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Biomedical subjects

J C Jensen

Publications and source records attributed to J C Jensen.

At least 37 records · Page 2Linked to original sources
PubMed1990

Cachectic effects of recombinant human tumor necrosis factor in rats.

Treatment of rats with either intermittent bolus i.v. injections or continuous i.v. infusions of the same sublethal daily dose of tumor necrosis factor (TNF) results in decreased food intake and decreased nitrogen balance compared to saline-treated control rats. After 4 days of treatment, rats treated with intermittent bolus doses of TNF develop tolerance to the nutritional effects and consume normal amounts of food and have nitrogen balance similar to those of saline treated rats. Rats receiving the continuous infusion of TNF do not. Rats treated with both routes of TNF lose more weight than pair fed rats who eat the same mean amount as the continuous TNF treated group. In addition, 56% of rats receiving continuous infusion TNF die during the 8-day experimental period while rats receiving either intermittent bolus TNF or similar food intake (pair fed) do not. Body composition studies of rats that completed the 8 days of treatment indicate that rats receiving either continuous infusion or intermittent bolus TNF have increased percentages of body water and reduced percentages of body solid compared to saline treated control rats. Rats pair fed to the food intake of continuous TNF treated rats also had increased percentages of body water and reduced percentages of body solid, but changes were significantly less than those observed in continuous TNF infused rats. Continuous TNF infusion reduced total body nitrogen and potassium while pair feeding did not reduce potassium and reduced nitrogen to a lesser degree. Pair feeding and continuous TNF infusion reduced total body fat to a similar extent. Twice a day administration of TNF resulted in lesser changes in carcass water, solid, nitrogen, lipid, and potassium than continuous infusion of the same dose of TNF. The results indicate that continuous infusion of TNF can produce anorexia, weight loss, edema, loss of body protein, lipid and cell mass, and lethality which is markedly ameliorated with bolus doses of TNF. The findings are consistent with the hypothesis that slow continuous secretion of sublethal amounts of TNF may mediate cancer cachexia.

Animals↗
PubMed1990

Lactic acidosis increases tumor necrosis factor secretion and transcription in vitro.

Lactic acid has been shown to affect numerous biologic processes. We investigated the role of lactic acidosis as a signal for the production of TNF by macrophages in vitro. Male F344 rats were administered thioglycolate media intraperitoneally. Macrophages were recovered 7 days later, cultured for 24 hr in complete media (CM), or CM with L-lactic acid (5, 10, or 15 mM), or with endotoxin (LPS) (10 micrograms/ml). TNF levels were measured in the supernatants. Female C57BL/6 mice were similarly treated, and macrophages were harvested and cultured in CM or CM containing lactic acid (15 mM), or LPS (10 micrograms/ml). RNA was extracted after 24 hr, separated by electrophoresis, and transferred to nitrocellulose. Human 32P-cDNA TNF and actin probes were used to determine relative TNF gene expression. Gel densitometry was used to calculate the TNF expression index (EI) in lactic acid and LPS treated cells as described. pH levels of the supernatant indicated that increasing concentrations of lactic acid caused increasing acidosis. Trypan blue exclusion demonstrated that lactic acidosis did not reduce cell viability. LPS significantly increased secretion of TNF relative to control (P less than 0.001). Each concentration of lactic acid significantly increased TNF secretion (P less than 0.05), but not in a dose-dependent manner. TNF gene transcription was elevated in macrophages cultured with lactic acid and LPS relative to control (EI = 1.13 and 1.18, respectively). This suggests that lactic acid concentration can regulate TNF secretion at the level of transcription, and is consistent with the hypothesis that local levels of lactic acid (lactic acidosis) may be a regulator of cytokine secretion.

Acidosis, Lactic↗
PubMed1989

Antipyrine metabolism is not affected by terbinafine, a new antifungal agent.

