Vaikų gydimo vaistais teisinio reglamentavimo aspektai.

The paper discusses the present-day practical and legal situation in children’s treatment with medicines, highlights the historical preconditions of treating children with drugs which have not been clinically tried by pediatric population are highlighted, and reviews the legal acts that regulate the development of medicines for children’s treatment. Most drugs being developed are only tried on adults before they are approved, both because of practical and technical difficulties in doing research on children as weIl as ethical considerations on inclusion of children in the trial of new drugs. Recently more attention has been drawn to the fact that pharmacotherapy in children does not have the same evidence-based platform as in adults: pediatricians are forced to prescribe medications off-label with uncertain efficacy and safety. In US, approximately 75% of all medications on the market do not have approved pediatric labeling. Children have been described as "therapeutic orphans" because of the deficit of appropriate studies in their age group. Many differences exist in physiology, pathology, pharmacokinetics, and pharmacodynamics between children of different age. The participation of minors in clinicaI triaIs is essential to provide a safe and effective treatment of children. In 1989, the United Nations General Assembly approved the Convention on the Rights of the Child. The prineipIe articulated in this convention is of fundamental importance: children have the right to the highest attainable level of health. Later on, detailed guidelines for clinicaI investigations of medicinaI products in the pediatrie population are provided by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), although encouraging efforts have been made to address these issues in the United States and later in Europe. In 1998, the American Food and Drug Administration established that studies in children should include in the development of new drugs. This was le gaIly formalized in the Best Pharmaceuticals for Children Act in 2002, which resulted in re-evaluation of severaI drugs primarily developed for adults but frequently used by children. In Europe, there is a strong commitment to establish cooperation between the pharmaceutical industry and pediatrie networks in order to increase and facilitate drug studies with children. The European Medieines Agency (EMEA) plays the central role in this work by developing lists of drugs for which pediatrie studies are needed and thus prevent unnecessary duplication. The European Regulation on medieines for pediatrie use entered into force on 26 January 2007. As a reward or incentive for conducting pediatric studies, companies will be entitled to extensions of patent protection and market exclusivity. The Regulation establishes the European network of pediatric clinicaI triaIs for off patent medicines. The Pediatric Committee at the EMEA will be responsible for the pediatric investigation plans (PIPs) of all medicines. The European pediatric clinicaI triaIs database, partly accessible to the public, will hold the details and the results of all pediatric triaIs conducted in line with these PIPs. The article also elucidates the legal requirements for pediatric clinicaI triaIs in Lithuania.Daugelis vaistų vaikams naudojami neatlikus klinikinių vaistinių preparatų tyrimų, o tai reiškia, jog gamintojai, o kartu ir gydytojai, skirdami vaisto dozes pagal vaiko amžių ir svorį, neturi reikalingų veiksmingumo bei saugumo duomenų, nežino, kokia tokio gydymo nepageidaujamo poveikio tikimybė. Vaisto skyrimo būdai ir vartojamo vaisto formos vaikams turi būti moksliškai pagrįsti, nes kitaip yra galimybė gydyti nepakankama vaisto doze ar vaistas gali būti perdozuotas. Straipsnio tikslas - apžvelgti istorines susiklosčiusios vaikų gydymo vaistais padėties prielaidas bei apibendrinti teisinį pediatrinių klinikinių vaistinių preparatų tyrimų reglamentavimą, kuriuo siekiama užtikrinti, jog vaikai būtų gydomi saugiais ir veiksmingais vaistais Jungtinės Amerikos Valstijose ir Europos Sąjungoje. Straipsnyje tai pat pateikiama ir Lietuvos Respublikos teisės aktų, kurie reglamentuoja vaikų klinikinių tyrimų atlikimą, apžvalga

