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Biomedical subjects

J Splawinski

Publications and source records attributed to J Splawinski.

15 recordsLinked to original sources
PubMed2006

Evaluation of drug toxicity in clinical trials.

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding pre-approval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding the difference in efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected "unimportant" number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease -- and treatment -- specific. The modification of clinical trials according to the proposed changes may increase the trials' sensitivity at detecting adverse effects of drugs.

Clinical Trials as Topic↗
PubMed2005

Bioequivalence of two preparations of ticlopidine evaluated using a pharmacodynamic end point.

OBJECTIVE: To evaluate the bio-equivalence of 2 ticlopidine preparations, 250 mg Iclopid tablets (Pabianickie Zaklady Farmaceutyczne, Polfa, Poland; test formulation) and 250 mg Ticlid tablets (Sanofi, France; reference formulation) using a pharmacodynamic end point, i.e the platelet aggregation test ex vivo. SUBJECTS, MATERIALS AND METHODS: The study was open, randomized, multiple-dose, two-period, crossover with a four-week washout interval. Volunteers were screened for sensitivity towards the platelet aggregation (ex vivo) effect of ADP (30 micromol/l) and sensitivity to the antiplatelet activity of ticlopidine (250 mg daily, for 3 consecutive days). Only those responding to 30 micromol/l of ADP with aggregation in the range of 40 - 75% of control (0.9% NaCI), and those responding to ticlopidine within 40 - 75% of inhibition of platelet aggregation to ADP ex vivo were randomized to the study. The dose of ticlopidine in each phase was 250 mg daily for four days. Blood samples were taken on Day 0 and Days 2, 4 (last day of ticlopidine administration), 5, 6, 9, 11 and 16 in order to follow platelet recovery. The pharmacodynamic parameter measured was expressed as the percentage inhibition of ex vivo platelet aggregation calculated from the number of platelets in the sample of whole blood remaining after ADP (30 micromol/l) compared to the control sample. The following values were calculated: area under the inhibition curve of platelet aggregation (AUC(inh 1-16)), maximal inhibition of platelet aggregation (Max(inh)) and time at which maximal inhibition of aggregation occurred (T(max inh)). RESULTS: The ratios (90% confidence intervals) of Iclopid/Ticlid for AUC(inh 1-16), Max(inh), and T(max inh) were: 1.008 (0.973 - 1.044), 1.009 (0.991 - 1.028) and 1.015 (0.988 - 1.043), respectively, satisfying the bioequivalence criteria. CONCLUSIONS: The test and the reference products are bioequivalent on the basis of the ex vivo platelet aggregation test. Our study has shown that the bioequivalence of two different preparations can be assessed by measuring a pharmacodynamic end point in a suitably selected group of subjects.

Adult↗
PubMed1996

The efficacy and potency of antiplatelet activity of ticlopidine is increased by aspirin.

Concomitant therapy with ticlopidine (T) and aspirin (ASA) profoundly increases spectrum of antiplatelet activities of both drugs. It was hypothesized that in addition to increased spectrum of activity (efficacy) each drug may potentiate the specific antiplatelet activity (potency) of the other. In 32 volunteers whole blood platelet aggregation (PA) in response to ADP, collagen, and arachidonic acid was evaluated ex vivo following 10-day treatments with normal or subthreshold doses of T or ASA with addition of second drug on the 5th day of administration of the first. PA was measured before, on day 5 and 10 of treatment. The results indicate that ASA increased spectrum of activity of T, i.e. T and ASA in combination, were significantly more effective against collagen-induced PA than either drug alone. This increased efficacy was retained when subthreshold dose of T (100 mg, qd) was used. T was without effect on AA-induced and ASA on ADP-induced PA. However, ASA potentiated effect of T on ADP-induced PA; the subthreshold dose of T (100 mg, qd) in presence of ASA (100 mg, qd) exerted powerful inhibition. Thus, combination therapy increases both efficacy and potency of T allowing for reduction of the dose.

Adenosine Diphosphate↗
PubMed1996

Pharmacodynamics of ticlopidine: relation between dose and time of administration to platelet inhibition.

