Biomedical subjects

J M Smit

Publications and source records attributed to J M Smit.

At least 19 recordsLinked to original sources

PubMed2006

Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer.

BACKGROUND: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. PATIENTS AND METHODS: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). RESULTS: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade (3/4) toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. CONCLUSIONS: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer.

PURPOSE: The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. PATIENTS AND METHODS: One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. RESULTS: The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. CONCLUSIONS: Irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.

Adult↗

PubMed2005

A phase II study of raltitrexed and gemcitabine in patients with advanced pancreatic carcinoma.

Advanced adenocarcinoma of the pancreas has a very poor prognosis. The aim of this study was to assess the efficacy and tolerability of a combination of the chemotherapeutic agents gemcitabine and raltitrexed. Chemonaive patients with advanced adenocarcinoma of the pancreas were treated with a combination of raltitrexed (3.5 mg m(-2) on day 1 of a 21-day treatment cycle) and gemcitabine (800 mg m(-2) intravenously (i.v.) on days 1 and 8 of a 21-day cycle). Between April 2000 and February 2003, 27 patients were enrolled onto the study. The mean duration of treatment was 11 weeks. Four of 27 patients experienced at least one episode of grade 3 or 4 neutropenia. One patient with grade 4 neutropenia died due to sepsis. Four of 27 patients experienced grade 4 diarrhoea. There was one partial remission (4%) and 12 patients experienced disease stabilisation (44%). The 6-month and 1-year survival rates were 37 and 11%, respectively. Symptomatic benefit occurred in seven (26%) patients. We conclude that a combination of raltitrexed and gemcitabine, using the schedule and doses in this study, cannot be recommended for patients with advanced pancreatic cancer.

Adenocarcinoma↗

PubMed2005

Pulsed dye laser treatment, a review of indications and outcome based on published trials.

INTRODUCTION: Pulsed dye laser (PDL) treatment is based on the principle of selective photothermolysis and is widely considered to be the treatment of choice for a variety of cutaneous vascular lesions. OBJECTIVE: To review the indications and outcome of PDL treatment and summarise new developments. METHOD: A literature-based study has been conducted entailing the review of publications over the period January 1993-December 2003 using the databases Medline and Cochrane CENTRAL. RESULTS: The PDL was found to be effective in port wine stain, facial telangiectasia, leg telangiectasia <0.5 mm, scars, hypertrophic scars and ulcerated haemangioma. DISCUSSION: Essential characteristics of lesions suitable for PDL treatment are discussed and guidelines are presented for future research.

Cicatrix↗

PubMed2003

Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain.

OBJECTIVE: This randomised, multicentre, direct open comparative trial evaluated the efficacy, treatment convenience, tolerability and safety aspects of transdermal therapeutic system (TTS)-fentanyl and sustained-release oral morphine (SRM) in both opioid-naïve patients with moderate-to-severe cancer-related pain and in patients who had already been using opioids for mild-to-moderate pain. The two treatment groups were run in parallel. Special attention was paid to constipation, nausea/vomiting, drowsiness and respiratory depression. PATIENTS AND METHODS: The 131 enrolled patients started the 4-week treatment at low doses of opioid (25 microg/h TTS-fentanyl for 3 days or 30 mg SRM every 12 h) and were individually titrated. Tolerability, efficacy and safety were assessed throughout the study period. Frequency of constipation was the primary study variable and accordingly the study was powered for this. Both patients and investigators made a global treatment evaluation. RESULTS: TTS-fentanyl and SRM were shown to be equally effective. Pain control and sleep quality improved with both treatments. None of the patients developed respiratory depression. Statistically significantly more patients in the SRM treatment group discontinued the trial prematurely (59% vs 27%; p < 0.001), particularly due to adverse events (36% vs 4%; p < 0.001). Fewer patients in the TTS-fentanyl than in the SRM treatment group reported constipation during the trial. This finding was statistically significant after 1 week of treatment (27% vs 57%; p = 0.003). The favourable tolerability profile of TTS-fentanyl was also reflected in both the patient and the investigator global evaluation of the treatment. Patient assessment favoured TTS-fentanyl treatment in terms of a significantly lower rate of troublesome side-effects ('quite a bit' to 'very much' troublesome side-effects in 14% vs 36% of patients; p = 0.003) and less interruption of daily activities (absence of any interruption of daily activities in 88% vs 63% of patients; p = 0.012). Investigators scored TTS-fentanyl as significantly better with respect to 'side-effects' (p = 0.039) and 'overall impression' (p = 0.013). Sub-analyses of opioid-naïve users gave similar results. CONCLUSION: These data indicate that TTS-fentanyl, when used as an opioid of first choice in the treatment of cancer-related pain, is as effective as, but better tolerated than, SRM, including in opioid-naïve patients.