Cisplatin increases urinary sodium excretion in rats: gender-related differences

Objective. There are well-documented reports of cisplatin-associated hyponatremia in the literature, but there are no data on gender-dependent differences. The aim of the present study was to define characteristics of 24-hour urinary sodium excretion in young adult Wistar rats of both genders and to evaluate the gender-related effect of cisplatin. Materials and methods. Twelve control Wistar rats (6 males and 6 females) and 12 cisplatintreated Wistar rats (6 males and 6 females) after a single and repeated injection of cisplatin (once a day for 3 days) at a dose of 2.5 mg/kg body weight into the caudal vein were examined. The experiment was carried out by measuring 24-h urinary sodium, potassium, chloride, magnesium, creatinine excretion and pH in the urine of age-matched male and female rats. Results. The 24-h urinary sodium excretion, sodium/chloride ratio, and diuresis showed no gender-related differences in control rats. After a single administration of 2.5 mg/kg cisplatin, 24-h urinary sodium excretion was not significantly higher in cisplatin-treated rats than in gender-matched controls. After repeated cisplatin administration, 24-h urinary sodium excretion was significantly higher in cisplatin-treated male rats as compared to matched controls (P<0.05). No such effect was found in cisplatin-treated female rats. Conclusion. The study data show that cisplatin enhances urinary sodium excretion in male but not in female rats. The mechanism of such a gender-related effect is not yet clear. Further investigations are necessary to elucidate the mechanism of this pharmacological effect of cisplatin

Access to information supporting availability of medicines for patients suffering from rare diseases looking for possible treatments: the EuOrphan Service

Currently in Europe, approximately 30 million people suffer from rare diseases, and a major problem is that many patients do not have access to quality healthcare for their disorders. Moreover, there is also a lack of quality information and a networking system aimed at supporting interaction among patients, clinicians, researchers, pharmaceutical industries, and governmental bodies. The purpose of this article is to inform physicians, public health care professionals, and other health care providers about EuOrphan service, the aim of which is to ensure easier access to quality information on rare diseases and their treatment. A set of web-based services is available at www.euorphan.com where information for target-users on treatments and products available worldwide for rare disease care as well as indications about healthcare centers are provided. Moreover, the service aims at providing consultancies for pharmaceutical companies to ultimately support the European legislation in bringing new drugs of a high ethical standard to the market and to exert a positive impact on the large population of patients suffering from rare diseases in Europe. The services provided by EuOrphan can facilitate concrete networking among patients, patient associations, doctors, and companies and also support the organization of clinical trials. In this perspective, EuOrphan could become a very valuable tool for globalizing the information about the availability of treatment (authorized or under development) of orphan patients

Legal aspects of children’s treatment with medicines

Most medications, intended for children are used without performing clinical tests, which means that the manufacturers, as well as doctors, when prescribing the children’s doses according to the child’s age and weight, do not have the necessary efficiency and safety data and do not know the probability of adversary effect of the treatment. The ways of prescribing the medication and the forms of use of medication by children must be based scientifically otherwise there is a probability of treatment by an insufficient dose or even an overdose situation. The aim of the article is to provide an overview of the historical prerequisites of the situation, pertaining to treatment of children with medication and to summarize the legal regulation of pediatric clinical tests of medicinal preparations, in order to ensure that children are treated by safe and efficient medications in the United States of America and in the European Union. The article also provides the overview of the legal acts of the Republic of Lithuania, regulating the performance of pediatric clinical tests

Access to information supporting availability of medicines for patients suffering from rare diseases looking for possible treatments: the EuOrphan Service

