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Biomedical subjects

W Kreis

Publications and source records attributed to W Kreis.

At least 55 records · Page 3Linked to original sources
PubMed1992

Phenotypic analysis of 1-B-D-arabinofuranosylcytosine deamination in patients treated with high doses and correlation with response.

Two phenotypes for 1-B-D-arabinofuranosylcytosine (ara-C) deamination corresponding to a ratio of distribution for "slow" (ratio, less than or equal to 14) vs "fast" (ratio, greater than 14) deaminators of 70%:30%, have been determined on the basis of studies on plasma ratios of 1-B-D-arabinofuranosyluracil/ara-C (ara-U/ara-C) in 56 subjects treated with high-dose ara-C (3 g/m2 infused i.v. over 3 h). A positive correlation of age with the concentration of ara-U was observed. In a subgroup of 36 patients with leukemia, the ara-U/ara-C pattern was similar to that observed for all 56 subjects. In these leukemic patients, who were treated with combinations of ara-C plus other conventional agents, a tendency toward a positive response (complete response + partial response) was found for those showing low ara-U/ara-C ratios (slow deaminators). The phenotypic effect of deamination in acute leukemia needs to be evaluated prospectively.

Adolescent↗
PubMed1992

12 beta-Hydroxylation of digitoxin by suspension-cultured Digitalis lanata cells: production of digoxin in 20-litre and 300-litre air-lift bioreactors.

A biotransformation process for the production of digoxin was developed using Digitalis lanata cell suspension cultures. Digitoxin was used as the substrate for biotransformation. Digoxin production was carried out in a variety of vessels, including 1-l exsiccators, 20-l glass reactors and a 300-l air-lift bioreactor. A culture volume of 200 l was established after 28 d and the cells were then cultured semi-continuously in a 300-l bioreactor employing the draw-fill cultivation method. Maximal digoxin production was achieved in an 8% glucose medium with a production optimum after 40-60 h of incubation in the presence of 0.65-0.8 mmol digitoxin per l. Levels of 0.52, 0.53 and 0.60 mmol digoxin per l suspension were achieved in 1-l, 20-l and 300-l vessels, respectively. About 80% of the digoxin produced was found in the bathing medium.

Air↗
PubMed1992

Production of Forskolin by Axenic Coleus forskohlii Roots Cultivated in Shake Flasks and 20-l Glass Jar Bioreactors*.

Root cultures of COLEUS FORSKOHLII Briq. were initiated from primary callus or IBA-treated suspension cultures and maintained on Gamborg's B5 medium containing 1 mg/l IBA. Transformed root cultures were established by infecting surface-sterilized leaves with AGROBACTERIUM RHIZOGENES strain 15834. Transformation was confirmed by mannopine detection. These cultures displayed the typical characteristics of hairy root cultures, with the sole exceptions of slow growth in hormone-free medium and accelerated growth on medium containing phytohormones. All root cultures examined formed forskolin and its derivatives in amounts ranging from 500 to 1300 mg/kg dry weight, corresponding to about 4 to 5 mg/l. During cultivation roots could be cut into small pieces without affecting growth and forskolin production. Scale-ups of the cultivation procedure were performed in 20-l glass jars with a working volume of 10 to 13l. Forskolin production in bioreactors was better than in shake flasks. Levels of almost 14 mg/l could be reached after 21 d of cultivation. As in the shake flask experiments cutting the roots did not affect growth or productivity in a negative way.

Journal Article↗
PubMed1991

Therapy of refractory/relapsed acute leukemia with cytosine arabinoside plus tetrahydrouridine (an inhibitor of cytidine deaminase)--a pilot study.

