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Biomedical subjects

Z Zylicz

Publications and source records attributed to Z Zylicz.

At least 37 records · Page 2Linked to original sources
PubMed1997

[Laxative policy for terminal patients ineffective].

OBJECTIVE: To determine the prevalence of constipation and the use of laxatives in terminal patients. DESIGN: Retrospective. SETTING: Hospice Rozenheuvel, Rozendaal, the Netherlands. METHOD: Of patients who were admitted for terminal care between 1 January 1995 and 15 July 1996 the anamnestic data were recorded about presence of constipation and use of medicines, notably opioids and laxatives. RESULTS: The study population (n = 121) consisted of 65 male and 56 female patients. 95 patients (79%) suffered from cancer. The median survival time was 18 days (spread from 1-180 days). 58 (48%) of the patients were constipated at the time of admission and 62 (51%) used opioids. The opioid users were more often constipated (68% versus 27%; p < 0.001). 35 out of 62 (56%) opioid users were given laxatives. The laxative users, however, were more often constipated (65% versus 36%; p < 0.01). Neither in users nor in non-users of opioids did laxatives have any effect on presence of constipation. Of the laxative users 37 (73%) were given lactulose in a fixed dosage. CONCLUSION: Present laxative policy in terminal patients is ineffective. Monotherapy with fixed lactulose doses is not effective as a laxative in either users or non-users of opioids.

Adult↗
PubMed1993

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan-phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9-hydroxyrisperidone, exhibited CYP2D6-related polymorphism. The plasma area under the concentration-time curve from time zero to infinity ratio of 9-hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half-life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) varied little among subjects (mean terminal half-life, 20 +/- 2 1/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.

Adult↗
PubMed1991

Oral opioids in the treatment of cancer pain.

Persistent severe cancer pain should be treated with opioid drugs, principally morphine. It can be administered orally, rectally and parenterally. Morphine is metabolised in the liver mainly to glucuronides, of which morphine-6-glucuronide is a powerful analgesic. Oral morphine should be administered regularly and in individualized doses. The use of morphine is frequently accompanied by adverse effects such as constipation, nausea, vomiting and sedation. Management of these is critical for successful pain treatment. Although alternatives are available none has any clear advantage over morphine in cancer pain, and should be reserved for special situations. Oral morphine is successful in more than 90% of cancer pain patients. Slow release morphine sulphate tablets (MS Contin) are often the best choice. For the few patients who need parenteral medication, continuous subcutaneous morphine sulphate infusion is generally the most suitable. Some pains are morphine resistant, especially those due to nerve injury. In these cases pain is best treated with tricyclic antidepressants and/or anticonvulsants.

Drug Tolerance↗
PubMed1990

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs.

N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 beta was 0.2 hours (12 minutes) and t1/2 tau was 0.75 +/- 0.1 hours (45 +/- 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 tau was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.

Animals↗
PubMed1990

In vitro and in vivo anticancer activity of mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow.

The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, mitozolamide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 micrograms/ml mitozolomide, given by continuous exposure, was active (colony number of test less than 30% of the control group) in 12/42 (29%) human tumor xenografts as well as in the four murine tumors, P388, L1210, B16 melanoma and colon carcinoma 38, whereas the two human bone marrows showed no significant suppression of the ability to form colonies in culture. The comparison of in vitro with in vivo activity suggests that the in vitro dose of 3 micrograms/ml corresponds best to the activity observed in animal experiments. The highest activity was observed in small-cell cancer of the lung (4/5), followed by melanomas (2/7) and non-small-cell cancer of the lung (2/9). Furthermore, activity was found in a cancer of the large bowel, stomach, breast and in one sarcoma. In the treatment of nine human tumor xenografts growing subcutaneously in nude mice, mitozolomide effected a complete or partial remission in 6 out of 9 tumors. In comparison to standard drugs mitozolomide is one of the most effective compounds in these tumors. These data indicate that mitozolomide possesses potent broad-spectrum activity in human tumor xenografts. Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human tumor xenografts and in 4/5 of the murine tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose. However, the high in vitro activity in murine tumors is incompatible with the in vivo activity. In mice the only responsive tumor was leukemia P388, whereas the L1210, B16 melanoma and colon carcinoma 38 were resistant. At the dose level of 0.03 microgram/ml only 3/30 (10%) of the human tumor xenografts were sensitive. In an earlier clinical phase I study the dose-limiting adverse effect was eye toxicity and not bone-marrow suppression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Metabolic response to enteral food in different phases of cancer cachexia in rats.