In spite of long clinical experience with ticlopidine (T) knowledge of its pharmacodynamics is limited. In this study relation between dose and time of administration of T to platelet inhibition was investigated in 62 healthy volunteers ex vivo in whole blood and platelet rich plasma. Gender-related sensitivity of platelets to ticlopidine was also evaluated. Inhibition of ADP-induced platelet aggregation by T, 500 mg, daily, was almost identical in both sexes. 100 mg daily did not inhibit ADP-induced platelet aggregation even after 14 days of administration. 250 mg daily induced strong inhibition on day 5 of administration comparable to the inhibition obtained with 500 mg daily dose. The antiplatelet (ADP) effect of T (500 mg, daily) was present on day 2-3 and full inhibitory effect on day 4 of administration. T1/2 of antiplatelet (ADP) activity of T was 5.3 days and full recovery of platelets activity 11-13 days. No rebound phenomenon was present. T (regardless the dose) inhibited platelet aggregation induced by small but not high concentrations of collagen and was without effect on arachidonic acid-induced platelet aggregation. Therefore, T is not suitable for treatment of acute event, 250 mg daily dose should be used especially for combination with other drugs and 11 days washout interval seems necessary to change the treatment or to perform surgery.

Adenosine Diphosphate↗
PubMed1992

Reproducibility of isoproterenol tilt-table tests in patients with syncope.

To assess the reproducibility of head-up tilt-table testing 46 patients each underwent 2 isoproterenol tilt-table tests 1 to 6 weeks apart. Of 20 patients with an initially asymptomatic negative test result, 17 (85%) had a second negative test result. Of 20 patients whose initial test ended in syncope, 18 had a second test ending in syncope (n = 12) or presyncope (n = 6). Five of 6 patients whose first test ended in presyncope had a second test that ended in presyncope, and 1 had a second test that was asymptomatic. Finally, a total of 14 patients had at least 1 test (either the first or second) ending in presyncope, and 11 of these (79%) had another test ending in presyncope or syncope. The dose-dependence of isoproterenol was irreproducible. The reproducibility of the duration of head-up tilt necessary to elicit symptoms of presyncope or syncope was determined in the 23 patients who had these symptoms on both tests. Symptoms developed monoexponentially with duration of head-up tilt with half-times of 1.4 to 2.6 minutes, but these times did not correlate significantly between tests. In a selected subgroup of 12 patients who developed syncope in the first test and either presyncope or syncope in the second test during administration of isoproterenol (5 micrograms/min), the time of onset of presyncope correlated well (r = 0.73, p = 0.007) as did that of syncope (r = 0.86, p = 0.012). Finally, hemodynamic changes during symptoms were compared between the 2 tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Angiogenic activity and neovascularization in adenocarcinoma of endometrium.

Angiogenic activity of adenocarcinoma of endometrium was evaluated by qualitative and quantitative assays that measure vessel growth in chorioallantoic membrane (CAM) of chick embryo and incorporation of [3H] thymidine to DNA of CAM, respectively. In addition, histological specimens of adenocarcinoma with the vascular system filled with contrasting medium, were examined for the presence of neovascularization. Both qualitative and quantitative assays on CAM indicated that adenocarcinoma of endometrium possessed angiogenic activity. Histological analysis suggested that neovascularization took place during development of adenocarcinoma. It is therefore possible that neovascularization in this tumor is stimulated by its angiogenic activity.

Adenocarcinoma↗
PubMed1988

Angiogenesis: quantitative assessment by the chick chorioallantoic membrane assay.

The aim of the present work was to improve quantitative assessment of angiogenesis by chick chorioallantoic membrane (CAM) assay based on measurement of DNA synthesis. Following incubation of [3H]thymidine (3H-T) with CAM in vivo, incorporation of 3H-T to DNA fraction was expressed as percent of total 3H-T present in the initial homogenate of CAM, regardless of CAM weight and full recovery of applied radioactivity. The assay required simple, partial isolation of DNA to remove traces of free or unspecifically bound 3H-T. These modifications gave a reproducible assay with adequate precision (10-20%). DNA content of CAM did not change between 10-15 days of embryo development and growth of CAM was completed on day 11. 10 to 12-day old CAMs were used for evaluation of the assay. Using a qualitative approach (visual scoring), tissues of several tumors were implanted on CAM. Extracts of tumors that produced the highest score stimulated DNA synthesis in CAM. A similar effect was induced by EGF while cytostatics inhibited DNA synthesis in CAM. Since stimulation of angiogenesis is not a cell type-specific phenomenon, the assay in the present modification should aid the studies on angiogenic factors. With the help of this assay the angiogenic activity of adenocarcinoma of human endometrium was described.

