András Telekes - Academia.edu (original) (raw)
Papers by András Telekes
Pathology & Oncology Research, May 18, 2022
In the original article, there was a mistake in Table 2. In the last column of PLR the wrong pati... more In the original article, there was a mistake in Table 2. In the last column of PLR the wrong patient number is 57. The correct patient number is 47. The corrected Table 2 appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
![Research paper thumbnail of A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)�Pro�NH2 (BW443C)] in healthy volunteers](https://attachments.academia-assets.com/113892198/thumbnails/1.jpg)
](European Journal of Clinical Pharmacology, 1988
We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C gi... more We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 ~tg.kg-1 for 60 min and increasing to a maximum of 2.0 ug.kg-l-min-1 for 180rain. Subsequently 12 different subjects received single i.v. infusions of 10 lxg. kg-1. rain-1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN. Dry mouth and some nasal stuffiness were reported and postural hypotension occurred :in 5/16 subjects at plasma concentrations >0.8 gg. ml-1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60-90 rain of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations. The disposition of the peptide was adequately described by a 2-compartment model with a mean _+ SD plasma clearance of 123 + 18 ml. rain-1 and a half-life of 2.0 + 0.4 h.
British Journal of Clinical Pharmacology, Dec 1, 1987
The mechanism of the pain relief produced by opiates in normal volunteers in the cold induced pai... more The mechanism of the pain relief produced by opiates in normal volunteers in the cold induced pain test has been investigated. In a double-blind placebo controlled study, hand skin temperature during a 3 min immersion in water at 1°C was not affected by either the opioid dipipanone 8 mg or the vasodilator nifedipine 10 and 20 mg. During this immersion, dipipanone produced significant pain relief. Nifedipine reduced pre-immersion blood pressures and raised heart rates, however, it did not significantly alter pain scores. It is concluded that vasodilatation and local warming do not play a role in the relief of pain by opiates in the cold immersion test.
European Journal of Clinical Pharmacology, Mar 1, 1990
443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, ce... more 443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, central, cardiovascular and endocrine effects of two i.v. doses of 443C81 were investigated in 12 healthy male volunteers. Its effects were compared with those of placebo and the classical opiate dipipanone given orally using a double dummy design. 443C81 produced dose-related analgesia; dipipanone 10 mg had a greater effect than the high dose 443C81. In contrast to dipipanone, 443C81 did not cause significant miosis or reduce minute volume on rebreathing CO2 and there was no evidence of sedation. Dry mouth was reported frequently and associated with reduced salivation after all active treatments. Both 443C81 and dipipanone increased circulating prolactin and growth hormone and reduced cortisol levels. This novel enkephalin appears to possess analgesic activity and some other properties of opiates but is devoid of clinically relevant narcotic effects.
Annals of Oncology, May 1, 2012
New diagnostics and therapies have been made available to breast cancer patients in the last ten ... more New diagnostics and therapies have been made available to breast cancer patients in the last ten years, however they came with an important economic impact on the NHS. Study objective was to assess the long-term cost-effectiveness of using the 21-gene breast cancer assay (Oncotype DX) in the French clinical practice from the perspective of the NHS. A Markov model was developed to evaluate the long-term costs and clinical outcomes associated with the introduction of Oncotype DX to inform decisions on adjuvant chemotherapy for patients with ER + , node negative early-stage breast cancer in France. The model projected life expectancy, and costs, based on recurrence rates for low, intermediate and high-risk patients (NSABP 20 study) as well as French mortality data. Annual cycles were modeled across three health states: recurrence-free (in which all patients start the simulation), recurrence (following a distant recurrence event) and dead (following a mortality event). In the absence of French specific decision impact data, the model compared the assignment of adjuvant chemotherapy based on the conventional approach or based on the Oncotype DX Recurrence Score using data from a meta-analysis of nine decision impact studies. Costs associated with chemotherapy were collected through a retrospective study at Tenon hospital. Costs associated with long term recurrence were collected from the literature. According to French pharmaco-economic guidelines, costs and outcomes were discounted at 5% per annum. One-way sensitivity analyses were conducted to test the robustness of key parameters. When compared to the current clinical practice, using Oncotype DX is expected to decrease chemotherapy cost (-630 euros per patient) through patients who are spared unnecessary chemotherapy, and to increase outcomes (0.13 life years gained per patient) through patients reclassified towards chemotherapy following the availability of the Recurrence Score. Oncotype DX is therefore expected to be cost-saving in the French clinical practice. Details of one-way sensitivity analyses will be presented in details.
