PROG at a median follow-up duration of 313 days (range, 35 to 749+). Treatment-related mortality occurred in six patients (18%). CONCLUSION: The feasibility of combining DTIC in high doses with the CBV regimen has been demonstrated. Dose-limiting hypotension is transient and reversible when DTIC is administered at 3,900 mg/m2 with CBV. Future trials to evaluate the effect of the addition of DTIC to the CBV regimen on response rate and relapse-free survival are encouraged.

Adolescent↗
PubMed1993

TH2 activated cells prevent experimental autoimmune uveoretinitis, a TH1-dependent autoimmune disease.

Mercuric chloride (HgCl2) injections protect (Lewis x Brown-Norway) F1 (F1) rats against experimental autoimmune uveoretinitis (EAU) induced by immunization with the retinal S antigen (S-Ag); in contrast HgCl2-injected F1 rats develop EAU following transfer of lymph node (LN) cells from rats immunized with S-Ag alone. In the present study we demonstrate that the ability of LN cells from rats protected against EAU to transfer the disease into naive F1 rats was considerably reduced. These LN cells neither produced interleukin (IL)-2 nor (interferon (IFN)-gamma but exhibited mRNA for IL-4. In contrast, LN cells from diseased rats easily transferred EAU into naive F1 rats, produced significant IL-2 and IFN-gamma levels but barely exhibited mRNA for IL-4. Furthermore protected rats predominantly produced IgG1 anti-S-Ag antibodies, while diseased rats produced IgG2b anti-S-Ag antibodies and the increase in expression of MHC class II molecules on B cells was higher in protected rats than in diseased rats. These data suggest that (1) to exert a protective effect, HgCl2 must act at an early stage of differentiation of precursors of S-Ag specific T cells, and (2) this effect is related to the preferential activation of TH2 cells to the detriment of uveitogenic TH1 cells. Finally, these results indicate that activation of TH2 cells protect from a TH1-dependent autoimmune disease.

Animals↗
PubMed1993

Human immunoglobulin preparations for intravenous use prevent experimental autoimmune uveoretinitis.

We have evaluated the effect of human Igs for intravenous use (IVIg) on the onset and development of experimental autoimmune uveoretinitis (EAU), a T cell-dependent autoimmune disease induced in rats by a single immunization with retinal S-antigen (S-Ag). Five consecutive daily infusions of IVIg, starting on the same day as S-Ag immunization, protected (Lewis x Brown-Norway) F1 rats against EAU. The prevention of EAU was IVIg-specific, i.e. mediated by pooled human IgG from multiple donors, since neither infusions of BSA nor infusions of pooled Ig from only two healthy individuals were effective. Treatment with IVIg decreased lymphocyte proliferative and antibody responses to S-Ag and the proliferative response to concanavalin A. Lack of proliferation was not dependent upon generation of suppressor cells. Lymph node (LN) cells from IVIg-treated and S-Ag-immunized animals neither proliferated nor secreted IL-2 in response to S-Ag but proliferated when co-cultured with LN cells from rats immunized with S-Ag. Our findings are compatible with an induction of a state of functional inactivation/anergy of T lymphocytes by infusions of IVIg. This functional inactivation may be due to the presence in IVIg of antibodies that bind both in vivo and in vitro to rat lymphocytes. Results from the present study suggest a novel mechanism by which IVIg may be beneficial in human autoimmune diseases.

Animals↗
PubMed1993

Anti-interleukin-2 receptor monoclonal antibody therapy supports a role for Th1-like cells in HgCl2-induced autoimmunity in rats.

Brown-Norway (BN) rats injected with HgCl2 develop an autoimmune disease characterized by a T-dependent polyclonal B-cell activation. Increase in major histocompatibility complex class II molecule expression on B cells concomitant with enhancement of serum IgE concentration supports the involvement of the T helper 2 (Th2)-like subset in the induction of the disease. The mercury disease is autoregulated and does not develop in Lewis (LEW) rats. Considering the reciprocal regulation, well defined in mice, between the Th1 and Th2 subsets, we addressed the role of the Th1-like subset in this disease. Brown-Norway and LEW rats injected with HgCl2 were treated with NDS61, a mouse anti-rat-IL-2R MoAb that blocks mainly Th1 cells. Data reported herein show that: (1) HgCl2 treatment does not modify either the percentage of IL-2R+ cells or IL-2R expression in both BN and LEW rats; (2) treatment of BN rats with NDS61 MoAb does not modify the induction phase of the mercury disease but delays in part the regulation phase; (3) such a treatment leads to some immune abnormalities in LEW rats; (4) HgCl2 markedly potentiates the anti-mouse Ig antibody response in BN rats which probably limits the effect of this treatment. This study supports a role for the Th1-like subset in HgCl2-induced autoimmunity in the rat.