Administration, Cutaneous↗

PubMed2002

A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicentre trial.

BACKGROUND: Proton pump inhibitors (PPIs) have proved to be effective in treating reflux oesophagitis. Until now, no study had compared the PPIs omeprazole Multiple Unit Pellet System (MUPS), lansoprazole and pantoprazole in patients with reflux oesophagitis. AIM: To compare omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg for treatment effect in symptomatic reflux oesophagitis. METHOD: Patients with grade I-IV symptomatic reflux oesophagitis were randomized to double-blind omeprazole 20 mg once morning, lansoprazole 30 mg o.m. or pantoprazole 40 mg o.m. Patient satisfaction and symptoms were evaluated after 4 and 8 weeks. Patients not satisfied after 8 weeks were treated for another 4 weeks with omeprazole 40 mg MUPS (open). Successful treatment was followed by 3 months' maintenance treatment with omeprazole MUPS 20 mg (patients satisfied after 4 or 8 weeks) or omeprazole MUPS 40 mg (patients satisfied after 12 weeks). RESULTS: On intention-to-treat (ITT) analysis (n = 461) at 4 and 8 weeks, respectively, 84% and 87% (omeprazole MUPS), 78% and 81% (lansoprazole), and 84% and 89% (pantoprazole) were free of heartburn. Equivalence was found between omeprazole MUPS and pantoprazole (heartburn relief), but not with lansoprazole. Patient satisfaction after 4 and 8 weeks, respectively, was 79% and 89% (omeprazole MUPS), 76% and 86% (lansoprazole), and 79% and 91% (pantoprazole). Patient satisfaction was similar in all treatment groups. During maintenance, 87% in the omeprazole MUPS 20 mg group and 81% in the omeprazole MUPS 40 mg group were satisfied after 3 months. CONCLUSIONS: Omeprazole MUPS 20 mg and pantoprazole 40 mg have equivalent efficacy in the treatment of reflux oesophagitis. Based on patient satisfaction, omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg are equally effective.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2001

Deacylation of the transmembrane domains of Sindbis virus envelope glycoproteins E1 and E2 does not affect low-pH-induced viral membrane fusion activity.

The envelope glycoproteins E1 and E2 of Sindbis virus are palmitoylated at cysteine residues within their transmembrane domains (E1 at position 430, and E2 at positions 388 and 390). Here, we investigated the in vitro membrane fusion activity of Sindbis virus variants (derived from the Toto 1101 infectious clone), in which the E1 C430 and/or E2 C388/390 residues had been substituted for alanines. Both the E1 and E2 mutant viruses, as well as a triple mutant virus, fused with liposomes in a strictly low-pH-dependent manner, the fusion characteristics being indistinguishable from those of the parent Toto 1101 virus. These results demonstrate that acylation of the transmembrane domain of Sindbis virus E1 and E2 is not required for expression of viral membrane fusion activity.

Acylation↗

PubMed2001

PE2 cleavage mutants of Sindbis virus: correlation between viral infectivity and pH-dependent membrane fusion activation of the spike heterodimer.

The spike glycoprotein E2 of Sindbis virus (SIN) is synthesized in the infected cell as a PE2 precursor protein, which matures through cleavage by a cellular furin-like protease. Previous work has shown that SIN mutants impaired in PE2 cleavage are noninfectious on BHK-21 cells, the block in infection being localized at a step after virus-receptor interaction but prior to RNA replication. Here, we studied the membrane fusion properties of SIN PE2 cleavage mutants and observed that these viruses are impaired in their ability to form an E1 homotrimer and to fuse with liposomes at a mildly acidic pH. The block in spike rearrangement and fusion could be overridden by exposure of the mutant viruses to very low pH (<4.5). Cleavage mutants with second-site resuscitating mutations in PE2 were highly infectious for BHK-21 cells. The ability of these viruses to form E1 homotrimers and to fuse at a mildly acidic pH was completely restored despite a sustained lack of PE2 cleavage.