Thirty two patients with refractory or recurrent acute leukemia or blast crisis of chronic myelocytic leukemia were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight doses. Two of 13 (15.3%) evaluable patients in group I achieved a complete response, both of whom had acute myelocytic leukemia. In group II, seven of 14 evaluable patients (50%) obtained objective responses--six with complete responses (42.8%) and one with partial response (7%). Myelosuppression was seen in all patients with a median duration of 32.5 days (group I) and 36.3 days (group II), respectively. Non-hematologic toxicity consisted of nausea, vomiting, diarrhea, conjunctivitis, skin rash, hepatocellular toxicity, hemorrhage, and renal toxicity. Pharmacokinetic studies revealed, for group I, mean peak plasma Ara-C levels at 3 h (Cp3h) of 1254 ng/ml, area under the curve (AUC) 4651 ng x h/ml, total body clearance (TBC) 32.65 l/h/m2, renal clearance (RC) 7.04 l/h/m2 with a mean of 12.36% of the injected amount of Ara-C excreted unchanged in urine over the first 24 h. The corresponding mean values for group II are Cp3h 3305 ng/ml, AUC 15080 ng x h/ml, TBC 20.48 l/h/m2, RC 7.02 l/h/m2 and 26.23%. Ara-C 200 mg/m2 combined with THU gave serum Ara-C levels and response rates comparable to those achieved with high dose Ara-C (HiDAC) (greater than or equal to 1 g/m2). Central nervous system toxicity associated with HiDAC was not seen. Pharmacokinetics for uracil arabinoside (Ara-U) in patients treated with Ara-C 200 mg/m2 plus THU, were comparable to values seen with Ara-C for Cp3h, AUC and 24 h urine, amounting to 3160 ng/ml, 21717 ng x h/ml and 23.62% whereas TBC was significantly lower (p less than 0.001) for Ara-U than for Ara-C (3.02 versus 20.48 l/h/m2).

Adult↗
PubMed1990

Phase I trial of intravenous vinzolidine (LY 104208) given on a biweekly dosing schedule.

Vinzolidine (VZL) is a semisynthetic vinca alkaloid with broad antitumor activity in animal models of malignancy but had unpredictable toxic effects when given orally to humans. To minimize the toxic effects due to potential erratic gastrointestinal absorption, this drug was restudied in man as an intravenous preparation given as a rapid injection every two weeks. The maximum tolerated dose (MTD) on this schedule was 9.0 mg/m2 with unpredictable leukopenia (usually occurring 5-14 days post treatment but appearing erratically), constipation, paralytic ileus, and inappropriate ADH syndrome as major toxicities. Nonhematologic toxicities were dose-limiting. Repetitive dosing at two week intervals was associated with leukopenia at D 14-15 in some but not all patients treated above 5.0 mg/m2 precluding further treatment on schedule. In contrast, the oral MTD of this agent in our prior studies was 45 mg/m2 with no evidence of delayed leukopenia. Intrapatient variability of toxicity was small; interpatient variability of toxicity was substantial and did not correlate with prior therapy. Because of the presence of delayed hematologic toxicity on repetitive dosing schedules, intravenous VZL should be given on a dosing schedule longer than 14 days. No antitumor activity was seen in this study.

Adult↗
PubMed1990

Clinical pharmacokinetics of intravenously injected tritiated vinzolidine.

Vinzolidine (VZL), a novel, semi-synthetic vinca alkaloid showing evidence of oncolytic activity in phase I/II clinical trials, was studied in six patients for its pharmacokinetic and metabolic behavior. Following i.v. administration of [3H]-VZL at doses of 5, 6.7, and 9 mg/m2, blood and urine samples were collected and analyzed by sample oxidation and HPLC. Following a single i.v. dose, decay of total tritium in plasma was tetraphasic, with a rapid initial t1/2 alpha of 0.044 +/- 0.013 h, followed by a t1/2 beta of 0.54 +/- 0.22 h and a t1/2 gamma of 9.48 +/- 4.89 h; the terminal t1/2 gamma was 219 +/- 57 h. The mean plasma clearance of total tritium was 0.054 +/- 0.044 l.kg/h, and the mean volume of distribution was 14.3 +/- 5.4 l/kg; mean urinary excretion was 13.6% +/- 4.3% of the delivered radioactivity. Qualitative analysis of plasma and urine revealed the predominance of unchanged VZL plus two unidentified metabolites with different elution times. In comparison with oral VZL, as previously reported, i.v. injected VZL showed comparable values with respect to the volume of the central compartment (VC), plasma clearance (Clp), and terminal t1/2 for total tritium. Qualitatively, the metabolites observed in plasma and urine were comparable in number and quantity with values obtained in analyses after oral administration.