Allantois↗
PubMed1987

Effects of inhibition of thromboxane A2 synthesis in aspirin-induced asthma.

Since inhibition of cyclooxygenase precipitates asthmatic attacks in patients with aspirin idiosyncrasy, we have evaluated the effects of pharmacologic inhibition of thromboxane A2 (TXA2) synthetase, next to cyclooxygenase enzyme in arachidonic acid cascade. Sixteen patients with aspirin-induced asthma received increasing doses on 3 days (25 to 400 mg) of an imidazole derivative, OKY-046, which specifically blocks TXA2 synthetase. Twenty-three healthy control subjects received a single dose of 400 mg of OKY-046. In both patients and control subjects, the inhibitor at a dose of 400 mg produced (1) a pronounced fall in thromboxane B2 serum levels, (2) a rise in serum 6-keto-prostaglandin F1 alpha, and (3) a depression in platelet aggregability to arachidonic acid and adenosine diphosphate. The drug, however, neither precipitated attacks of asthma nor impaired pulmonary function tests throughout a 24-hour observation period. Five patients, but none of the control subjects, developed transient nasal congestion about 1 hour after taking the drug. Thus, inhibition of TXA2 synthetase, contrary to inhibition of cyclooxygenase, does not affect bronchopulmonary function in patients with asthma and aspirin intolerance.

Acrylates↗
PubMed1984

Anti-aggregatory activity of PGI2 in whole blood measured by platelet counter.

Anti-aggregatory effect of PGI2 was evaluated by two methods. First, by measurement of the number of free platelets in a sample of whole citrated blood after addition of ADP, and second, by monitoring changes in light transmission induced by ADP in platelet-rich plasma. Platelet aggregation in response to ADP, as assessed by the first method, was dose-dependent, reproducible, and stable during 10-60 min storage of blood samples. EC50's for ADP were (microM): 0.7 (first method) and 2.9 (second method). IC50's for anti-aggregatory effect of PGI2-tested with 1 microM of ADP were (nM): 0.48 (first method) and 2.32 (second method), the difference suggesting higher sensitivity of the first method. Measurement by the first methods can be performed 1 min after blood collection. It is concluded that evaluation of the anti-aggregatory effect of PGI2 by monitoring the free platelet number in ADP-treated whole blood is more sensitive than the conventional turbidimetric technique since it allows detection of blood PGI2 levels more than 100 times smaller than the turbidimetric method and seems suitable for monitoring PGI2 therapy in clinical studies.

Adult↗
PubMed1983

Fenflumizole: interactions with the arachidonic acid cascade.

Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new non-steroidal anti-inflammatory agent, was investigated for interference with cyclo-oxygenase activity in vivo, ex vivo and in vitro in comparison with indomethacin (and aspirin). Fenflumizole was comparable to indomethacin ex vivo in inhibition of thromboxane (TX)A2 production in rabbit platelets and inhibition of prostaglandin (PG)I2 (approximately prostacyclin) generation in rabbit mesenteric arteries and in vivo as an inhibitor of PGE2 formation in inflammatory exudates in rats. Fenflumizole was 18 times less active than indomethacin in inhibition of PGE2 synthesis in vitro and 170 times weaker as an inhibitor of PGI2 generation in the rat stomach mucosa ex vivo. Fenflumizole was 20-50 times more potent than indomethacin in vivo in inhibition of arachidonic acid induced bronchoconstriction in guinea-pigs, in inhibition of platelet aggregation on tendons superfused with blood from rabbits and in vitro in inhibition of aggregation of human and rabbit platelets. Neither fenflumizole nor indomethacin inhibited TXA2-synthetase in vitro. Aspirin-when tested-was less potent than fenflumizole and indomethacin. It is concluded that fenflumizole is a potent cyclo-oxygenase inhibitor. The very potent activity of fenflumizole against platelet aggregation and bronchoconstriction suggests a selectivity in the mode of action. The weak inhibition of gastric PGI2 generation may account for the previously observed weak gastro-ulcerogenicity of fenflumizole.

