Comparison of physicochemical properties of suppositories containing starch hydrolysates.

The purpose of this work was to determine the effect of starch hydrolysates (SH) on the physicochemical properties of suppositories. The study was conducted with suppositories with acetaminophen (AAP) a typical antipyretic analgesic, as model drug on lipophilic (cocoa butter) and hydrophilic base (polyethylene glycol 1500 + 400). The suppositories with and without the addition of SH were examined for physicochemical tests according to European Pharmacopoeia 8th edition (Ph. Eur.): the uniformity of mass of single-dose preparation test, the softening time determination of lipophilic suppositories test, the disintegration of suppositories test, and dissolution test with flow-through apparatus. The results confirm the possibility of using starch hydrolysates as a cheap and safe addition to modify physicochemical properties of suppositories.

Assessment of physical properties of granules with paracetamol and caffeine.

Caffeine increases the analgesic properties of acetaminophen and therefore it is reasonable to use both substances together in one drug form in stronger pain. Currently, there are no commercially available pharmaceutical combination products containing acetaminophen and caffeine, which is present as granules. The aim of the study was to obtain twelve different granules with these therapeutic substances and determine the effect of various excipients on the quality of the drug form. All the granules were made by wet granulation. Two types of binders were used: polyethylene glycol 6000 (PEG) and polyvinylpyrrolidone K30 (PVP) as well as different types of fillers. The physical properties of granules were assessed in accordance to the requirements of the European Pharmacopoeia 8th ed. The highest apparent density was found in preparations containing calcium hydrophosphate (0.609 g/mL) and the lowest - containing mannitol (0.353 g/mL) as a filler. The Hausner ratio of most prepared granules ranged from 1.05 to 1.11, while the compressibility index ranged from 4.59 to 10.48%. The evaluation of properties of individual granules helped to indicate formulation with good features, which perhaps will be a good alternative to currently available painkillers with caffeine and acetaminophen.

EFFECT OF STARCH HYDROLYSATES IN THE PROCESS OF DISSOLUTION OF SOLIDS.

The purpose of this work was to investigate the influence of starch hydrolysates in the dissolution process of the substance practically insoluble in water. Progesterone and ibuprofen were chosen as model substances. The study was conducted with a constant amount of the drug (25 mg/mL) or constant amount of starch hydrolysate (50 mg/mL). Next, the influence of ethanolic solutions (10-30% v/v) on solubility of drug was tested. The results confirm the possibility of using starch hydrolysate as a cheap and safe addition to increase the solubility of practically insoluble drugs.

THE INFLUENCE OF EXCIPIENTS ON PHYSICAL PROPERTIES OF TABLETS AND DISSOLUTION OF CAFFEINE.

Caffeine is a common component of everyday diet but also a popular ingredient of some analgesics. Before it is administered to a patient, it has to be properly prepared using appropriate procedures to get the suitable drug form with various excipients. The tablets with caffeine were obtained using a wet granulation method. Three groups with four series of tablets were obtained with the constant concentration of caffeine but with different combinations of excipients, including potato starch and lactose, microcrystalline cellulose and lactose and D-mannitol alone. The binder solution of polyvinylpyrrolidone was added in all series of granules used in tabletting but in different quantities. A number of pharmacopoeial tests were conducted to determine the properties of the obtained tablets. All series of tablets positively passed physical tests. More than 80% of caffeine dissolved after 45 min from most series. Only two of 12 series of tablets did not meet pharmacopoeial requirements in a dissolution test. The results of the study indicated that proposed compositions of the tablets are suitable for administration of caffeine in that drug form.

[Erythrocytes - the new application in medicine]. / Erytrocyty - nowe zastosowanie w medycynie.

The new forms of drugs with better proprieties from traditional ones were sought for a long time. Erythrocytes applied as carriers of therapeutic substances are among promising. They are characterized by slower release of active substances, less toxicity, as well as better biocompatibility and biodegradation in the organism. It is especially important in administration of drugs with numerous side effects in therapy of chronic diseases e.g. malignancies. Investigations conducted from over twenty years showed, that erythrocytes are universal carriers in which different therapeutic substances were successfully closed, e.g. cytostatics, antibiotics, hormones and vitamins, as well as enzymes and vaccines. Some of the erythrocyte drug delivery systems are now studied at the clinical level, e.g. dexamthasone 21-phosphate in treatment of inflammatory bowel disease and chronic obstructive pulmonary disease. This substance encapsulated in human erythrocytes was also officially registered by European Medicines Agency, as the orphan drug in treatment of cystic fibrosis: Reports on application of carrier erythrocytes in patients with rare genetic diseases have also appeared.

[Cardiovascular complications of phosphodiesterase-5 inhibitors]. / Powiklania sercowo-naczyniowe inhibitorów fosfodiesterazy-5.