Antineoplastic Agents, Phytogenic↗
PubMed1990

Inhibition of HIV replication by Hyssop officinalis extracts.

Crude extracts of dried leaves of Hyssop officinalis showed strong anti-HIV activity as measured by inhibition of syncytia formation, HIV reverse transcriptase (RT), and p17 and p24 antigen expression, but were non-toxic to the uninfected Molt-3 cells. Ether extracts from direct extraction (Procedure I), after removal of tannins (Procedure II), or from the residue after dialysis of the crude extract (Procedure III), showed good antiviral activity. Methanol extracts, subsequent to ether, chloroform and chloroform ethanol extractions, derived from procedure I or II, but not III, also showed very strong anti-HIV activity. In addition, the residual material after methanol extractions still showed strong activity. Caffeic acid was identified in the ether extract of procedure I by HPLC and UV spectroscopy. Commercial caffeic acid showed good antiviral activity in the RT assay and high to moderate activity in the syncytia assay and the p17 and p24 antigen expression. Tannic acid and gallic acid, common to other teas, could not be identified in our extracts. When commercial products of these two acids were tested in our assay systems, they showed high to moderate activity against HIV-1. Hyssop officinalis extracts contain caffeic acid, unidentified tannins, and possibly a third class of unidentified higher molecular weight compounds that exhibit strong anti-HIV activity, and may be useful in the treatment of patients with AIDS.

Antiviral Agents↗
PubMed1990

Two-stage cultivation of Digitalis lanata cells: semicontinuous production of deacetyllanatoside C in 20-litre airlift bioreactors.

A two-stage cultivation method was employed to develop a semicontinuous biotransformation process for the production of deacetyllanatoside C, a cardenolide of the important digoxin series. Digitoxin was used as the substrate for biotransformation. The process was optimized in 1-l shake flasks and then established on the 20-l scale using two airlift bioreactors, one for cell growth (working volume 12 litres) and another for deacetyllanatoside C production (working volume 18 litres). Growth and production phases were synchronized and the process finally ran semicontinuously in 7-d cycles. Six consecutive production runs were performed yielding a total of 43.8 g deacetyllanatoside C.

Biotransformation↗
PubMed1990

Transdermal versus subcutaneous leuprolide: a comparison of acute pharmacodynamic effect.

Transdermal administration of peptides has been limited by the barrier properties of the skin. We compared the acute luteinizing hormone (LH) response to subcutaneous and transdermal administration of an LH-releasing hormone agonist (leuprolide). Eighteen volunteers received 5 mg leuprolide added to electrically powered patches delivering a current of 0.22 microA (transdermally). One week later, they received a 5 mg subcutaneous dose. LH response was measured. The area under the curve for LH response, maximum LH response, and time to maximum LH response were similar. Time to first response was shorter (147 +/- 108 minutes [transdermally] and 73 +/- 74 minutes [subcutaneously]; p less than 0.05), and the area under the curve for the first 150 minutes was greater (3655 +/- 2246 mIU.min/ml [transdermally] and 8666 +/- 4067 mIU.min/ml [subcutaneously]; p less than 0.05) for subcutaneous delivery. No major adverse effects were seen. This electrically powered transdermal technique merits further study.

Administration, Cutaneous↗
PubMed1990

Predictive initial parameters for response of stage D prostate cancer to treatment with the luteinizing hormone-releasing hormone agonist goserelin.