British Journal of Clinical Pharmacology, Jul 1, 1987
Twelve healthy volunteers took part in a study of the interaction between the antihistamine tripr... more Twelve healthy volunteers took part in a study of the interaction between the antihistamine triprolidine and the opioid dipipanone in the cold induced pain (CP) test and tests of sedation. They received placebo, triprolidine 2.5 mg, dipipanone 8 mg or the combination of the two active treatments according to a double-blind, randomised, balanced, crossover design. 2 Antihistamine activity was demonstrated by triprolidine reducing the size of wheals and flares produced by intradermal histamine 1.6 jig. However, triprolidine produced no analgesia in the CP test, nor did it enhance the analgesia produced by dipipanone alone. 3 Neither treatment alone produced statistically significant sedation, assessed by visual analogue scales (VAS), side effect check list, body sway and reaction times. However, the combination did cause significant sedation. 4 Dipipanone reduced pupil size, depressed respiration, and decreased salivation. Triprolidine had no effects on pupil size and respiration, but reduced salivation slightly. It was concluded that histaminergic (H1) mechanisms are unlikely to be involved in pain produced by cold.
Pain, 1987
The sensitivity of the cold-induced pain (CP) model to the non-steroidal anti-inflammatory drug (... more The sensitivity of the cold-induced pain (CP) model to the non-steroidal anti-inflammatory drug (NSAID) indomethacin was studied in healthy volunteers. Effects on the central nervous system were also sought. Subjects received single oral doses of indomethacin 50 and 100 mg, dipipanone 8 mg and placebo, according to a double-blind, randomised, balanced, cross-over design with an interval of 7 days between occasions. A test battery was performed before each treatment and then at 45, 105 and 165 min post treatment. Pain scores were unaltered by indomethacin at either dose, but the drug certainly affected the CNS, increasing respiratory drive and changing self-assessed mood. It is concluded that the CP model is insensitive to indomethacin. even in doses which have clear-cut CNS effects. The respiratory stimulant action of indomethacin may deserve further study.
The Lancet Oncology, 2021
BACKGROUND PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive ... more BACKGROUND PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. METHODS KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. FINDINGS Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. INTERPRETATION The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. FUNDING Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
Journal of Clinical Oncology, 2007
14143 Background: The positive effect of the wheat germ extract Avemar has already been proved in... more 14143 Background: The positive effect of the wheat germ extract Avemar has already been proved in cancer. Compared to the control group significantly longer survival times were achieved in both in vivo experiments and clinical studies. Inhibition of cell growth was also detected in K562 human leukaemia cell line in vitro. Avemar given p.o.(3 g/kg) resulted in significant increase of the survival time compared to the control group (p<0.005 Mann-Whitney) in i.v. implanted K562 xenograft model, which was practically the same as the effect of Gleevec treatment. Since, the mechanism(s) of action of Avemar is still not properly characterized a kinase expression panel in K562 in vitro model was examined. Methods: K562 cells (8x105 cell/ml), were treated with Avemar (500 μg/ml) and mRNS from 3–3 parallel samples and their appropriate controls were isolated 24, 48 hours after the treatment and 24 hours after washing the cells previously treated with Avemar for 48 hours. To determine the k...
