A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside.

OBJECTIVE: Warfarin and nonvitamin-K oral anticoagulants including dabigatran, rivaroxaban, and apixaban are commonly used in the prophylaxis and treatment of systemic embolism and deep vein thrombosis. In this study, we aimed to compare the cytotoxic effects of warfarin and new oral anticoagulants and to show a possible correlation between cell cytotoxicity and gastrointestinal side effects in the real-life setting. METHODS: L929 cells were incubated with test materials. At 24 and 48 hours, morphological changes and cell viability were evaluated. RESULTS: At 24 and 48 hours, dabigatran resulted in altered cell morphology in all dilutions, while rivaroxaban, apixaban, and warfarin showed similar morphology with the control group, except for dilution I. Dabigatran and warfarin at 24 hours and at 48 hours had a statistically significantly lower cell viability in all dilutions, compared to the control group. CONCLUSION: Gastrointestinal side effect profiles of these four agents in a real-life setting is consistent with the results obtained from the present study. There is no sole factor with the potential of explaining the entire gastrointestinal side effect profiles of anticoagulant agents. However, direct cytotoxic effects of anticoagulants should be considered primarily for gastrointestinal side effects in accordance with the results of present head-to-head cytotoxicity study (Tab. 5, Fig. 3, Ref. 28).

Effects of self-etching primers on vascular responses in rat carotid artery.

To investigate the effect of self-etching bonding systems on the control of pulpal haemorrhage in direct pulp exposures by observing the contraction of pulp blood vessels using the rat carotid artery model. Six dentine-bonding agents (Mac Bond, One-Up Bond F, Clearfil SE Bond, FL Bond, Prompt L-Pop and Prime and Bond NT) were used. The efficacy of bonding agents were compared with that of epinephrine for dose and the contraction forces (vasoconstriction) induced on the smooth muscle and the results recorded using a force displacement transducer. Dose-dependent relaxations caused by the test materials were recorded in the same manner in comparison with papaverine. FL Bond, SE Bond, One Up Bond, Mac Bond produced dose-dependent relaxations, while Prompt L-Pop and Prime&Bond NT produced epinephrine-like contractions on the rat carotid artery. For self-etching primers, which produce vascular relaxation, haemorrhage control with additional chemicals should be considered if direct pulp capping is to be performed using such adhesive systems.

Tramadol encapsulated into polyhydroxybutyrate microspheres: in vitro release and epidural analgesic effect in rats.

BACKGROUND: Controlled release techniques are used to increase the duration of action and decrease the toxicity of drugs. Any controlled release form of tramadol in spinal or epidural blocks has not been studied previously. Tramadol was encapsulated into polyhydroxybutyrate (PHB) microspheres and release kinetics was studied. The epidural analgesic effect of this solution in rats was also compared with free tramadol. METHODS: Controlled release of tramadol from PHB microspheres into 10 ml of phosphate buffer solution at pH 7.4 and 37 degrees C was studied in vitro. In vivo studies were performed in 40 rats. Epidural catheters were placed during general anaesthesia. Rats were randomly allocated into one of the four study groups to receive normal saline, 4 mg of tramadol, PHB microspheres without tramadol, or 4 mg of tramadol encapsulated into PHB microspheres. Analgesia was evaluated with tail flick tests performed at 52.5 +/- 0.5 degrees C before injection and at intervals up to 30 h after injection. Catalepsy and loss of corneal reflexes were considered as signs of supraspinal toxicity. RESULTS: In vitro drug release was observed for more than 6 days. Epidural analgesic effects of tramadol released from PHB microspheres were observed for 21 h, whereas an equal dose of free tramadol was effective for less than 5 h. No signs of toxicity were observed. CONCLUSION: Controlled release of tramadol from PHB microspheres is possible, and pain relief during epidural analgesia is prolonged by this drug formulation compared with free tramadol.

Neurotoxic effects of fifth-generation dentin adhesives on rat sciatic nerve.

This study evaluated the effect of the fifth-generation dentin adhesives, Single Bond (SB), Excite (EX), Prime & Bond NT (PB), and Optibond Solo (OS) on nerve conduction. Isolated rat sciatic nerves were placed between two suction electrodes in a bath containing tyrode solution. The bonding agents were brought into contact with the nerves and the evoked compound action potentials (cAPs) were recorded before and after contact with the materials. SB, EX, and PB caused total inhibition of the cAPs, with PB being the fastest (73 +/- 5.8 min). All cAPs except one in the PB group were irreversibly inhibited in the SB, EX, and PB groups. As for OS the reduction in cAP was not 50% after an application time of 200 min. Recovery of the cAPs in this group was recorded in an average time of 35 min.

Effect of a fifth-generation bonding agent on vascular responses in rats.

In the last years, several single-bottle dental adhesives have been developed. They are supposed to chemically adhere to dentin, and a liner to protect pulp is not thought to be necessary. In the case of direct pulp capping, hemorrhage control is an important step in success, but little is known about the effect of these new bonding agents on pulpal bleeding. The aim of this study was to evaluate the effect of a new one-step single-bottle adhesive on the smooth muscle contraction of rat uterine muscle and carotid arteries. Efficacy of the bonding agent was compared with that of epinephrine (control), and the contraction forces induced were recorded using a force displacement transducer. Statistical analysis of data revealed that the bonding material produced epinephrine-like concentration-dependent contractions of the smooth muscle, suggesting that one-step bonding agents may act as candidates for hemorrhage control without the use of an additional agent in direct pulp capping procedures.