One hundred eighteen patients with stage D (D1 or D2) prostate cancer with a mean age of 69 years were treated with monthly goserelin (Zoladex; ICI 118, 630; ICI Americas Inc, Wilmington, DE, property of Imperial Chemical Industries PLC) injections and the data were analyzed for predictive parameters for best response and time to treatment failure (National Prostatic Cancer Project [NPCP] and Eastern Cooperative Oncology Group [ECOG] criteria). For best response in a univariate analysis, the performance status (PS 0-1 v 2-3) (P = .01), hematocrit (P = .04), and pain (P = .04) were significant. For time to treatment failure by univariate analysis, ECOG performance status (0-1 v 2-3) was most predictive (P less than .0001), followed by pain at entry (P = .0002), initial testosterone (T) level (greater than 250 ng/dL) (P = .0005), age less than 69 years (P = .02), alkaline phosphatase (less than 115 IU/L) (P = .03), hemoglobin (less than 14 g/dL) (P = .03), whereas normal acid phosphatase (less than 3 IU/mL) (P = .29) was not predictive. In multivariate analysis for time to treatment failure, only the ECOG performance status was of significance (P = .01). Estimated median time to treatment failure for PS of 0-1 was 88 weeks and for PS of 2-3 was 31 weeks.

Age Factors↗
PubMed1990

[Ventricular arrhythmias and QT/QS2 index in patients with ischemic heart disease].

This multicenter study comprised a group of 900 patients (207 females and 693 males, aged 23-68 years, mean 53) with ischaemic heart disease. Go medications other than nitrates, nifedipine and diuretics were administered at the time of study. In all patients a simultaneous standard 12-lead ecg and a phonocardiogram was registered. QT and QS2 intervals were then measured, and the QT/QS2 index calculated. QT/QS2 ratio 1.0 was considered as a normal one. A 24-h Holter ecg monitoring was performed in each patients, and ectopic ventricular activity was graded according to the Lown's classification. For patients with each class of arrhythmia the mean value of QT/QS2 was calculated. All means were similar, with values 1.0. Proportion of patients with abnormal values of QT/QS2 index was similar in patients showing different Lown classes of arrhythmia. Since a 24-hour monitoring does not give a full information about the arrhythmic events, patients with the history of VT/VF were analyzed separately. In this group an increase of QT/QS2 index was observed significantly more frequently than in other patients (37% vs 19%, p = 0.016). It is concluded that no close relationship exists between QT/QS2 index and the type of ventricular arrhythmia found on the Holter monitoring. However, pathologic QT/QS2 values seem to characterize the patients with increase risk of VT/VF.

Adult↗
PubMed1988

Pharmacokinetic and phase I evaluation of esorubicin (4'-deoxydoxorubicin) by continuous infusion over forty-eight hours in patients with leukemia.

Sixteen patients with previously treated acute nonlymphocytic leukemia or chronic myelogenous leukemia in blast crisis were given one to three courses of esorubicin by continuous infusion over 48 h. Dosage levels extended from 35 to 85 mg/m2. Four patients showed partial responses of short duration. Nonhematological toxicity observed at dosages of 55 to 85 mg/m2 were mucositis, diarrhea, skin rash, transaminitis, nausea, vomiting, and cardiac dysfunction. One patient receiving 85 mg/m2 developed acute florid congestive heart failure within hours of administration of the drug. Pharmacokinetic analysis revealed large interpatient variation in plasma drug levels. At the end of infusion, plasma decay of esorubicin was rapid initially but slow thereafter, with a terminal half-life of 20 to 54 h. The metabolite 4'-deoxy-13-hydroxydoxorubicin reached significant plasma levels. Total body clearance, renal clearance, volume of distribution at steady state, and mean residence time show little variation during dose escalation for both esorubicin and 4'-deoxy-13-hydroxydoxorubicin. Urinary excretion of esorubicin and 4'-deoxy-13-hydroxydoxorubicin accounted for 10.5 and 1.5%, respectively, of the administered dose.