Pain, 1985
The analgesic activity of an opiate was studied in 12 healthy volunteers using a cold-induced pai... more The analgesic activity of an opiate was studied in 12 healthy volunteers using a cold-induced pain (CP) model. Effects on the central nervous system (CNS) were also measured. According to a double-blind, randomised, balanced, cross-over design with an interval of 7 days between occasions, subjects received single oral doses of 2, 4 and 8 mg dipipanone (D2, D4, D8) and a placebo. The CP test and a battery of measurements of CNS function were performed 3 times on each study day, once before and again 1.5 h and 3.0 h after treatment. Mean pain scores on a computerised visual analogue scale were significantly higher after placebo than those after 4 mg (P < 0.05) and 8 mg (P < 0.01) dipipanone and a dose-response relationship was evident. The opiate did not affect baseline blood pressure before the CP test but the hypertensive response to the painful cold stimulus was diminished 3 h after D8. Scores on scales for subjective assessment of alertness were significantly reduced 3 h after the 8 mg dose and pupil diameters were significantly smaller after all 3 doses of dipipanone. Body sway and visual near points were not significantly altered by the opiate. It is concluded that the CP test is a sensitive model for measurement of opiate-induced analgesia in healthy volunteers. Pupillometry and visual analogue scales are useful for the assessment of central effects of opiates.
Clinical and experimental rheumatology
To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rhe... more To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA). Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used. At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed. Supplementation of standard therapies with a continuous administration of Avemar is beneficial fo...
Acta microbiologica et immunologica Hungarica, 1994
Replication and transformation by adenoviruses involve their interaction with several cellular re... more Replication and transformation by adenoviruses involve their interaction with several cellular regulatory mechanisms. Alterations in the phosphorylation of both cellular and viral polypeptides by secondary messenger cAMP and cGMP dependent protein kinases (PK) determining outcome of viral effects may be influenced by external physiological stimuli, among them by prostaglandins (PG). HEp-2 cells infected with representative serotypes of human adenovirus (Ad) groups and two temperature sensitive (ts) mutants were treated prior to and late postinfection at permissive (32 degrees C) and restrictive (39 degrees C) temperatures by different PGs. PGF2 alpha augmented replication of both oncogenic Ad-12 and latent Ad-1, Ad-5 serotypes as well as Ad-5 mutants at 32 degrees C and that of mutant ts18 (defective in pVI phosphorylation) but not that of ts19 (defective in pX phosphorylation) at 39 degrees C. PGE2 was shown to be inhibitory, but the replication of nononcogenic Ad-8 was not affecte...
Acta virologica, 1990
Several prostaglandins are continuously produced in every cell. They activate protein kinases by ... more Several prostaglandins are continuously produced in every cell. They activate protein kinases by regulating cyclic nucleotide synthesis. Modifications of the phosphorylation of virus polypeptides and alterations in the microtubular system of host cells can result in the reactivation of latent viruses. Prostaglandins have a very important role in directing cell cycle. Abnormal tyrosine kinase activities during viral cell transformation are responsible for the malignant changes and consequently severe alterations are observed in the endogenous prostaglandin production. External modification of this cascade can revert malignant signs to normal. Furthermore, virus infection or cell transformation could be promoted by the immunosuppressive effects of overproduced prostaglandins. They damage interferon release and co-operation between the different cell types of the immune system. Enzyme inhibitors of the prostaglandin cascade or prostaglandin analogues may exert influence on all of these...
Oncology, 1990
The objective of this trial was to define the antitumor activity and toxicity of etoposide for se... more The objective of this trial was to define the antitumor activity and toxicity of etoposide for second-line treatment of patients with bulky ovarian carcinoma. Between February 1, 1986 and November 1, 1988 we recruited 82 patients. Out of them 77 (93.9%) were evaluable for toxicity and 71 (86.6%) for response. Patient characteristics are as follows: median age 57 years (range 15-75), median performance status: WHO 1, prior chemotherapy with more than 3 drugs 24 patients, with previous cisplatin 63 patients, with previous adriamycin 47 patients, with previous irradiation plus chemotherapy 17 patients. The following treatment schedule was applied: each patient started with 150 mg/m2 of etoposide administered i.v. on days 1-3. If this first cycle was well tolerated the dosage was escalated to 200 mg/m2 days 1-3. This higher dosage was then repeated at 4-week intervals. For evaluation of response the WHO criteria were used. One patient (1.4%) achieved complete remission and 5 (7.0%) partial remission. In 48 patients (67.6%) minor response or stabilisation of the disease were observed. Seventeen patients (24%) showed no response. The median duration of remission was 5.5 months (range 2-20). The median duration of stabilisation was 3 months (range 2-24). The median survival time was 10 months with a range of 2-30 months. The myelotoxic side-effects are as follows: WBC less than 2,000 was recorded in 6 patients and greater than 1,000 in 2 patients. Thrombocytopaenia with platelet count less than 50,000 occurred in 1 patient. 26 patients had anaemia WHO grades 2 and 3. Non-haematological toxicity consisted of nausea and vomiting (WHO grade 2:20 patients and grade 3:2 patients), alopecia (WHO grades 2-3:14 and 24 patients, respectively). Though the remission rate in this trial was low, the 10-month median survival with an acceptable quality of life can be taken as a fairly good salvage therapy result.