Effect of different single-bottle dentin adhesives on vascular responses in rat carotid artery.

PURPOSE: To investigate the effect of one-bottle dentin bonding systems on pulpal hemorrhage control in direct pulp exposures through contraction of pulp blood vessels using the rat carotid artery model. MATERIALS AND METHODS: Four dentin bonding agents (Prime & Bond 2.1, Prime & Bond NT, Syntac Single Component and Single Bond) were used. The efficacy of bonding agents were compared to that of epinephrine (control) in the viewpoint of the concentration applied and the contraction forces induced on the smooth muscle were recorded using a force displacement transducer. RESULTS: Three of the test materials produced epinephrine-like contractions on the rat carotid artery (smooth muscle) while no reading could be achieved with Single Bond. A ranking between the bonding agents for contraction forces was obtained as follows: Prime & Bond NT > Prime & Bond 2.1 > Syntac Single Component (P < 0.05).

Three New Tazettine-Type Alkaloids from Galanthus gracilis and Galanthus plicatus Subsp. byzantinus.

Three new tazettine-type alkaloids were isolated from two different GALANTHUS species of Turkish origin. (+)-Isotazettinol and (+)-3- O-demethylmacronine are obtained from G. GRACILIS, while (+)-3- O-demethyl-3-epimacronine is found in G. PLICATUS subsp. BYZANTINUS. The known base, trispheridine, is reported for the first time in GALANTHUS genus.

In vivo degradation and release kinetics of chloramphenicol-loaded poly(D,L)-lactide sponges.

Poly(d,l)-lactide (PDLLA) homopolymer, with an average molecular weight of 20,000 daltons, was produced by the ring-opening polymerization of d,l-lactide in the presence of SnCl(2).2H(2)O as the catalyst. The PDLLA sponges loaded with chloramphenicol were prepared by a solvent evaporation technique. The drug loadings achieved were 14.84 and 25.23 mg for the PDLLA sponges with 35 and 70 mg total weights, respectively. These sponges were implanted in Wistar rats, and in vivo degradation, drug release, and tissue reactions were followed. The PDLLA sponges carrying no drug degraded with time linearly. Almost 80% of the sponges were degraded in about 180 days. While the drug-loaded PDLLA sponges were degraded much faster in 4 weeks (about 35% of the matrix was degraded), then the degradation slowed down significantly. Drug release from the sponges was parallel to the degradation. Almost 60% of the loaded drug released in 4 weeks. There were no acute inflammatory reactions in the initial period, either for the plain or for the drug-loaded PDLLA sponges. Macrophages and multinuclear giant cells start to appear after 7 days of implantation. The fibroblastic activity also started after the same period. After that, there were decreases in the number of some cells (neutrophils, lymphocytes, and macrophages), while multinuclear giant cells and fibroblastic activities gradually increased. Granulation tissue started at about 1 month, and new connective tissue was gradually formed until 180 days of implantation. There were significant numbers of inflammatory cells after 60 days, which were replaced by fibroblasts after 180 days. There was almost no significant neovascularization after 180 days, but implant fragmentation gradually increased (which slows the degradation) with time. It was concluded that this novel drug release sponge may be safely and effectively used as an active soft tissue-filling material.

Effect of encapsulation of chloramphenicol in albumin microspheres on its in vitro transfer across the human placenta.

The possibility of reducing drug transfer across the placenta was tested in two of our previous studies. The aim of those studies was to demonstrate an alternative method of drug application during pregnancy which we think would yield a dual benefit, i.e. protecting the foetus from the harmful effects of drugs while curing the mother. The present study was planned as a continuation of the testing of the same idea and we tried to see the effect of albumin microsphere encapsulation of chloramphenicol on its transfer across the human placenta in vitro. Microspheres containing chloramphenicol were prepared according to the method previously described. The mean per cent encapsulation of chloramphenicol in albumin microspheres was found to be 42 +/- 4.3 per cent (n = 5) and the mean size of the albumin microspheres was 3.08 +/- 0.6 mm. In vitro stability of the drug-carrying microspheres was measured by dialysing them at 37 degrees C for 24 h. Chloramphenicol was released from the microspheres gradually leaving about 50 per cent of the entrapped drug in the microspheres after 1.5 h. About 20 per cent of the chloramphenicol was retained in the microspheres at 24 h postincubation. The persistence of the antibacterial effect of the released chloramphenicol is confirmed by antibiogramme tests. In the perfusions the initial free drug concentration was kept at 100 mg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Decrease in the placental transfer of chloramphenicol when administered in albumin microspheres into rats.

Chloramphenicol is an antibiotic which can pass across the human placenta and has teratogenic effects in the foetus. When this antibiotic is entrapped in albumin microspheres and administered to pregnant rats intravenously its placental transport is significantly lowered when compared with that of free drug. Drug modifications such as entrapment are suggested as an alternative way to prevent harmful effects of drugs in case of consumption during pregnancy.