Search PubMed⌕ Search

Biomedical subjects

T Cerny

Publications and source records attributed to T Cerny.

At least 109 records · Page 6Linked to original sources
PubMed1991

Subcutaneous continuous infusion of ifosfamide and cyclophosphamide in ambulatory cancer patients: bioavailability and feasibility.

The oxazaphosphorines ifosfamide (IFO) and cyclophosphamide (CTX) are standard alkylating agents. Both drugs show an increased therapeutic index when given as a fractionated dosage over several days. Maximal fractionation is achieved by continuous infusion. We have studied the feasibility and bioavailability of a subcutaneously (s.c.) administered isotonic and neutral (pH 7) solution of IFO (10 h up to 5 days infusion) and CTX (12-24 h infusion) in patients with advanced cancer. A portable disposable gas-driven infusor syringe was used for ambulatory patients. Our results show 90%-100% bioavailability of s.c. IFO and CTX. The isotonic solution of IFO and CTX (pH 7) showed no significant local toxicity (one local infection in 51 cycles) during or after s.c. administration of 33 cycles with IFO and 18 with CTX. Haematotoxicity of both drugs was equal after s.c. and i.v. application. For IFO-treated patients no uro- or neurotoxicity was observed. We conclude that this novel continuous s.c. oxazaphosphorine infusion over a prolonged period is a rational, well-tolerated and economic way of delivering this drug on an outpatient basis.

Adult↗
PubMed1991

Continuous 5-day infusion of ifosfamide with mesna in inoperable pancreatic cancer patients: a phase II study.

Phase II studies on ifosfamide and mesna in pancreatic cancer have mostly been inconclusive. In all of these studies ifosfamide was administered as an i.v. bolus or by short infusions. Since dose fractionation of ifosfamide over several days increases its therapeutic index, we chose to maximize the dose fractioning by selecting a continuous-infusion schedule (1.75 g/m2 on days 1-5 every 21-28 days, with mesna 60%-100% of the ifosfamide dose up to 12 h after ifosfamide). Since 1987 29 patients (performance status less than or equal to 2) with advanced inoperable adenocarcinoma of the pancreas were studied (8 women and 21 men; median age 58 years: 36-73 years). A total of 25 patients are evaluable for response (1 ineligible; 3 inevaluable: 2 early deaths due to disseminated intravascular coagulation, 1 refusal). One female patient with a complete response on computed tomography scan (after five cycles) but residual liver metastases on surgical exploration survived for 473 days. Three male patients with partial response survived for 205, 335 and 355 days. Six more patients with minor response (3) or no change (3) but significant decrease of tumour marker CA 19-9 had a median survival of 213 days (106-243). Responders seemed to benefit in terms of pain relief and general well-being. The median overall survival of all patients was 148 days (21-473). Haematotoxicity was rarely dose-limiting [median nadirs: white blood cells = 2.1 x 10(9)/l (0.45-6.4), Hb = 10.7 g/dl (7.5-13), platelets = 137 x 10(9)/l (21-411)]. Nausea and vomiting were mild with prophylactic oral metoclopramide. No central nervous system toxicity or urotoxicity was observed. Alopecia was seen in all patients who had received at least two cycles. Continuous infusion of ifosfamide was generally well tolerated and useful for palliation in 10 of 25 patients. A higher dose intensity is recommended.

Adenocarcinoma↗
PubMed1991

Metabolism and pharmacokinetics of oral and intravenous ifosfamide.