European Journal of Cancer, 1997
Carcinogenesis, 2001
It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in ... more It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in laboratory animals. Four-week-old inbred male F-344 rats were used in the study. Colon carcinogenesis has been induced by azoxymethane (AOM). Ten rats served as untreated controls (group 1). For the treatment of the animals in group 2, AOM was dissolved in physiologic saline and the animals were given three subcutaneous injections 1 week apart, 15 mg/kg body weight (b/w) each. In two additional groups Avemar (MSC), a fermented wheat germ extract standardized to 2,6-dimethoxy-p-benzoquinone was administered as a tentative chemo-preventive agent. MSC was dissolved in water and was given by gavage at a dose of 3 g/kg b/w once a day. In group 3, animals started to receive MSC 2 weeks prior to the first injection of AOM daily and continuously thereafter until they were killed 32 weeks later. In group 4 the basal diet and MSC were administered only. At the end of the experiment all the rats were killed by exsanguination, the abdominal large vessels were cut under a light ether anesthesia and a complete autopsy was performed. Percentage of animals developing colon tumors and number of tumors per animals: group 1-0 and 0; group 2-83.0 and 2.3; group 3-44.8 (P < 0.001) and 1.3 (P < 0.004), group 4-0 and 0. All the tumors were of neoplastic nature also histologically. The numbers of the aberrant crypt foci (ACF) per area (cm 2) in group 2 were 4.85 while in group 3 the ACF numbers were 2.03 only (P < 0.0001).
British Journal of Cancer, 2003
MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies sugge... more MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients' choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, Po0.01; new metastases: 7.6 vs 23.1%, Po0.01; deaths: 12.1 vs 31.7%, Po0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P ¼ 0.0184) and overall survivals (P ¼ 0.0278) probabilities. Survival predictors in Cox's proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival.
Journal of Clinical Oncology, 2007
21132 Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on... more 21132 Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF1 mice. The tumor bearing animals were treated p.o. with Avemar. Then the most effective Avemar dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with Avemar was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by Avemar was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Com...
Absztrakt A 48 eves nőbetegnel 2006-ban pleuralis folyadek, hasi fajdalom es ascites miatt indult... more Absztrakt A 48 eves nőbetegnel 2006-ban pleuralis folyadek, hasi fajdalom es ascites miatt indult kivizsgalas soran a panaszok es tunetek hattereben előrehaladott stadiumu ovariumcarcinoma igazolodott, amely miatt hysterectomia es ketoldali adnexectomia tortent. A szovettani vizsgalat FIGO IIIB stadiumu papillaris adenocarcinomat mutatott. Posztoperativan a standard, 6 ciklus taxol-carboplatin kezelesben reszesult. 2008-ban retroperitonealis nyirokcsomo-metasztazisok miatt reindukcios taxol-carboplatin kezeles indult, azonban progresszio miatt hamar kezelesvaltas valt szuksegesse. Ezt kovetően meg hatfele kemo- vagy biologiai terapias kezelesben reszesult, koztuk a hetedik vonalban off-label megigenyelt FOLFOX-4-kezeles. A FOLFOX-4-terapia mellett is jelentős regresszio igazolodott, a progressziomentes tuleles mintegy 9 honap volt. A valtott kezelesek soran a beteg mindvegig kielegitő altalanos allapotban volt, lenyegeben toleralhato mellekhatasok mellett. A teljes tuleles 98 honapn...