Animals↗

PubMed1999

Low-pH-dependent fusion of Sindbis virus with receptor-free cholesterol- and sphingolipid-containing liposomes.

There is controversy as to whether the cell entry mechanism of Sindbis virus (SIN) involves direct fusion of the viral envelope with the plasma membrane at neutral pH or uptake by receptor-mediated endocytosis and subsequent low-pH-induced fusion from within acidic endosomes. Here, we studied the membrane fusion activity of SIN in a liposomal model system. Fusion was followed fluorometrically by monitoring the dilution of pyrene-labeled lipids from biosynthetically labeled virus into unlabeled liposomes or from labeled liposomes into unlabeled virus. Fusion was also assessed on the basis of degradation of the viral core protein by trypsin encapsulated in the liposomes. SIN fused efficiently with receptor-free liposomes, consisting of phospholipids and cholesterol, indicating that receptor interaction is not a mechanistic requirement for fusion of the virus. Fusion was optimal at pH 5.0, with a threshold at pH 6.0, and undetectable at neutral pH, supporting a cell entry mechanism of SIN involving fusion from within acidic endosomes. Under optimal conditions, 60 to 85% of the virus fused, depending on the assay used, corresponding to all of the virus bound to the liposomes as assessed in a direct binding assay. Preincubation of the virus alone at pH 5.0 resulted in a rapid loss of fusion capacity. Fusion of SIN required the presence of both cholesterol and sphingolipid in the target liposomes, cholesterol being primarily involved in low-pH-induced virus-liposome binding and the sphingolipid catalyzing the fusion process itself. Under low-pH conditions, the E2/E1 heterodimeric envelope glycoprotein of the virus dissociated, with formation of a trypsin-resistant E1 homotrimer, which kinetically preceded the fusion reaction, thus suggesting that the E1 trimer represents the fusion-active conformation of the viral spike.

Animals↗

PubMed1992

Steady-state pharmacokinetics and sputum penetration of lomefloxacin in patients with chronic obstructive pulmonary disease and acute respiratory tract infections.

Oral doses of 400 mg of lomefloxacin were administered once daily prior to breakfast to 10 middle-aged to elderly hospitalized patients with chronic obstructive pulmonary disease during treatment for bronchopulmonary infections. Serial plasma and sputum samples and fractional urine samples were obtained over a steady-state dosing interval. Lomefloxacin concentrations were determined in duplicate by a validated agar well diffusion microbiological assay. The maximum plasma lomefloxacin concentration (4.5 +/- 1.8 mg/liter), the time of occurrence of the maximum concentration (1.7 +/- 1.6 h), and the apparent volume of distribution associated with the terminal phase (2.19 +/- 1.05 liter/kg) were comparable to the values reported for healthy, young volunteers. Compared with the data reported for young adults, the elimination half-life (12.7 +/- 4.67 h) was longer and the apparent total body clearance (132 +/- 36.6 ml/min/1.73 m2) was lower in middle-aged to elderly patients. These differences were most likely attributable to age-related decreases in renal function, as evidenced by the lower lomefloxacin renal clearance (70.3 +/- 33.5 ml/min) in patients. The presence of acute respiratory infection per se did not appear to alter lomefloxacin pharmacokinetics. The peak lomefloxacin concentration in purulent, expectorated sputum samples of 4.3 +/- 1.2 mg/liter occurred 3.1 +/- 1.7 h after dose administration and subsequently declined to 1.7 +/- 0.5 mg/liter at the end of the 24-h dosing interval. The percent penetration into sputum, as assessed by comparing the area under the curve for sputum and plasma samples, was 120 +/- 39.8 (range, 70 to 185). The steady-state lomefloxacin concentrations in plasma and sputum samples from ill, older patients were in excess of the MICs for 90% of the strains tested of common, susceptible respiratory pathogens over most of the dosing interval.