The initial metabolism of ifosfamide (IF) consists of two different pathways: enzymatic hydroxylation at carbon-4 forms the cytostatically active metabolite 4-OH-IF ("activated ifosfamide") whereas side-chain oxidation results in the liberation of chloroacetaldehyde, a compound with possible neurotoxic properties. The pharmacokinetics of ifosfamide and its activated form were investigated in 12 cancer patients, who received both oral and i.v. treatment in a randomized sequence on days 1 and 3 at a dose of 1 g/m2 (n = 7) or 1.5 g/m2 (n = 5). In 3 patients the pharmacokinetics of chloroacetaldehyde were also investigated. After oral application, ifosfamide absorption proceeded rapidly, the oral bioavailability was 0.92. Independent of the route of ifosfamide application on day 1, the terminal half-life on day 3 (when the drug was given by the alternative route) was decreased in 6 out of the 12 patients, thus indicating self-induction of hepatic metabolism. 4-OH-IF was already present 20 min after ifosfamide administration. In the individual patient the concentrations of 4-OH-IF were always higher after oral than after i.v. IF application: the mean p.o.:i.v. ratios for cmax and the area under the concentration/time curve were 2.3 and 1.7 respectively (P less than 0.05). In a first series of 3 patients the chloroacetaldehyde concentrations measured after oral ifosfamide application were about twice as high as those when the drug was given intravenously. These results indicate that (in comparison to the i.v. route) orally administered ifosfamide may be more cancerotoxic but also leads to higher levels of chloroacetaldehyde. This would explain the neurotoxic side-effects previously seen after oral administration of comparatively low ifosfamide doses.

Acetaldehyde↗
PubMed1990

[Preventive and therapeutic measures in cytostatic-associated toxicity].

Strategies (both prophylactic and therapeutic) to reduce side effects of chemotherapy are reviewed. In particular, issues concerning proper patient information are discussed which should help to increase patient compliance. Chemotherapy, especially regimens with a curative intent, must normally be administered under the guidance of an oncologist. However, close cooperation with the general practitioner is essential in order to ensure high quality counselling and treatment of the outpatient.

Alopecia↗
PubMed1990

[Sense and nonsense of tumor markers in practice].

Tumor markers can be used for screening, diagnosis, planning and monitoring of therapy, for early detection of relapse and for psychological reasons. Unfortunately none of the currently available tumor markers can be used for all these purposes. An ever increasing number of tumor markers can be determined; however, the advantage for the individual patient's management is less obvious. We therefore critically review the routine use of some tumor markers such as CEA, AFP, beta-HCG, LDH, CA-125, CA 19-9, prostate acid phosphatase, prostate specific antigen and CA 15-3. The use of tumor markers requires a sound knowledge of the biology of the marker, the neoplastic disease and the available treatment. When tumor markers do not add new information and have no diagnostic or therapeutic consequences, their use becomes an expensive medical nonsense!

Antigens, Neoplasm↗
PubMed1990

Bioavailability of subcutaneous ifosfamide and feasibility of continuous outpatient application in cancer patients.

The oxazaphosphorine prodrug Ifosfamide (IFO) in conjunction with the uroprotective agent Mesna is becoming a standard alkylating agent. It has an increased therapeutic index when given as a fractionated dosage over 3-5 days. Maximal fractionation is achieved by continuous infusion over several days and has been shown to be less emetic and neurotoxic than regimens with bolus infusions. We have studied in patients with advanced cancer the feasibility and bioavailability of a subcutaneously administered isotonic and neutral (pH 7) IFO solution given continuously over 10 h for up to 5 days. A portable disposable gas-driven infusor syringe was used. Our results show 90-100% bioavailability of sc administered IFO. The isotonic solution of IFO (pH 7) showed no significant local toxicity during or after sc administration. Haematotoxicity was equal for sc and iv application. No uro- or neurotoxicity has been observed in 24 sc cycles. We conclude that this novel continuous sc IFO infusion over several days is a rational, well-tolerated and economical way of delivering this drug on an outpatient basis.

Aged↗
PubMed1990

The effect of age on the pharmacokinetics of ifosfamide.

The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half-life of ifosfamide and age (r = 0.48, 0.05 less than P less than 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 less than P less than 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.

Adult↗
PubMed1990

The symptomatic control of cytostatic drug-induced emesis. A recent history and review.

This article outlines the historical development of anti-emetic therapies and reviews the pathophysiology and clinical aspects of cytostatic drug-induced vomiting. The methodology and the factors affecting the results of clinical trials with anti-emetics are discussed. Advances in knowledge of the role of 5-hydroxytryptamine in cytostatic drug-induced vomiting have improved current anti-emetic therapy with the development of 5-HT3 receptor antagonists such as granisetron. Early trials show granisetron to be a very effective anti-emetic and suggest useful advantages over the regimens currently considered to be standard therapy for prophylaxis and treatment of cytostatic drug-induced emesis.