Pathology & Oncology Research, May 18, 2022
In the original article, there was a mistake in Table 2. In the last column of PLR the wrong pati... more In the original article, there was a mistake in Table 2. In the last column of PLR the wrong patient number is 57. The correct patient number is 47. The corrected Table 2 appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
European Journal of Clinical Pharmacology, 1988
We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C gi... more We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 ~tg.kg-1 for 60 min and increasing to a maximum of 2.0 ug.kg-l-min-1 for 180rain. Subsequently 12 different subjects received single i.v. infusions of 10 lxg. kg-1. rain-1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN. Dry mouth and some nasal stuffiness were reported and postural hypotension occurred :in 5/16 subjects at plasma concentrations >0.8 gg. ml-1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60-90 rain of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations. The disposition of the peptide was adequately described by a 2-compartment model with a mean _+ SD plasma clearance of 123 + 18 ml. rain-1 and a half-life of 2.0 + 0.4 h.
British Journal of Clinical Pharmacology, Dec 1, 1987
The mechanism of the pain relief produced by opiates in normal volunteers in the cold induced pai... more The mechanism of the pain relief produced by opiates in normal volunteers in the cold induced pain test has been investigated. In a double-blind placebo controlled study, hand skin temperature during a 3 min immersion in water at 1°C was not affected by either the opioid dipipanone 8 mg or the vasodilator nifedipine 10 and 20 mg. During this immersion, dipipanone produced significant pain relief. Nifedipine reduced pre-immersion blood pressures and raised heart rates, however, it did not significantly alter pain scores. It is concluded that vasodilatation and local warming do not play a role in the relief of pain by opiates in the cold immersion test.
European Journal of Clinical Pharmacology, Mar 1, 1990
443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, ce... more 443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, central, cardiovascular and endocrine effects of two i.v. doses of 443C81 were investigated in 12 healthy male volunteers. Its effects were compared with those of placebo and the classical opiate dipipanone given orally using a double dummy design. 443C81 produced dose-related analgesia; dipipanone 10 mg had a greater effect than the high dose 443C81. In contrast to dipipanone, 443C81 did not cause significant miosis or reduce minute volume on rebreathing CO2 and there was no evidence of sedation. Dry mouth was reported frequently and associated with reduced salivation after all active treatments. Both 443C81 and dipipanone increased circulating prolactin and growth hormone and reduced cortisol levels. This novel enkephalin appears to possess analgesic activity and some other properties of opiates but is devoid of clinically relevant narcotic effects.
Annals of Oncology, May 1, 2012
New diagnostics and therapies have been made available to breast cancer patients in the last ten ... more New diagnostics and therapies have been made available to breast cancer patients in the last ten years, however they came with an important economic impact on the NHS. Study objective was to assess the long-term cost-effectiveness of using the 21-gene breast cancer assay (Oncotype DX) in the French clinical practice from the perspective of the NHS. A Markov model was developed to evaluate the long-term costs and clinical outcomes associated with the introduction of Oncotype DX to inform decisions on adjuvant chemotherapy for patients with ER + , node negative early-stage breast cancer in France. The model projected life expectancy, and costs, based on recurrence rates for low, intermediate and high-risk patients (NSABP 20 study) as well as French mortality data. Annual cycles were modeled across three health states: recurrence-free (in which all patients start the simulation), recurrence (following a distant recurrence event) and dead (following a mortality event). In the absence of French specific decision impact data, the model compared the assignment of adjuvant chemotherapy based on the conventional approach or based on the Oncotype DX Recurrence Score using data from a meta-analysis of nine decision impact studies. Costs associated with chemotherapy were collected through a retrospective study at Tenon hospital. Costs associated with long term recurrence were collected from the literature. According to French pharmaco-economic guidelines, costs and outcomes were discounted at 5% per annum. One-way sensitivity analyses were conducted to test the robustness of key parameters. When compared to the current clinical practice, using Oncotype DX is expected to decrease chemotherapy cost (-630 euros per patient) through patients who are spared unnecessary chemotherapy, and to increase outcomes (0.13 life years gained per patient) through patients reclassified towards chemotherapy following the availability of the Recurrence Score. Oncotype DX is therefore expected to be cost-saving in the French clinical practice. Details of one-way sensitivity analyses will be presented in details.