Animals↗
PubMed1993

Phase I clinical trial of taxotere administered as either a 2-hour or 6-hour intravenous infusion.

PURPOSE: To determine the potential efficacy and dose-limiting toxicity of taxotere, a hemisynthetic inhibitor of tubulin depolymerization. PATIENTS AND METHODS: Fifty-eight patients were administered taxotere in this phase I clinical trial as a 6-hour or a 2-hour infusion repeated every 21 days. Forty patients received 181 courses on the 6-hour infusion schedule, and 18 patients received 105 courses on the 2-hour infusion schedule. RESULTS: Neutropenia was the dose-limiting toxicity on both schedules. The maximally tolerated dose was 100 mg/m2 on the 6-hour infusion schedule and 115 mg/m2 on the 2-hour infusion schedule. The most prominent nonhematologic toxicities included mucositis (more prominent on the 6-hour infusion schedule), transient rash (more common on the 2-hour infusion schedule), and alopecia. Hypersensitivity reactions were seen in five patients. There was no evidence of neurotoxicity or cardiotoxicity. One partial response was noted on the 6-hour infusion schedule (one in refractory breast cancer) and four additional partial responses were noted on the 2-hour infusion schedule (two in adenocarcinoma of the lung, one in refractory breast cancer, one in cholangio-carcinoma). In addition, 10 patients had minor responses. Pharmacokinetic studies showed plasma concentrations of taxotere declined in a triexponential manner, with a terminal half-life of 11.8 hours. CONCLUSION: The recommended starting dose for phase II taxotere trials is 100 mg/m2 administered as a 2-hour infusion, repeated every 21 days. Taxotere is a promising antineoplastic agent worthy of extensive phase II testing in patients with a variety of malignancies.

Adult↗
PubMed1992

Selection and analysis of non-interactive mutants in the Escherichia coli tryptophan synthase alpha subunit.

The inherent infidelity of Taq DNA polymerase in the polymerase chain reaction was exploited to produce random mutations in the trp A gene. Screening of the resulting clones allowed selection of non-interactive mutant alpha subunits retaining their intrinsic catalytic activity. Two single changes responsible for this phenotype were identified by DNA sequencing as: alpha 126 valine (GTG)----glutamic acid (GAG) and alpha 128 valine (GTT)----aspartic acid (GAT). Three single changes giving a non-interactive phenotype with an impaired intrinsic catalytic activity were identified by DNA sequencing as alpha 66 asparagine (AAC)----aspartic acid (GAC); alpha 109 lysine (AAA)----arginine (AGA); alpha 118 cysteine (TGC)----arginine (CGC). Where possible, we individually assessed the importance of these residues in alpha beta interaction in light of structural information from X-ray crystallography and by intergeneric protein sequence comparison.

Amino Acids↗
PubMed1992

A stable Escherichia coli-Mycobacterium smegmatis plasmid shuttle vector containing the mycobacteriophage D29 origin.

A plasmid shuttle vector for Escherichia coli and mycobacteria was constructed from an E. coli plasmid containing the ColE1 origin, a 2.6-kb PstI fragment from bacteriophage D29 that grows in numerous mycobacterial species, and the kanamycin resistance gene either of Tn903 or of Tn5. The resultant plasmid is 7.63 kb and can be introduced via transformation into Mycobacterium smegmatis with high efficiency. In M. smegmatis the plasmid is stable and apparently present in multiple copies. Bioluminescence (luxA and luxB of Vibrio harveyi and fischeri) has been expressed in M. smegmatis from the aminoglycoside transferase promoter of Tn5. The D29 fragment should carry an origin of replication and some associated genes that act on it since various mutations destroy the ability of this fragment to replicate in M. smegmatis. The fragment was localized on the D29 genome map.

DNA Transposable Elements↗
PubMed1992

Susceptibility and resistance to autoimmunity following neonatal injection of semi-allogeneic spleen cells in rats.