Currently in Europe, approximately 30 million people suffer from rare diseases, and a major problem is that many patients do not have access to quality healthcare for their disorders. Moreover, there is also a lack of quality information and a networking system aimed at supporting interaction among patients, clinicians, researchers, pharmaceutical industries, and governmental bodies. The purpose of this article is to inform physicians, public health care professionals, and other health care providers about EuOrphan service, the aim of which is to ensure easier access to quality information on rare diseases and their treatment. A set of web-based services is available at www.euorphan.com where information for target-users on treatments and products available worldwide for rare disease care as well as indications about healthcare centers are provided. Moreover, the service aims at providing consultancies for pharmaceutical companies to ultimately support the European legislation in bringing new drugs of a high ethical standard to the market and to exert a positive impact on the large population of patients suffering from rare diseases in Europe. The services provided by EuOrphan can facilitate concrete networking among patients, patient associations, doctors, and companies and also support the organization of clinical trials. In this perspective, EuOrphan could become a very valuable tool for globalizing the information about the availability of treatment (authorized or under development) of orphan patients

Su lytimi susiję natrio apykaitos skirtumai, vaistų sukelta hiponatremija

Gender-related differences in sodium (Na+) metabolism, Na+ transport through cell membrane, intracellular Na+ concentration, and Na+ urinary excretion review is presented in the article. Literature data on gender-related differences in the occurrence of hyponatremia and related neurology are overviewed. Some of the drugs used in neurology (carbamazepine, oxcarbazepine, thiazides, antidepressants) are pointed out as eventual sources of hyponatremia. This disorder shows a clear-cut preference of the feminine gender. The authors present literature data on gender-related differences in the mechanisms of Na+ transport (Na+/H+ exchange, Na+/K+/2Cl– cotransport, Na+, K+-ATPase). The reasons for such differences are not yet known. Investigative tests with animals of both genders, cellular studies and clinical investigations with human males and females could help to answer question why females are more prone to hyponatremia, to select more efficient measures for prevention of hyponatremia and to differentiate specific peculiarities of treatment for patients of either sex

Coronary atherosclerosis and blood groups of ABO system in women (own data and review)

Earlier we have shown significantly more frequent B blood group and a significantly more rare O blood group of ABO blood group system in men aged under 45 years suffering from coronary atherosclerosis compared with these frequencies in the population of Lithuania. The aim of the study was to investigate the frequency of blood groups of ABO system in women with coronary atherosclerosis. MATERIALS: The frequency of the ABO blood groups was examined in 441 women, suffering from coronary atherosclerosis, divided into two groups: I group - 109 women till 60 years old (mean age 55.1+/-4.8) and II group - 332 women aged over 60 years (mean age 68.1+/-5.0). For all patients coronary atherosclerosis was diagnosed by coronary angiography and confirmed during coronary bypass surgery. The frequency of the ABO blood group in the studied pts was compared with the frequency of the blood group in the control group of healthy blood donors (n=595). To evaluate the significance of data, we compared the frequency of ABO blood groups with the data in women long-livers (n=75, mean age 94.1+/-3.8). Earlier our studies showed that long-livers are an important antiatherosclerotic control group for evaluation of the genetic markers of atherosclerosis. RESULTS: The O blood group was found significantly more rarely in the women group I as compared to that of healthy donors group (28.4% vs 38.2%, p<0.04). The B blood group was significantly more often in group II (22.9% vs 15.0%, p<0.04) compared with the frequency of the B blood group in the healthy donors' group. In the long-livers' group the frequency of the B group was significantly more rare than in healthy donors (6.7% vs 15%, p<0.01) as well as in the groups of tested pts (20.2% and 22.9% respectively, p<0.01). We did not find any significant changes in the frequency of AB blood group in women with coronary atherosclerosis. [...]

Sodium Valproate Inhibits Small Cell Lung Cancer Tumor Growth on the Chicken Embryo Chorioallantoic Membrane and Reduces the p53 and EZH2 Expression