The resting energy expenditure (REE) and postprandial energy expenditure (PPEE) were measured using closed-circuit indirect calorimetry in Walker 256 carcinosarcoma-bearing rats. The results were compared to the appropriate controls. The PPEE measurements were performed after oral test feeding. At the beginning of the tumor growth, the REE and PPEE were similar in all groups. In the second week, the tumor-bearing rats showed increased REE and decreased PPEE. The tumor-bearing rats lost weight and became anorectic. After day 14, the REE rapidly dropped to very low values and the body weight continued to decrease. This study makes it possible to differentiate three phases of cancer cachexia: silent or preclinical, hypermetabolic and hypometabolic.

Animals↗
PubMed1989

Potentiation of cisplatin antitumor activity on L1210 leukemia s.c. by sparsomycin and three of its analogues.

Sparsomycin (Sm) is a known antibiotic derived from Streptomyces. Its potential antitumor activity stimulated the search for a synthetic production method and the development of new derivatives. In a recent screening investigation, three Sm analogues appeared to be more active and considerably less toxic than the parent drug. Sparsomycins became especially interesting when it was shown that Sm potentiates the antitumor activity of cisplatin. In the present study Sm and its three promising analogues: deshydroxy-Sm (dSm), ethyl-deshydroxy-Sm (EdSm) and n-pentyl-Sm (PSm) were studied for their cisplatin potentiating effect. The experiments were performed on CD2F1 mice inoculated with 10(6) L1210 cells s.c. Sparsomycins were administered i.p. 3 h before cisplatin on days 1, 5 and 9. Three of the drugs, Sm, dSm and PSm, showed no potentiating effect in this tumor model. At a dose of 10 mg/kg, EdSm potentiated cisplatin antitumor activity 2.8 times (P less than 0.01) without an increase in weight loss. These results warrant further investigation.

Animals↗
PubMed1989

Lipophilic analogues of sparsomycin as strong inhibitors of protein synthesis and tumor growth: a structure-activity relationship study.

Fourteen derivatives of sparsomycin (1) were synthesized. Six of them were prepared following a novel synthetic route starting from the L-amino acid alanine. Some physicochemical properties, viz. lipophilicity and water solubility, of selected derivatives were measured. The biological activity was tested in vitro in cell-free protein synthesis inhibition assays, in bacterial and tumor cell growth inhibition assays, and in the L1210 leukemia in vivo model in mice. Also for selected drugs the acute toxicity in mice was determined. Ribosomes from both an eukaryotic and a prokaryotic organism were used in the protein synthesis inhibition systems. A linear correlation between the lipophilicity parameters measured was observed. Water solubility and drug toxicity in mice were found to be linearly correlated with lipophilicity. All the derivatives studied are more lipophilic than 1. The deshydroxysparsomycin analogues (30-33) showed an interesting phenomenon: increase in hydrophobicity was accompanied by a considerable increase in water solubility. We found that an increase in hydrophobicity of the drug as a result of replacing the SMe group of 1 with larger alkylthio groups causes an increase in the biological activity of the drug. However, not only the hydrophobicity but also shape and size of the substituent are important; in the homologous series 1-9-10-11-12, 21-22-23-24, and 30-31-32-33, highest protein synthesis inhibitory and in vitro cytostatic activity is found with compounds 11, 23, and 32, respectively, and in comparison with the highly active n-butyl compound 10, the isomeric tert-butyl compound 13 is rather inactive. Polar substituents replacing the SMe group, i.e. Cl in 17 and 35, also render the molecule inactive. Substituting the bivalent sulfur atom for a methylene group decreases the drug's activity. This effect can be compensated for by increasing the length of the alkylsulfinyl side chain. The agreement between the results derived from cell-free and "in vivo" tests is good. The assays using ribosomes of bacterial and eukaryotic organisms give similar results although the latter seem to be more sensitive to changes in hydrophobicity of the drug. Our results confirm the presence of a hydrophobic region at the peptidyl transferase center of the ribosome; the interaction of sparsomycin with this region is more pronounced in the eukaryotic particles. The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