British Journal of Clinical Pharmacology, Jul 1, 1987
Twelve healthy volunteers took part in a study of the interaction between the antihistamine tripr... more Twelve healthy volunteers took part in a study of the interaction between the antihistamine triprolidine and the opioid dipipanone in the cold induced pain (CP) test and tests of sedation. They received placebo, triprolidine 2.5 mg, dipipanone 8 mg or the combination of the two active treatments according to a double-blind, randomised, balanced, crossover design. 2 Antihistamine activity was demonstrated by triprolidine reducing the size of wheals and flares produced by intradermal histamine 1.6 jig. However, triprolidine produced no analgesia in the CP test, nor did it enhance the analgesia produced by dipipanone alone. 3 Neither treatment alone produced statistically significant sedation, assessed by visual analogue scales (VAS), side effect check list, body sway and reaction times. However, the combination did cause significant sedation. 4 Dipipanone reduced pupil size, depressed respiration, and decreased salivation. Triprolidine had no effects on pupil size and respiration, but reduced salivation slightly. It was concluded that histaminergic (H1) mechanisms are unlikely to be involved in pain produced by cold.
Pain, 1987
The sensitivity of the cold-induced pain (CP) model to the non-steroidal anti-inflammatory drug (... more The sensitivity of the cold-induced pain (CP) model to the non-steroidal anti-inflammatory drug (NSAID) indomethacin was studied in healthy volunteers. Effects on the central nervous system were also sought. Subjects received single oral doses of indomethacin 50 and 100 mg, dipipanone 8 mg and placebo, according to a double-blind, randomised, balanced, cross-over design with an interval of 7 days between occasions. A test battery was performed before each treatment and then at 45, 105 and 165 min post treatment. Pain scores were unaltered by indomethacin at either dose, but the drug certainly affected the CNS, increasing respiratory drive and changing self-assessed mood. It is concluded that the CP model is insensitive to indomethacin. even in doses which have clear-cut CNS effects. The respiratory stimulant action of indomethacin may deserve further study.
The Lancet Oncology, 2021
BACKGROUND PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive ... more BACKGROUND PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. METHODS KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. FINDINGS Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. INTERPRETATION The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. FUNDING Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
Journal of Clinical Oncology, 2007
14143 Background: The positive effect of the wheat germ extract Avemar has already been proved in... more 14143 Background: The positive effect of the wheat germ extract Avemar has already been proved in cancer. Compared to the control group significantly longer survival times were achieved in both in vivo experiments and clinical studies. Inhibition of cell growth was also detected in K562 human leukaemia cell line in vitro. Avemar given p.o.(3 g/kg) resulted in significant increase of the survival time compared to the control group (p<0.005 Mann-Whitney) in i.v. implanted K562 xenograft model, which was practically the same as the effect of Gleevec treatment. Since, the mechanism(s) of action of Avemar is still not properly characterized a kinase expression panel in K562 in vitro model was examined. Methods: K562 cells (8x105 cell/ml), were treated with Avemar (500 μg/ml) and mRNS from 3–3 parallel samples and their appropriate controls were isolated 24, 48 hours after the treatment and 24 hours after washing the cells previously treated with Avemar for 48 hours. To determine the k...