Doxorubicin↗
PubMed1988

Effect of tetrahydrouridine on the clinical pharmacology of 1-beta-D-arabinofuranosylcytosine when both drugs are coinfused over three hours.

When 1-beta-D-arabinofuranosylcytosine (ara-C), 25 mg/m2, is infused over 3 h together with tetrahydrouridine (THU) at 10 to 350 mg/m2 to heavily pretreated patients with solid tumors, Michaelis-Menten type kinetic values are observed with leveling off of delta area under the curve, delta ara-C levels at 3 h, and delta total body clearance after 150 mg/m2 of THU. When the ara-C dose was increased to 50, 75, and 100 mg/m2 coinfusion of 250 or 350 mg/m2 of THU significantly increased plasma ara-C at peak and area under the curve. In contrast, total body clearance and volume of distribution decreased significantly. At 100 mg/m2 of ara-C coinfused with high doses of THU, i.e., at 350 mg/m2, the pharmacokinetics of plasma ara-C was changed from a biphasic decay of plasma ara-C at peaks (control) to a curve similar or identical to a monophasic curve, indicating that THU not only inhibits deamination but also changes the distribution of ara-C. This combination provides plasma ara-C levels (greater than or equal to 10 microM) comparable to high dose ara-C at 1 g/m2. Such plasma ara-C levels are considered to be sufficient for saturation of the kinases catalyzing the production of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. This reduced ara-C dose necessary to achieve saturation of kinases also reduces plasma 1-beta-D-arabinofuranosyluracil levels substantially. Toxicity of this combination was predominantly confined to bone marrow and gastrointestinal toxicity.

Adult↗
PubMed1988

Successful transdermal administration of therapeutic doses of a polypeptide to normal human volunteers.

The human stratum corneum constitutes a relatively impermeable barrier to the transdermal absorption of most substances, including polypeptides and proteins. This double-blind, randomized, crossover study in 13 normal men evaluated whether a low level of electrical current could induce changes in cutaneous permeability sufficient to produce absorption of a polypeptide. We compared cutaneous absorption of 5 mg of leuprolide (a 9 amino acid luteinizing hormone releasing hormone analogue) in transdermal patches containing 0.2 mA electrical current (active) and in patches containing no electrical current (passive). Serum luteinizing hormone (LH) concentration was measured 12 times during an 8-hour period as a measure of drug effect. Similar baseline LH levels were seen in each group: active = 11.3 +/- 3.1 mIU/ml and passive = 13.7 +/- 4.7 mIU/ml (p not significant). Significant elevations of LH were seen in active compared with passive patches (p = 0.0084). As predicted, passive patches produced no elevation of LH concentration (LH = 11.8 +/- 7.1 mIU/ml at 4 hours). However, active patches produced elevations comparable to those achieved with subcutaneous administration of the drug (LH = 56.4 +/- 49.6 mIU/ml at 4 hours and p = 0.003 compared with passive). The patches were well tolerated without significant cutaneous toxicity. It is concluded that the use of low levels of electrical current can induce changes in the permeability of the stratum corneum. These changes are sufficient to promote the transdermal absorption of therapeutically relevant amounts of a polypeptide. This has major importance for our understanding of skin permeability and for the development of new techniques for drug administration.

Double-Blind Method↗
PubMed1988

Oestrogen pre-treatment abolishes luteinising hormone-releasing hormone testosterone stimulation.

In patients with histologically confirmed prostate cancer, oestrogen priming with diethylstilboestrol (DES) (3 mg/day) for 4 weeks prior to the first injection of the LHRH agonist Zoladex (3.6 mg depot form) prevented any rise in the serum testosterone concentration. In contrast, in the groups pre-treated with DES, the first, but not subsequent, injections with Zoladex were associated with a marked surge in luteinising hormone. Treatment with DES beyond the time of the first administration of Zoladex did not provide further endocrinological advantage. Oestrogen priming for 1 month prior to treatment with Zoladex may prevent an exacerbation of signs and symptoms of prostate cancer.

Buserelin↗