Animals↗
PubMed1979

A new anti-inflammatory derivative of imidazole which is less ulcerogenic than indomethacin in rats.

The mechanism of the anti-inflammatory activity and ulcerogenicity of (2-dimethylamino-1(2)-methyl) ethyl ester of the 1-(2-carboxyethyl)-2-(p-chlorophenyl)-4,5-bis-(p-methoxyphenyl)-imidazole (A-162-ester) was compared with that of indomethacin in rats and enzymatic preparations derived from other species. A-162-ester was found to be deesterified in plasma to A-162. A-162-ester was about 3 times less anti-inflammatory and about 17 times less ulcerogenic than indomethacin. A-162-ester, when given orally, decreased prostaglandin I2 (PGI2) biosynthesis by gastric mucosa. The IC50 was close to the ulcerogenic ED50. Indomethacin--in the same test--was 37 times more potent than A-162-ester and the PGI2 inhibition and ulcerogenic dose-response curves for indomethacin were parallel. In other in vitro systems of prostaglandin (PG) biosynthesis, the inhibitory activity of A-162 was comparable to that of indomethacin. It is concluded that the ulcerogenicity of indomethacin results from a high affinity of this drug to gastric mucosal wall PG-synthetase which leads to decreased PGI3 formation at this site. The relatively low ulcerogenicity of A-162-ester most probable results from a lower affinity of this drug to the same site.

Animals↗
PubMed1979

Endogenous mechanisms which regulate prostacyclin release.

When infused intravenously into anaesthetized cats angiotensin II (1--4 micrograms/kg) released into the circulation an unstable substance that caused de-aggregation of platelet clumps, relaxed a strip of bovine coronary artery, and its release was blocked by aspirin and indomethacin. Because of these characteristics this substance is likely to be prostacyclin. Catecholamines and phenylephrine did not induce the release of prostacyclin. It is suggested that a chemical modification of the molecule of angiotensin II may render a peptide with little hypertensive properties which will be an activator of prostacyclin biosynthesis.

Angiotensin II↗
PubMedDate not supplied

Antiangiogenic effect of sulindac sulfide could be secondary to induction of apoptosis and cell cycle arrest.

BACKGROUND: The development of colon cancer is probably angiogenesis-dependent. Recently, sulindac sulfide was shown to possess anti-angiogenic activity. In the present work, the question of whether this activity reflects a specific interaction with angiogenesis or is secondary to the effect of sulindac sulfide on the survival of endothelial cells was addressed. MATERIALS AND METHODS: Endothelial and normal mouse fibroblast cell lines were incubated with non-steroidal anti-inflammatory drugs (NSAIDs), arachidonic acid (AA) and prostaglandin E2 (PGE2). Cell viability (survival), PGE2 synthesis, cell cycle and apoptosis were measured. Western blotting and semi-quantitative RT-PCR multiplex methods verified the changes in the levels of pro-apoptotic proteins and their expressions, respectively. RESULTS: Sulindac sulfide and celecoxib inhibited the survival of endothelial cells, whereas other NSAIDs were ineffective. In contrast to celecoxib, sulindac sulfide did not affect the survival of normal fibroblast cells. Both agents inhibited the production of PGE2 from AA and arrested the cell cycle in the S-phase. Moreover, sulindac sulfide activated caspases 3 and 8, decreased the levels of Bax and Bid proteins, caused cleavage of PARP and increased the expressions of the bax and caspase 3 genes. CONCLUSION: The results suggest that the anti-angiogenic activity of sulindac sulfide is secondary to the inhibition of endothelial cell survival resulting from cell cycle arrest and apoptosis.

Angiogenesis Inhibitors↗