Pain, 1985
The analgesic activity of an opiate was studied in 12 healthy volunteers using a cold-induced pai... more The analgesic activity of an opiate was studied in 12 healthy volunteers using a cold-induced pain (CP) model. Effects on the central nervous system (CNS) were also measured. According to a double-blind, randomised, balanced, cross-over design with an interval of 7 days between occasions, subjects received single oral doses of 2, 4 and 8 mg dipipanone (D2, D4, D8) and a placebo. The CP test and a battery of measurements of CNS function were performed 3 times on each study day, once before and again 1.5 h and 3.0 h after treatment. Mean pain scores on a computerised visual analogue scale were significantly higher after placebo than those after 4 mg (P < 0.05) and 8 mg (P < 0.01) dipipanone and a dose-response relationship was evident. The opiate did not affect baseline blood pressure before the CP test but the hypertensive response to the painful cold stimulus was diminished 3 h after D8. Scores on scales for subjective assessment of alertness were significantly reduced 3 h after the 8 mg dose and pupil diameters were significantly smaller after all 3 doses of dipipanone. Body sway and visual near points were not significantly altered by the opiate. It is concluded that the CP test is a sensitive model for measurement of opiate-induced analgesia in healthy volunteers. Pupillometry and visual analogue scales are useful for the assessment of central effects of opiates.
Clinical and experimental rheumatology
To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rhe... more To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA). Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used. At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed. Supplementation of standard therapies with a continuous administration of Avemar is beneficial fo...
Acta microbiologica et immunologica Hungarica, 1994
Replication and transformation by adenoviruses involve their interaction with several cellular re... more Replication and transformation by adenoviruses involve their interaction with several cellular regulatory mechanisms. Alterations in the phosphorylation of both cellular and viral polypeptides by secondary messenger cAMP and cGMP dependent protein kinases (PK) determining outcome of viral effects may be influenced by external physiological stimuli, among them by prostaglandins (PG). HEp-2 cells infected with representative serotypes of human adenovirus (Ad) groups and two temperature sensitive (ts) mutants were treated prior to and late postinfection at permissive (32 degrees C) and restrictive (39 degrees C) temperatures by different PGs. PGF2 alpha augmented replication of both oncogenic Ad-12 and latent Ad-1, Ad-5 serotypes as well as Ad-5 mutants at 32 degrees C and that of mutant ts18 (defective in pVI phosphorylation) but not that of ts19 (defective in pX phosphorylation) at 39 degrees C. PGE2 was shown to be inhibitory, but the replication of nononcogenic Ad-8 was not affecte...
Acta virologica, 1990
Several prostaglandins are continuously produced in every cell. They activate protein kinases by ... more Several prostaglandins are continuously produced in every cell. They activate protein kinases by regulating cyclic nucleotide synthesis. Modifications of the phosphorylation of virus polypeptides and alterations in the microtubular system of host cells can result in the reactivation of latent viruses. Prostaglandins have a very important role in directing cell cycle. Abnormal tyrosine kinase activities during viral cell transformation are responsible for the malignant changes and consequently severe alterations are observed in the endogenous prostaglandin production. External modification of this cascade can revert malignant signs to normal. Furthermore, virus infection or cell transformation could be promoted by the immunosuppressive effects of overproduced prostaglandins. They damage interferon release and co-operation between the different cell types of the immune system. Enzyme inhibitors of the prostaglandin cascade or prostaglandin analogues may exert influence on all of these...
Oncology, 1990
The objective of this trial was to define the antitumor activity and toxicity of etoposide for se... more The objective of this trial was to define the antitumor activity and toxicity of etoposide for second-line treatment of patients with bulky ovarian carcinoma. Between February 1, 1986 and November 1, 1988 we recruited 82 patients. Out of them 77 (93.9%) were evaluable for toxicity and 71 (86.6%) for response. Patient characteristics are as follows: median age 57 years (range 15-75), median performance status: WHO 1, prior chemotherapy with more than 3 drugs 24 patients, with previous cisplatin 63 patients, with previous adriamycin 47 patients, with previous irradiation plus chemotherapy 17 patients. The following treatment schedule was applied: each patient started with 150 mg/m2 of etoposide administered i.v. on days 1-3. If this first cycle was well tolerated the dosage was escalated to 200 mg/m2 days 1-3. This higher dosage was then repeated at 4-week intervals. For evaluation of response the WHO criteria were used. One patient (1.4%) achieved complete remission and 5 (7.0%) partial remission. In 48 patients (67.6%) minor response or stabilisation of the disease were observed. Seventeen patients (24%) showed no response. The median duration of remission was 5.5 months (range 2-20). The median duration of stabilisation was 3 months (range 2-24). The median survival time was 10 months with a range of 2-30 months. The myelotoxic side-effects are as follows: WBC less than 2,000 was recorded in 6 patients and greater than 1,000 in 2 patients. Thrombocytopaenia with platelet count less than 50,000 occurred in 1 patient. 26 patients had anaemia WHO grades 2 and 3. Non-haematological toxicity consisted of nausea and vomiting (WHO grade 2:20 patients and grade 3:2 patients), alopecia (WHO grades 2-3:14 and 24 patients, respectively). Though the remission rate in this trial was low, the 10-month median survival with an acceptable quality of life can be taken as a fairly good salvage therapy result.