Phosphodiesterase type 5 inhibitors increase the intracellular level of cyclic guanosine monophosphate that is a potent nitric oxide dependent vasodilatation and antiproliferation agent. Unlike vardenafil and tadalafil which are prescribed in the erectile dysfunction, sildenafil is also used in a treatment of the pulmonary arterial hypertension, both congenital and acquired. The drug administration may let to various side effects such epistaxis, headache, flushing, eye problem including blurry vision, retinal hemorrhage and nonarteritic anterior ischemic optic neuropathy. It may be also complicated by high reduction of blood pressure and syncope especially in patients concomitantly treated with oral nitrate medications. High caution should be also taken in patients with a heart failure.

Influence of size and density of particles on flow properties of granules.

The patent apparatus for measurement of pouring of powders and granules, as well as enlarged version of apparatus for measurement of angle of repose were applied for examination of granules and their mixtures. Straightlinear association of flow time with diameter of particles of the fraction was revealed. The relation was described with linear equations. Changes of the angle's value of their mixtures were influenced by variation of the apparent density of granule, as well. The patent apparatus and their modification are suitable devices for investigation of the angle of repose and the flow time of granules.

[Genetic base of esophageal squamous cell carcinoma susceptibility]. / Genetyczne podloze podatnosci na raka plaskonablonkowego przelyku.

The esophageal squamous cell carcinoma is multifactorial disease involving genetic and environmental factors. The paper presents most important human data on the polymorphisms of selected genes that have been linked with higher risk of the neoplasm. The most widely studied group were genes encoded molecules engaged in biotransformations of xenobiotics, in particular potential carcinogens, like alcohol (ADH2) and aldehyde (ALDH2) dehydrogenases, various isoenzymes of cytochrome P450 (CYP1A1, CYP2E1) and glutathione S-transferase (GSTM1, GSTT1, GSTP1). High interest was also put for polymorphism in DNA repair genes, i.e., OGG1, XRCC1, XPD, XPG and MGMT as well as genes associated with nucleotide biosyntesis like methylenotetrahydrofolate reductase and thymidylate synthase and in control of cell cycle and apoptosis e.g., p53, Fas, FasL or TNF. Furthermore, it was revealed that predisposition to cancer in certain individual could be determined by coexistence of unprofitable allele of a few genes. Introduction of genetic screening test allows effective, purpose-oriented methods of prevention and in patients suffered from the cancer--application of optimal therapy and minimization of side-effects.

[Cyclooxygenase inhibitors in chemoprevention and treatment of esophageal squamous cell carcinoma]. / Inhibitory cyklooksygenazy w chemoprewencji i leczeniu raka plaskonablonkowego przelyku.

Cyclooxygenase inhibitors (COX) are a complex group of pharmacological compounds characterized by significant efficacy in chemoprevention of epithelial origin tumors, especially colorectal ones. It was found that inducible isoform of COX - COX-2 plays an important role in cancer growth and dissemination, e.g., by increase of cellular proliferation, reduction of apoptosis, promotion of local invasiveness and angiogenesis. COX inhibitors decrease prostaglandins' synthesis, but COX-independent mechanisms of their preventive and therapeutical activity were also proven. The influence of COX inhibitors on growth of esophageal squamous cell carcinoma and its precursor lesions was not completely clear. Most studies based on human cancer cell lines revealed antiproliferative and proapoptotic ability of both nonselective (previously called non-steroidal antiinflammatory drugs--NSAIDs) and selective COX-2 inhibitors (coxibs). In in vivo studies performed on animals exposed to chemical carcinogens, the chemopreventive effect was achieved exclusively after administration of experimental selective COX-2 inhibitors, but in the only human trial, supplementation of selective COX-2 inhibitor--celecoxib turned out ineffective. However, many epidemiological data proved effect of prolonged administration of nonselective COX inhibitors, especially acetylsalicylic acid on decreased risk of esophageal squamous cell carcinoma. Few reports concerning application of selective COX-2 inhibitors in patients with invasive squamous cell carcinoma are insufficient for ultimate evaluation of this method of therapy.

[Coffee and caffeine - enemies or alliantes of a cardiologist?]. / Kawa i kofeina ­ wrogowie czy sprzymierzency kardiologa?

Caffeine is a widespread known psychoactive substance that is present mainly in coffee, tea, soft and energy drinks. As a natural methylopxanthine it blocks A1 and A2 adenosine receptors and in high doses inhibits the phosphodiesterase activity. Caffeine also decreases calcium ion accumulation in the mitochondria of cardiomyocytes. A clinical and experimental data indicates that the caffeine and coffee increase the arterial wall stiffness, blood pressure and endothelium-dependent flow mediated dilatation. Caffeine also elevates cholesterol and homocysteine blood level. Moderate coffee consumption decreases the mortality of the cardiac infarct. However, acceleration of acute ischemic cardiac disease correlates with high coffee intake. The metyloxantine easily crosses the blood-placenta barrier, and may induce intrauterine growth retardation. Due to chronotropic and inotropic activity it may induce fetal tachycardia and/or extrasystolic beats.