Antiemetics↗
PubMed1989

[Radioimmunoscintigraphy with a 99mTc-labeled F(ab')2 fragment of a monoclonal antibody (HMW-MAA 225.28S) in 71 patients with malignant melanoma].

In 71 patients with malignant melanoma 85 radioimmunoscintigraphies (RIS) with 99mTc-radiolabeled F(ab')2 fragments of a murine monoclonal antibody have been performed. The antibody is specific for an epitope of the HMW-MAA glycoprotein complex which is present in 90% of melanoma tissue samples. Sensitivity for RIS was 79% (73 metastatic sites out of a total of 92). 20 previously unknown lesions were found and there were also 2 false positives. Conventional staging procedures alone revealed 78% of the metastatic sites (72 of 92). No side effects were observed. RIS was especially useful for detection of lymph node metastases not found by conventional methods and is therefore considered complementary to conventional preoperative staging procedures.

Adult↗
PubMed1989

Relationships among cell survival, O6-alkylguanine-DNA alkyltransferase activity, and reactivation of methylated adenovirus 5 and herpes simplex virus type 1 in human melanoma cell lines.

O6-Alkylguanine-DNA alkyltransferase (ATase) activity and host cell reactivation (HCR) of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC)-methylated viruses were compared in human melanoma cell lines that were sensitive or resistant to killing by the antitumor DNA-methylating agent MTIC. Enhanced HCR of adenovirus 5 (defined as the Mer+ phenotype) generally showed a semiquantitative correlation with the natural or induced resistance of the host cells to the toxic effects of MTIC and to the level of ATase activity. However, one MTIC-resistant cell line was found (MM170) which had a low level of ATase and intermediate HCR of adenovirus. The HCR of herpes simplex virus type 1 (HSV-1) was enhanced in the Mer+ cells that had natural resistance to MTIC compared with Mer- cells. On the other hand, HCR of HSV-1 in Mer+ cells with induced resistance to MTIC was similar to that in Mer- cells. Neither adenovirus 5 nor HSV-1 infection induced ATase activity in Mer- cells. This indicates that resistance to the toxic effects of methylating agents is not invariably associated with high levels of ATase activity in human melanoma cells. Furthermore, while induction of the Mer+ phenotype from Mer- cells was usually accompanied by the recovery of ATase activity, induced Mer+ cells had less proficient repair than natural Mer+ cells, as judged quantitatively by slightly lower cellular resistance and qualitatively by deficient HCR response for HSV-1. These results suggest that the Mer- and induced Mer+ cells lack an ATase-independent DNA repair mechanism. No differences in MTIC-induced DNA repair synthesis or strand breaks were found between the Mer-, natural Mer+, and induced Mer+ phenotypes. However, UV-induced DNA repair synthesis was higher in the natural Mer+ than in the Mer- or induced Mer+ cells, both of which had increased cellular sensitivity to the antimetabolites methotrexate and hydroxyurea. These differences may be related to the effects observed with MTIC. A wide range of ATase activities was found in human melanoma biopsy material.

Adenoviruses, Human↗
PubMed1989

[Urinary bioavailability of sodium-2-mercaptoethanesulfonate (Uromitexan) following intravenous, subcutaneous and continuous subcutaneous administration].

The dose-limiting urotoxicity of the oxazaphosphorines (t1/2 = 4-15 h) is due to renal elimination of metabolites such as acrolein. The occurrence of hemorrhagic cystitis can be safely prevented by the concomitant use of i.v. or oral 2-mercaptoethanesulfonate sodium (DCI MESNA; Uromitexane). The bioavailability of oral MESNA is in the range of 20-50% and its unpleasant taste severely limits patient compliance. Due to the short half-life of MESNA (approx. 40 min) a regular fractionated or continuous administration is mandatory. In 6 healthy volunteers we have studied the pharmacokinetics of urinary MESNA elimination for the assessment of MESNA bioavailability after i.v. and s.c. drug administration. MESNA was given at doses of 400 mg for i.v. and s.c. bolus injections and 800 mg for continuous s.c. administration by a portable infusion pump. For the s.c. route an isotonic solution was prepared. The total amount of urinary thiols was assessed by the Ellman method (photometric reading at 412 nm). Total elimination of i.v. MESNA was 83.2 +/- 3.4% of the dose administered. The respective results for s.c. bolus and s.c. continuous drug administration were 81.9 +/- 3.4% and 79.4 +/- 3.6% of the dose. Continuous administration theoretically will provide optimal uroprotection from short term (hemorrhagic cystitis) and long term (bladder fibrosis and cancer) toxicity.