The potential to inhibit drug metabolism of the new antifungal agent terbinafine has been studied using antipyrine (single oral dose of 10 mg/kg) as a probe drug. In a cross-over study in 8 healthy volunteers, antipyrine was administered prior to, during and after 8 days of oral terbinafine 125 mg b.d. Antipyrine, its major metabolites 4-hydroxyantipyrine (4-OH-AP), 3-hydroxymethylantipyrine (3-OH-CH3-AP) and norantipyrine (Nor-AP) were analyzed by specific HPLC assays in multiple plasma and urine samples. During all three parts of the study, the pharmacokinetics of antipyrine viz. t1/2 (11.7 h), total plasma (38.5 ml.h-1.kg-1) and renal clearance (1.6 ml.h-1.kg-1), and its clearance rates to metabolites (CLM), eg. CLM for 4-OH-AP (12.3 ml.h-1.kg-1), CLM for 3-OH-CH3-AP (4.2 ml.h-1.kg-1) and CLM for Nor-AP (6.7 ml.h-1.kg-1) did not differ from the control values. Thus, all the cytochrome P-450-dependent isozymes involved in the metabolism of antipyrine and many other drugs should not be affected by therapeutic doses of terbinafine.

Adult↗
PubMed1989

A report of 4 patients with the Drash syndrome and a review of the literature.

Four patients with the Drash syndrome, represented by the triad of male pseudohermaphroditism, progressive renal insufficiency and Wilms tumor are discussed. This syndrome, which some have suggested should be expanded to include patients with nephropathy, Wilms tumor and any abnormality of gonadal differentiation, appears early in life. The first sign usually is genital ambiguity. However, proteinuria, hematuria and hypertension eventually require renal biopsy, which may reveal a variety of glomerular and interstitial changes. The nephropathy progresses rapidly, is unresponsive to steroids and eventually requires dialysis. Wilms tumor may appear as a mass on ultrasound or it may not be recognized until nephrectomy or even autopsy. Young children with gonadal dysgenesis and nephropathy are at high risk for nephroblastoma and gonadal tumors and, therefore, prophylactic nephrectomy and gonadectomy should be considered early in the course of this disease.

Disorders of Sex Development↗
PubMed1989

[The course of Crohn disease and side effect profile with long-term treatment using metronidazole].

In a prospective study 21 patients with Crohn's disease not responding to standard treatment (salazosulfapyridine and/or corticosteroids) received metronidazole in a dose of 12 to 20 mg per kg body weight over 6 and 12 months respectively. The objectives were documentation of side effects and pharmacokinetic behaviour of metronidazole in relation to the course of the disease. In 3 months intervals and 3 months after the end of treatment activity indices were determined, the side effects of metronidazole were recorded and the drug plasma concentration was measured. Compliance of drug intake was excellent (94%). Best-Index decreased to a minimum after 6 months, orosomucoid after 3 months. Side effects from metronidazole (black tongue, dark urine, paraesthesia, metallic taste, epigastric pain, skin reactions, nausea) were reported by over 80% of the patients at any time of the study. Nearly 50% of patients developed paraesthesia, which was still present 3 months after the end of treatment. A mean dose of 15.4 mg per kg corresponded to a mean plasma concentration of 10.9 micrograms/ml of metronidazole. Plasma concentrations were not related to treatment success nor to the incidence of side effects. Treatment of Crohn's disease with metronidazole for longer than 3 months is not recommended both because of lack of additional therapeutic gain and because of the increasing risk of side effects.

Adolescent↗
PubMed1988

Soluble Tac peptide is present in the urine of normal individuals and at elevated levels in patients with adult T cell leukaemia (ATL).

The T lymphocyte-derived lymphokine interleukin 2 and the cell-associated receptor for this molecule play major roles in the activation and regulation of the human immune response. An enzyme-linked immunosorbent assay has been developed to measure quantitatively a soluble form of one component of the human interleukin 2 receptor, namely the Tac peptide. In the present studies, soluble Tac peptide was measured in the urine of normal individuals (mean = 92 U/ml), a level not significantly different (0.01 less than P less than 0.05) from the corresponding serum concentrations (mean = 175). The urinary Tac peptide had a molecular weight of 40-45 kD by sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis and specifically bound interleukin 2. Elevated levels of urinary Tac peptide were found in four patients with adult T cell leukaemia who also had elevated serum levels of Tac peptide. Thus, urine may represent a valuable source of lymphokine-binding proteins that may serve as important markers of immunological activation.