A model of neonatal allotolerance was developed in rats. Brown-Norway (BN) neonates injected with semi-allogeneic (BN x Lewis) F1 hybrid spleen cells express a long-lasting chimerism and exhibit polyclonal B cell activation demonstrated by hyperimmunoglobulinemia affecting mainly IgE and IgG1, anti-laminin and anti-DNA autoantibodies as well as glomerulonephritis and anti-hapten antibodies. These abnormalities are autoregulated although the chimerism persists. In contrast, Lewis (LEW) neonates injected with semi-allogeneic (BN x LEW) F1 hybrid spleen cells exhibit a very short-lasting chimerism and transient activation of B cells, as reflected by increased allo-class II antigen expression, but do not develop an autoimmune disease. The autoimmune syndrome observed in BN rats is similar to that reported in mice during host-versus-graft reaction. Similarities between the drug-induced models of autoimmunity and allogeneic reactions in BN rats are also striking. The susceptibility of BN rats and the resistance of LEW rats to these autoimmune diseases might respectively reflect the involvement of TH2-like or of TH1-like subsets.

Animals↗
PubMed1992

[The "Emmerich Arthritis Record", function and acceptance within the scope of an integrated treatment concept].

For a comprehensive model of rheumatoid arthritis treatment, we designed an arthritis manual for continuous treatment of chronic illness. One goal of introducing the manual to the patients was the improvement of communication between patient and different doctors and therapists. The first part includes of a doctor's documentation sheet and a patient calendar (6 months each) for daily self-documentation of drug compliance. The second part is a daily pain-rating scale. The 3-year evaluation of 655 patient manuals for 286 patients was analyzed to estimate the compliance in using the manual. Overall, 87% of diagnoses, 83% of disease-modifying anti-rheumatic drugs (DMARDs), 87% of non-steroidal anti-rheumatic drugs (NSAIDs) had been documented in the manual. Data indicates that the general practitioner and the rheumatologist accepted the manual form. In addition, 85% of the documented patients used the DMARDs, 74% used the daily pain score, and 43% the daily physiotherapy. Subgroup data (n = 130 RA patients) suggest additional results: 1) there was no difference in sociodemographic data between the patient manual user group and the non-user group; 2) the user group consisted of patients with higher disease activity (ARA-criteria), higher pain score, and negative mood pattern. Furthermore, the user group was more active in daily physiotherapy, ergotherapy, and balneotherapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Citrate synthase from Mycobacterium smegmatis. Cloning, sequence determination and expression in Escherichia coli.

A Mycobacterium smegmatis PstI library was constructed by cloning these fragments downstream from the lac promoter of the expression vector pHG171. Three identically sized clones were isolated by complementation of an Escherichia coli strain (chi 2338) deficient in citrate synthase. One insert (pBL265) was used in hybridization experiments with DNA from E. coli and M. smegmatis and it was demonstrated that the clones were indeed from M. smegmatis. The transcription of the M. smegmatis citrate synthase gene in E. coli relied upon the lac promoter. In translation experiments performed in vitro pBL265 gave rise to a novel protein of about 42 kDa. This band was not seen in 'opposite-orientation' subclones. Various subclones in which the 5'-end was shortened nevertheless complement E. coli chi 2338 and produce the 42 kDa protein. This demonstrates that the M. smegmatis citrate synthase gene uses its own ribosome-binding site in E. coli. The relevant 1.8 kb of the 2.8 kb insert was sequenced. A consensus E. coli ribosome-binding site was found centred precisely 10 bp upstream of the methionine codon. Other interesting features revealed by the sequence are discussed. Citrate synthase activity was assayed in vitro and the mycobacterial enzyme was found to be similar to those of the Gram-positive bacteria.

Amino Acid Sequence↗
PubMed1991

Increased expression of class II major histocompatibility complex molecules on B cells in rats susceptible or resistant to HgCl2-induced autoimmunity.

Administration of HgCl2 to the susceptible Brown-Norway (BN) rats induces an autoimmune disease characterized by a T-dependent polyclonal activation of B cells responsible for a dramatic increase in serum IgE concentration. The resistant Lewis (LEW) rats injected with HgCl2 do not exhibit such autoimmune manifestations. We show here that, upon HgCl2 injections, major histocompatibility complex (MHC) class II molecule expression is increased very early in lymph nodes and spleen B cells from both strains. So far, it is the earliest marker (day 3) of the effect of HgCl2 on the immune system. In both strains this enhancement is transient, but regulatory mechanisms are much more efficient in the resistant LEW strain than in the susceptible BN strain. In addition, we observed that MHC class II molecule expression on B cells differs according to the organ and the rat strain tested. All these findings are discussed in an attempt to underline the role of MHC class II molecule expression in the occurrence of mercury-induced autoimmunity.