European Journal of Cancer, 1997
Carcinogenesis, 2001
It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in ... more It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in laboratory animals. Four-week-old inbred male F-344 rats were used in the study. Colon carcinogenesis has been induced by azoxymethane (AOM). Ten rats served as untreated controls (group 1). For the treatment of the animals in group 2, AOM was dissolved in physiologic saline and the animals were given three subcutaneous injections 1 week apart, 15 mg/kg body weight (b/w) each. In two additional groups Avemar (MSC), a fermented wheat germ extract standardized to 2,6-dimethoxy-p-benzoquinone was administered as a tentative chemo-preventive agent. MSC was dissolved in water and was given by gavage at a dose of 3 g/kg b/w once a day. In group 3, animals started to receive MSC 2 weeks prior to the first injection of AOM daily and continuously thereafter until they were killed 32 weeks later. In group 4 the basal diet and MSC were administered only. At the end of the experiment all the rats were killed by exsanguination, the abdominal large vessels were cut under a light ether anesthesia and a complete autopsy was performed. Percentage of animals developing colon tumors and number of tumors per animals: group 1-0 and 0; group 2-83.0 and 2.3; group 3-44.8 (P < 0.001) and 1.3 (P < 0.004), group 4-0 and 0. All the tumors were of neoplastic nature also histologically. The numbers of the aberrant crypt foci (ACF) per area (cm 2) in group 2 were 4.85 while in group 3 the ACF numbers were 2.03 only (P < 0.0001).
British Journal of Cancer, 2003
MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies sugge... more MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients' choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, Po0.01; new metastases: 7.6 vs 23.1%, Po0.01; deaths: 12.1 vs 31.7%, Po0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P ¼ 0.0184) and overall survivals (P ¼ 0.0278) probabilities. Survival predictors in Cox's proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival.
Journal of Clinical Oncology, 2007
21132 Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on... more 21132 Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF1 mice. The tumor bearing animals were treated p.o. with Avemar. Then the most effective Avemar dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with Avemar was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by Avemar was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Com...
Absztrakt A 48 eves nőbetegnel 2006-ban pleuralis folyadek, hasi fajdalom es ascites miatt indult... more Absztrakt A 48 eves nőbetegnel 2006-ban pleuralis folyadek, hasi fajdalom es ascites miatt indult kivizsgalas soran a panaszok es tunetek hattereben előrehaladott stadiumu ovariumcarcinoma igazolodott, amely miatt hysterectomia es ketoldali adnexectomia tortent. A szovettani vizsgalat FIGO IIIB stadiumu papillaris adenocarcinomat mutatott. Posztoperativan a standard, 6 ciklus taxol-carboplatin kezelesben reszesult. 2008-ban retroperitonealis nyirokcsomo-metasztazisok miatt reindukcios taxol-carboplatin kezeles indult, azonban progresszio miatt hamar kezelesvaltas valt szuksegesse. Ezt kovetően meg hatfele kemo- vagy biologiai terapias kezelesben reszesult, koztuk a hetedik vonalban off-label megigenyelt FOLFOX-4-kezeles. A FOLFOX-4-terapia mellett is jelentős regresszio igazolodott, a progressziomentes tuleles mintegy 9 honap volt. A valtott kezelesek soran a beteg mindvegig kielegitő altalanos allapotban volt, lenyegeben toleralhato mellekhatasok mellett. A teljes tuleles 98 honapn...