Adult↗
PubMed1987

[Inhibition of microsomal enzyme activity of the liver by various H2 receptor antagonists].

The inhibition of 7-ethoxycoumarin deethylase activity by four different H2-receptor antagonists was studied using rat liver microsomes. The compounds tested represent two classes of H2-antagonists, i. e. structures with (cimetidine and oxmetidine) and without (ranitidine and SKF 93479) an imidazole ring. The microsomes were prepared from untreated and phenobarbital-treated animals. It was found that all four compounds, even those without an imidazole ring, inhibited deethylase activity. The compounds inhibited in the following order: SKF 93479 (90%) greater than cimetidine (58%) = oxmetidine (58%) greater than ranitidine (23%). In microsomes from phenobarbital-induced animals, the inhibitory activity of oxmetidine was increased 5-fold. Only the inhibitory potency of cimetidine was increased by preincubation of the H2-antagonist with the microsomes prior to the addition of the substrate.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

Alternatives to CYVADIC combination therapy of soft tissue sarcomas.

The CYVADIC combination has been the preferred treatment for soft tissue sarcomas for the last 10 years. Other combination therapies are necessary, because the remission rate achieved with CYVADIC is only 30%. Alternative therapies for these tumors are combinations including cis-platinum, ifosfamide, epipodophyllin, and high-dose methotrexate. Our therapeutic results with combinations of cis-platinum and ifosfamide are comparable to those achieved with CYVADIC. However, the side-effects, such as nausea, vomiting and fatigue, of cis-platinum used in the palliative treatment of these tumors are intolerable for many patients. A combination of adriamycin and ifosfamide, which leads to a higher remission rate of 44% and has lower toxicity than CYVADIC, is giving encouraging results.

Adult↗
PubMed1986

Spontaneous and induced chromosomal aberrations and gene mutations in human lymphoblasts: mitomycin C, methylnitrosourea, and ethylnitrosourea.

The concentration-dependent mutagenic, clastogenic, and cytocidal activities of mitomycin C (MC), methylnitrosourea (MNU), and ethylnitrosourea (ENU) were measured in the human lymphoblast cell line TK6. For treatments resulting in fewer than 2 lethal hits, MNU, ENU, and MC gave rise to apparently linear dose-response curves for gene mutations (hgprt and tk genes) as well as for chromosomal aberrations. The numbers of induced mutants at the tk and hgprt loci were similar between the two loci for each compound. However, the ratio of mutagenic activity relative to the clastogenic activity (aberrations/cell) was lowest for mitomycin C, intermediate for methylnitrosourea, and highest for ethylnitrosourea. These results confirm in human cells the general observation that the processes of mutagenesis and clastogenesis are nonidentical: compounds vary independently in their mutagenic and clastogenic potentials.

Cell Line↗
PubMed1986

Studies of mutagenicity and clastogenicity of 5-azacytidine in human lymphoblasts and Salmonella typhimurium.

5-Azacytidine (5-AzaC) induced mutation in the TK+/- human lymphoblastoid line, TK6, at both the thymidine kinase (tk) locus as measured by resistance to trifluorothymidine (F3TdR), and the hypoxanthine-guanine phosphoribosyltransferase (hgprt) locus, as measured by resistance to 6-thioguanine (6TG). F3TdRR and 6TGR mutant fractions induced by 5-AzaC were observed after a normal phenotypic expression time and remained stable. Interestingly, 5-AzaC was 5-10 times more mutagenic at the tk locus than the hgprt locus. However, F3TdRR colonies from 5-AzaC-treated cultures behaved like TK-deficient mutants induced by other chemical mutagens. The TK or HGPRT phenotype had no effect on the toxicity of 5-AzaC, thus eliminating differential toxicity as a potential cause for the observed higher mutability at the tk locus. 5-AzaC did not induce F3TdRR cells in the parental TK+/+ lymphoblastoid line, indicating that 5-AzaC-induced F3TdRR variants were not due to a dominant alteration in gene expression. 5-AzaC did not induce chromosomal aberrations in TK6 cells, eliminating clastogenic events as a potential cause for the higher mutability at the tk locus. 5-AzaC was also found to be mutagenic in a forward mutation assay to 8-azaguanine resistance in Salmonella typhimurium.