Aged↗

PubMed1992

A quasi steady state ramp method for the estimation of the ventilatory response to CO2.

There are two suitable methods for estimating the ventilatory response to CO2: the steady state or the Read method. The latter is usually applied because of its shorter duration and its stimulus, near to tissue PCO2. From recent studies on a physiological model but also on the dynamics of the ventilatory CO2 response (G liters min-1 kPa-1), it can be shown, both theoretically and experimentally, that the Read method markedly overestimates the steady-state estimate of the ventilatory CO2 response (Gss). We have, therefore, applied two ramp approaches: one with an initial end-tidal PCO2 (PetCO2) step of 0.5 kPa and a mean PetCO2 ramp slope of 0.41 kPa/min (step-ramp method, SR) and one without an initial step and a mean ramp slope of 0.21 kPa/min (ramp method; R). As predicted by theory, the ventilatory CO2 response from the R method (GR) during the second 4-min interval of the 8-min procedure and the ventilatory CO2 response from the SR method (GSR) from the whole 6-min procedure, except for the first 30 s, should yield a good approximation of Gss. In a group of 12 normal volunteers we indeed found no differences between these estimates, and, as predicted by theory, we found both estimates to be larger than GR from the first 4-min interval. From the interindividual spread, only the difference with respect to GSR was significant (p less than 0.02). The volunteers preferred the R approach because of the lower PetCO2 attained and the smaller ventilation increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Gastrointestinal toxicity of chemotherapy and the influence of hyperalimentation.

The effect of combination chemotherapy on human small intestinal morphology and disaccharidase activities and their relation with clinical and chemical (fecal wet weight and K-excretion) parameters for gastrointestinal toxicity were evaluated in patients with disseminated malignant melanoma receiving enteral normoalimentation (NA). Also evaluated were the supposed protective effects on gastrointestinal toxicity of enteral hyperalimentation (HA) with an elemental diet. After chemotherapy, a comparable decrease in villus height, total mucosal height, and mitotic index was found in jejunal biopsy specimens of both groups. However, in the NA group, the crypt depth decreased (in contrast to the HA group), whereas the disaccharidase activities in the HA group deteriorated to lower values than in the NA group. The authors found no correlation between disaccharidase levels and mucosal morphology, nor was there a correlation between these variables, fecal parameters and clinical diarrhea, suggesting that diarrhea occurring after chemotherapy was not due to loss of mucosal tissue or decrease in enzyme activities. A protective effect of HA with an elemental diet on gastrointestinal toxicity could not be established.

Adult↗

PubMed1986

Evaluation of gastrointestinal toxicity following cytostatic chemotherapy.

A number of clinical and chemical parameters related to the gastrointestinal tract in patients treated with intensive chemotherapy for disseminated malignant melanoma were evaluated in order to find quantitative indicators for gastrointestinal toxicity and to investigate the cause of diarrhea after chemotherapy. In 11 patients 17 courses of polychemotherapy with bleomycin, DTIC, vindesine, and actinomycin D were administered, while the patients received complete liquid enteral nutrition. As clinical parameters for toxicity the diarrhea grading system according to the WHO criteria and the daily fecal consistency were used. Furthermore, in the feces Na+, K+, and Cl- (mmol/24 h), Na+/K+ ratio, dry and wet weight (g/24 h), lactate and bile acids (mmol/24 h), fat (g/24 h), pH, and osmolarity were determined. Both clinical parameters were closely correlated. The most important effects of the chemotherapy on the chemical parameters were an increased fecal fluid, K+, and fat excretion. The fecal wet weight and K+ excretion showed a high correlation with the two clinical parameters for gastrointestinal toxicity. We conclude that mucosal injury resulting from chemotherapy probably leads to increased small intestinal fluid and electrolyte secretion inducing diarrhea and that fecal wet weight and K+ excretion are probably the best quantitative indicators for gastrointestincal toxicity.

Adult↗

PubMed1986

Phase II study of bleomycin, actinomycin D, DTIC and vindesine in disseminated malignant melanoma.