NMDA and AMPA receptors are involved in the antidepressant-like activity of tianeptine in the forced swim test in mice.

It is known that tianeptine exhibits antidepressant-like activity. Its influence on the glutamatergic system is also known, but the mechanisms involved in this activity remain to be established. The aim of this study was to investigate the involvement of the glutamate pathway in the antidepressant-like action of tianeptine. We investigated the effects of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor ligands on tianeptine-induced activity in the forced swim test (FST) in mice. The antidepressant-like activity of tianeptine (30 m/kg, ip) was significantly antagonized by D-serine (100 nmol/mouse icv) and NBQX (10 mg/kg, ip). Moreover, low, ineffective doses of the glycine/NMDA site antagonist L-701,324 (1 mg/kg, ip) administered together with low, ineffective doses of tianeptine (20 mg/kg, ip) exhibited a significant reduction of immobility time in the FST. These doses of the examined agents, which did have an effect in the FST, did not alter locomotor activity. The present study indicates that the antidepressant-like activity of tianeptine in the FST involves both NMDA and AMPA receptors and suggests that the interaction between serotonergic and glutamatergic transmission may play an important role in the action of tianeptine.

Unusual interleukin-1 and -6 expression in fetal cartilage is associated with placental abnormalities.

Unusual expression of interleukin-1alpha, -1beta and -6 was previously found in the epiphyseal cartilage of rat fetuses prenatally exposed to various non-steroidal anti-inflammatory drugs (NSAID, i.e., ibuprofen, piroxicam, tolmetin) and selective cyclooxygenase-2 inhibitor (DFU). The aim of the present study was to evaluate the role of placenta in such phenomenon. Morphology of the organ, thickness of basal and labyrinth layer, immunoexpression of COX isoenzymes were examined, and confronted with maternal biochemical data and fetal developmental parameters. Higher maternal urea level, as well as lower placental weight and labyrinth thickness were found in the group of fetuses who revealed expression of genes coded the selected interleukins, when compared with the xenobiotic-exposed pups without the selected genes expression and untreated control. A significant correlation between placental weight and maternal total protein or urea level was revealed. Histological changes like inflammatory infiltration and calcification were observed sporadically. Location and intensity of COX-1 staining was similar in all cases. However, more intense COX-2 staining for majority of cells of the basal zone and in dispersed giant cells of the labyrinth was found in inflamed organs. It could be concluded that abnormal expression of the selected interleukins is associated with low placental weight and decrease of its thickness, especially labyrinth zone, as well as with high maternal urea level.

Morphology and physiology of the epiphyseal growth plate.

The epiphyseal growth plate develops from the cartilaginous-orientated mesenchymal cells that express SOX family genes. This multilayer structure is formed by the proliferation and hypertrophy of cells that synthesize the extracellular matrix composed of collagen (mainly type II, IX, X, XI) and proteoglycans (aggrecan, decorin, annexin II, V and VI). The resting zone is responsible for protein synthesis and maintaining a germinal structure. In the proliferative zone, cells rapidly duplicate. The subsequent morphological changes take place in the transformation zone, divided into the upper and lower hypertrophic layers. In the degenerative zone, the mineralization process becomes intensive due to increased release of alkaline phosphate, calcium and matrix vesicles by terminally differentiated chondrocytes and some other factors e.g., metaphyseal ingrowth vessels. At this level, as well as in the primary and secondary spongiosa zones, chondrocytes undergo apoptosis and are physiologically eliminated. Unlike adult cartilage, in fetal and early formed growth plates, unusual forms such as authophagal bodies, paralysis and dark chondrocytes were also observed. Their ultrastructure differs greatly from apoptotic and normal cartilage cells. Chondrocyte proliferation and differentiation are regulated by various endocrine, paracrine, and autocrine agents such as growth, thyroid and sex hormones, beta-catenin, bone morphogenetic proteins, insulin-like growth factor, iodothyronine deiodinase, leptin, nitric oxide, transforming growth factor beta and vitamin D metabolites. However, the most significant factor is parathyroid hormone-related protein (PTHrP) which is synthesized in the perichondrium by terminally differentiated chondrocytes. Secondary to activation of PTH/PTHrP receptors, PTHrP stimulates cell proliferation by G protein activation and delays their transformation into prehypertrophic and hypertrophic chondrocytes. When proliferation is completed, chondrocytes release Indian hedgehog (Ihh), which stimulates PTHrP synthesis via a feedback loop. Any disturbances of the epiphyseal development and its physiology result in various skeletal abnormalities known as dysplasia.