Animals↗
PubMed1991

A phase I trial of taxol given by a 6-hour intravenous infusion.

Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result, the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond, and premedication with diphenhydramine, dexamethasone, and cimetidine was initiated. Early studies showed antitumor activity, especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol, as a 6-hour IV infusion every 21 days, without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction, which was easily controlled using routine measures. Myelosuppression was dose-limiting, but sporadic, with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer, one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.

Alkaloids↗
PubMed1991

Prevention of experimental autoimmune uveoretinitis and experimental autoimmune pinealitis in (Lewis x Brown-Norway) F1 rats by HgCl2 injections.

Mercuric chloride (HgCl2) induces in Brown-Norway (BN) and (Lewis x Brown-Norway) F1 hybrid rats a transient autoimmune disease characterized by the production of various antibodies to self and non-self antigens and by a dramatic increase of serum IgE. Experimental autoimmune uveoretinitis (EAU) can be induced in Lewis (LEW) and (LEW x BN) F1 hybrid rats by a single immunization with retinal S-antigen (S-Ag). Besides uveoretinitis, animals immunized with S-Ag develop an autoimmune pinealitis (EAP). We demonstrate in this study that (LEW x BN) F1 hybrid rats, injected with HgCl2 7 days before S-Ag immunization, are quite efficiently protected against EAU and EAP. We also show that HgCl2-induced protection is neither due to a cytotoxic effect of HgCl2 nor to CD8+ T-cell dependent mechanisms nor to the HgCl2-induced increase of serum IgE concentration. The role of other hypothetical mechanisms, such as anti-S-Ag anti-idiotypic antibodies and/or HgCl2-induced unbalance between T-helper cell subsets, is discussed.

Animals↗
PubMed1990

Analysis of anticancer drugs in biological fluids: determination of taxol with application to clinical pharmacokinetics.

Taxol, a novel antimitotic, antitumor agent is currently undergoing Phase 1 clinical trials for the treatment of various tumors. An isocratic HPLC method has been developed for the determination of taxol in human plasma and urine. The method was then applied to the clinical pharmacokinetics of taxol following 6-h intravenous (i.v.) infusions at doses of 175 and 225 mg m-2. A mobile phase of methanol-acetate buffer (0.02 M, pH 4.5) (65:35, v/v) was used to elute a C8 column with detection at 227 nm. The sample preparation involved extraction with t-butyl methyl ether followed by further clean-up of the sample by solid-phase extraction. The method was linear from 0.10-10 microM injected, with a chromatographic run time of 6 min. The results obtained from the clinical study indicate that the plasma pharmacokinetics of taxol are best characterized by a two compartment open body model. Additionally, the present study resulted in the detection of a previously unreported peak which may be a metabolite of taxol.

Alkaloids↗
PubMed1988

Plasma exchange in a rat model of autoimmune glomerulonephritis.

Using an original technique permitting repeated plasma exchange in the rat, we have tested this therapeutic approach in animals actively immunised with horseradish peroxidase, and in rats with HgCl2-induced autoimmune glomerulonephritis. Plasma exchange effectively removes circulating IgG anti-horseradish peroxidase antibodies from the sera of immunised rats. When applied to the model of HgCl2-induced antiglomerular basement membrane glomerulonephritis in Brown-Norway rats, this technique is also remarkably effective. In these rats, proteinuria is abolished during the plasma exchange treatment period and no circulating antiglomerular basement membrane antibodies can be detected. These antibodies are, however, found in the ultrafiltrates of exchanged rats. Serum IgE, characteristically elevated in HgCl2-treated rats, is also markedly diminished in exchanged rats. Control rats treated with infusions of fresh frozen plasma or with heparin alone did not show any improvement in disease severity. These results suggest that plasma exchange alone can attenuate antiglomerular basement membrane nephritis in HgCl2-treated rats. This observation may be of relevance for the treatment of human antiglomerular-basement membrane-mediated glomerulonephritis.

Animals↗