Twenty-seven patients with disseminated malignant melanoma were treated with combination chemotherapy consisting of bleomycin, actinomycin D, DTIC and vindesine. There were 4 complete responses in patients with pulmonary metastasis, 5 patients had a partial remission, 2 of them had mainly lung lesions. Toxicity consisted mainly of leuco- and thrombocytopenia of short duration and sporadic severe mucositis.

Adult↗

PubMed1986

Eumelanin-related indolic compounds in the urine of treated melanoma patients.

A method was developed for the quantitation of six eumelanin-related indolic compounds in urine. The procedure employs methane ionization of the hexafluoroisopropyl and/or pentafluoropropionyl derivatives of 5,6-dihydroxyindole, 5-hydroxy-6-methoxyindole, 6-hydroxy-5-methoxyindole, 5-hydroxy-6-methoxyindolyl-2-carboxylic acid, 6-hydroxy-5-methoxyindolyl-2-carboxylic acid and 5,6-dimethoxyindolyl-2-carboxylic acid together with their deuterated analogues, and selected ion-monitoring. Deuterated analogues are added as internal standards to enzymatically hydrolysed urine before diethyl ether extraction. The method was used for monitoring urinary excretion in patients with malignant melanoma treated with cytostatics. In several cases, a decrease of the excretion of the eumelanin-related substances was recorded after the therapy. The usefulness of the individual indolic compounds for such follow-up studies is discussed.

Gas Chromatography-Mass Spectrometry↗

PubMed1985

Spermidine level as a parameter in the treatment of patients with malignant melanoma.

Before, during, and after 19 courses of chemotherapy given to patients with disseminated malignant melanoma plasma spermidine levels were determined with a radioimmunoassay. Baseline values were normal in 17 courses, a doubling of plasma levels following chemotherapy occurred in 13 courses. There was no relation between the occurrence of a tumor response and an increase in spermidine levels nor between hematological toxicity or digestive tract toxicity and spermidine levels.

Adult↗

PubMed1983

The effect of continuous enteral tube feeding on various nutritional parameters in patients with disseminated malignant melanoma during intensive chemotherapy.

In a prospective study the effect of continuous enteral tube feeding was evaluated on various nutritional parameters in patients with disseminated malignant melanoma during 13 chemotherapy courses employing bleomycin, DTIC, vindesine and actinomycin D. The patients received a quantity of calories according to their pretreatment intake, but complete metabolic equilibrium could not be obtained during chemotherapy. Although the weight/height index remained unchanged, a decrease of serum albumin and prealbumin level occurred during all 13 treatment courses. Transferrin level decreased during 11 of these courses and cholinesterase level during 12. Triceps skinfold thickness and arm muscle circumference diminished equally. Serum prealbumin was the first nutritional parameter to fall during chemotherapy and seems to be a very sensitive indicator of the occurrence of nutritional imbalance. The plasma vitamin C level was low before treatment while during treatment both vitamin C and vitamin A level fell quickly even though the nutritional intake of these vitamins was adequate. We conclude that continuous enteral tube feeding, which is a feasible method of feeding, can to some extent fulfill the nutritional needs of patients treated with intensive chemotherapy.

Journal Article↗

PubMed1983

Prognosis in severe chronic obstructive pulmonary disease with regard to the electrocardiogram.

A long-term prognostic study of 128 patients with severe chronic obstructive pulmonary disease (initial value for Forced Expiratory Volume in one second, [FEV1] less than or equal to 1,000 ml) with regard to electrocardiographic and lung function parameters as obtained at the entry visit is reported. Many initial ECG-variables and lung function parameters were significantly different between survivors and non-survivors after five years. We used a discriminant analysis to determine which factors actually provided independent information for detection of those subjects with a survival less than five years. In a discriminant analysis of the initial 25 ECG-variables only P-amplitude in lead II and S-amplitude in lead V6 were predictors of five-year survival (diagnostic accuracy 66.1%). In a discriminant analysis in which initial lung function variables were also considered next to the ECG-variables, the best prediction of five-year survival was made by P-amplitude in lead II, increase of FEV1 after thiazinamium i.m., and residual volume as percentage of total lung capacity [RV/TLC, %] (diagnostic accuracy 73.2%).

Adult↗