Azacitidine↗
PubMed1986

Inhibition of human liver cytochrome P-450 by omeprazole.

The effects of omeprazole on cytochrome P-450 mediated 7-ethoxycoumarin deethylation were studied in human liver microsomes. Omeprazole inhibited both the high and low affinity components of deethylation, with an estimated Ki of 0.03 mM for the high affinity component. The results are further evidence that the previously reported prolongation of the half-life of diazepam by omeprazole in vivo is due to inhibition of cytochrome P-450 monooxygenases.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

[Antimicrobial chemoprevention in colorectal interventions: a single parenteral dose at the start of surgery is adequate].

The effectivity in reducing septic complications after colorectal operations of oral 1 g Neomycin plus 0.25 g Metronidazol t.i.d. on the last preoperative day vs. intravenous single dose 5 g Mezlocillin plus 0.5 g Metronidazole was tested by sequential medical plan. There was no statistically significant difference between both chemoprophylaxis groups (p = 0.10). It is concluded that the intravenous chemoprophylaxis should be preferred because of the lowest dosage and therefore the fewest side-effects.

Administration, Oral↗
PubMed1985

Pharmacokinetics of oral and intravenous rifampicin during chronic administration.

We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.

Administration, Oral↗
PubMed1985

Factors predicting the therapeutic outcome of duodenal ulcer treatment with H2-receptor antagonists.

In a prospective trial 37 duodenal ulcer patients were treated daily with 1 g cimetidine. Personal and clinical data were obtained for all patients, acid secretion studies performed before and during treatment, and pharmacokinetic parameters of cimetidine determined. The healing rate after 4 weeks was 64.9% (24 patients). Non-Responders included a higher proportion of smokers, patients with a history of ulcer and previous treatment with H2-receptor antagonists than Responders. Basal acid output (BAO) and peak acid output (PAO) values were not different between the two groups, nor was the reduction of BAO and PAO under cimetidine. However, more Responders had complete suppression of BAO than Non-Responders. A correlation existed in both groups between cimetidine plasma concentration and PAO suppression but not with BAO suppression. Regular drug intake (compliance) was found in about 90% in both groups. Cimetidine bioavailability parameters were identical in both groups, but Non-Responders had a higher peak concentration and a shorter time of peak concentration. Discriminant analysis enabled a prediction of treatment response in 89.2% of the patients by using five factors: time of peak concentration of cimetidine, previous H2-receptor-antagonist treatment, peak concentration, smoking, and alcohol use. Prediction of treatment response is increased by use of drug related variables.

Adult↗
PubMed1985

Alternatives to CYVADIC-combination therapy of soft tissue sarcomas.

The CYVADIC combination has been the preferred treatment for soft tissue sarcomas for the last 10 years. Other combinations of therapy are necessary because the remission rate achieved with CYVADIC is only thirty per cent. Alternative therapies for these tumours are combinations including cis-platinum, ifosfamide, epipodophyllin and high-dose methotrexate. Our therapeutic results with combinations of cis-platinum and ifosfamide are comparable to CYVADIC. However, side-effects such as nausea, vomiting and fatigue due to cis-platinum in the palliative treatment of these tumours are intolerable for many patients. A combination of adriamycin and ifosfamide, which exhibits a higher remission rate of 44% and lower toxicity than CYVADIC, is giving encouraging results.

Adult↗