Biological Availability↗
PubMed1989

[Neurotoxicity with cytostatic therapy: a review].

Neurotoxicity is of increasing importance in the treatment of cancer patients. Since the dose-limiting hematological toxicity of most cytostatic drugs can now be overcome by modern supportive therapy, high-dose chemotherapy with curative intent can be used more often. Non-hematological toxicities such as neurotoxicity will therefore become dose-limiting with greater frequency, and to avoid disabling neurological side effects of chemotherapy the drug-induced neurological disturbances must be recognized before irreversible damage has occurred. The neurological side effects of the cytostatic drugs are reviewed.

Antineoplastic Agents↗
PubMed1989

[Autologous bone marrow transfusion in the treatment of adults with hematologic neoplasms. Experiences from Bern].

21 patients with hematological neoplasias (8 ALL, 4 AML, 4 NHL, 5 HD) were treated with high dose therapy and autologous bone marrow rescue (ABMT). At the time of ABMT 12 patients were in CR, 6 in PR and 3 in relapse. 66% of the patients were at high risk at the time of diagnosis. Before ABMT patients received an ablative regimen such as cyclophosphamide or ARA-C, VP-16, DNR and 12 Gy TBI in 6 fractions. In 9 patients the bone marrow was treated in vitro with monoclonal antibodies and complement. The hospital stay was a median 33 (24-57) days and isolation 19 (9-49) days. Complications were septicemia (7), herpes stomatitis (7), infections (6), fungal sepsis (1) and hemorrhagic cystitis (2). Late complications (up to 6 months after ABMT) were pneumococcal sepsis (1), cerebral toxoplasmosis (1) and herpes zoster (3). 10 of 19 evaluable patients are alive and relapse-free 1-33 months (median 10) after ABTM, and 3 of 10 more than 2 years later: 4 of 5 were transplanted in 1. CR, 4 of 6 in greater than or equal to 2. CR and 2 of 8 in PR. 4 patients are living in therapy sensitive relapse 2, 11, 11 and 39 months after ABMT in 2. CR or PR. 5 patients died 1-13 (median 3.5) months on relapse, 2 of 21 from septicemia. The morbidity of ABMT is comparable with conventional high dose chemotherapy. Relapse-free survival was significantly influenced by the remission status at ABMT. Long-term survivors can be expected even in patients with high risk hematological malignancies. However, only wider trials will serve to establish the efficacy of ABMT.

Adolescent↗
PubMed1989

[Chemotherapy of bronchus carcinoma].

The use of chemotherapy will eventually be discussed in most patients with lung cancer, due to the systemic nature of the disease. In small cell lung cancer combination chemotherapy will achieve a response in the majority of patients and will lead to a five-fold increase in median survival. A small proportion of these patients will survive disease-free for a prolonged period of time and may be cured of their disease. In non-small cell lung cancer about one third of all patients will achieve an objective tumor response with the use of cisplatin-based combination chemotherapy. There is a small, but definite increase in median survival with the use of combination chemotherapy compared to best supportive care alone. Also in non-small cell lung cancer a small proportion of patients will survive after combination chemotherapy for a prolonged period of time. The use of cytotoxic treatment in lung cancer is associated with considerable toxicity so that optimal supportive care is mandatory.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma.

20 patients with advanced non-small cell lung cancer were treated with ifosfamide and mesna 1.5 g/m2 daily for 5 days; 10 received the drug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5-day period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the i.v. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients' waking hours. Nadir blood counts and response rates were similar in both arms. The encephalopathy suggests that there are metabolic differences between the i.v. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. In addition it was shown that the total and nonrenal clearance of the drug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfamide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed i.v. doses.

Administration, Oral↗