The study aims to test the effect of different sodium valproate (NaVP) doses on small cell lung cancer NCI-H146 cells tumor in chicken embryo chorioallantoic membrane (CAM) model. Xenografts were investigated in the following groups: nontreated control and 5 groups treated with different NaVP doses (2, 3, 4, 6, and 8 mmol/L). Invasion of tumors into CAM in the nontreated group reached 76%. Tumors treated with 8 mmol/L NaVP doses significantly differed in tumor invasion frequency from the control and those treated with 2 mmol/L ( P < .01). The calculated probability of 50% tumor noninvasion into CAM was when tumors were treated with 4 mmol/L of NaVP. Number of p53-positive cells in tumors was significantly reduced when treated with NaVP doses from 3 to 8 mmol/L as compared with control; number of EZH2-positive cells in control significantly differed from all NaVP-treated groups. No differences in p53- and EZH2-positive cell numbers were found among 4, 6, and 8 mmol/L NaVP-treated groups. Invaded tumors had an increased N-cadherin and reduced E-cadherin expression. The results indicate the increasing NaVP dose to be able to inhibit tumors progression. Expression of p53 and EZH2 may be promising target markers of therapeutic efficacy evaluation

Sodium Is Not Required for Chloride Efflux via Chloride/Bicarbonate Exchanger from Rat Thymic Lymphocytes

Sodium-dependent Cl−/HCO3- exchanger acts as a chloride (Cl−) efflux in lymphocytes. Its functional characterization had been described when Cl− efflux was measured upon substituting extracellular sodium (Na+) by N-methyl-D-glucamine (NMDG). For Na+ and Cl− substitution, we have used D-mannitol or NMDG. Thymocytes of male Wistar rats aged 7–9 weeks were used and intracellular Cl− was measured by spectrofluorimetry using MQAE dye in bicarbonate buffers. Chloride efflux was measured in a Cl−-free buffer (Cl− substituted with isethionate acid) and in Na+ and Cl−-free buffer with D-mannitol or with NMDG. The data have shown that Cl− efflux is mediated in the absence of Na+ in a solution containing D-mannitol and is inhibited by H2DIDS. Mathematical modelling has shown that Cl− efflux mathematical model parameters (relative membrane permeability, relative rate of exchanger transition, and exchanger efficacy) were the same in control and in the medium in which Na+ had been substituted by D-mannitol. The net Cl− efflux was completely blocked in the NMDG buffer. The same blockage of Cl− efflux was caused by H2DIDS. The study results allow concluding that Na+ is not required for Cl− efflux via Cl−/HCO3- exchanger. NMDG in buffers cannot be used for substituting Na+ because NMDG inhibits the exchanger

Different Effects of Valproic Acid on SLC12A2, SLC12A5 and SLC5A8 Gene Expression in Pediatric Glioblastoma Cells as an Approach to Personalised Therapy

Valproic acid (VPA) is a histone deacetylase inhibitor with sex-specific immunomodulatory and anticancer effects. This study aimed to investigate the effect of 0.5 and 0.75 mM VPA on NKCC1 (SLC12A2), KCC2 (SLC12A5) and SLC5A8 (SLC5A8) co-transporter gene expressions in pediatric PBT24 (boy&rsquo;s) and SF8628 (girl&rsquo;s) glioblastoma cells. The SLC12A2, SLC12A5 and SLC5A8 RNA expressions were determined by the RT-PCR method. The SLC12A2 and SLC5A8 expressions did not differ between the PBT24 and SF8628 controls. The SLC12A5 expression in the PBT24 control was significantly higher than in the SF8628 control. VPA treatment significantly increased the expression of SLC12A2 in PBT24 but did not affect SF8628 cells. VPA increased the SLC12A5 expression in PBT24 and SF8628 cells. The SLC12A5 expression of the PBT24-treated cells was significantly higher than in corresponding SF8628 groups. Both VPA doses increased the SLC5A8 expression in PBT24 and SF8628 cells, but the expression was significantly higher in the PBT24-treated, compared to the respective SF8628 groups. The SLC5A8 expression in PBT24-treated cells was 10-fold higher than in SF8628 cells. The distinct effects of VPA on the expression of SLC12A2, SLC12A5 and SLC5A8 in PBT24 and SF8628 glioblastoma cells suggest differences in tumor cell biology that may be gender-related