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By W. Marius. Michigan Technological University. 2018.

Problems in the application of different pharmacological drugs and pathogenetic mechanisms of development generic 100 mg kamagra gold visa. The timely detection of adverse drugs reactions and conduct appropriate activities aimed at their prevention will improve the quality of the treatment purchase kamagra gold 100mg amex. To conduct a comparative analysis on the monitoring side effects of medicines authorized in the Republic of Kazakhstan for 2011-2014 generic kamagra gold 100mg with mastercard. Comparative Analysis on monitoring of side effects of drugs for 2011- 2014 years (numerical and percentages). It should be noted that the indicators of the side effects of drugs are increasing every year. One solution to this problem is to improve the quality of domestic drugs, improving pharmacovigilance Republic of Kazakhstan. There is a clear tendency of actively influence to the retail link in the behaviour of distributors. Current relationship of 1(one) wholesale and retail level of drug supply of Kazakhstan is characterized by the constant search for new forms of interaction and collaboration. Moreover, this is quite natural, since the interaction should be highly efficient, i. Objective: To review the logistics systems pharmaceutical market for the promotion of domestic product of the Republic of Kazakhstan. The results: The main problem is distribution of the duration of passage of goods through the channels of supply, and 80-90% of total time is spent on storage. The experience of other countries shows that reducing the time of movement of goods from production to the final consumer, as well as minimizing warehousing, handling, transport costs, possible with usage of logistic approach. The application of methods of logistics, according to domestic and foreign scientists, allows reducing inventory levels by 30-50% and reducing the movement of goods by 25-45%. Relevant importance is given to different regional conditions in the analysis of the situation of choice of supplier, the transition from simple criteria orders "cheaper", to the formation of more complex, integral criterion taking into account specifically established. The study and theoretical generalization of domestic and foreign literature on inventory management shows that the most promising direction in this field is the use of methods and techniques of logistics. It has been established that the activities of the distribution sector is characterized by greater concentration of companies active in establishing their own pharmacy chains, increasing the share of domestic drugs in the range of medicines, revitalization of the work of creating images for businesses and brands. Currently in logistics research and development uses two basic directions in inventory management. The pharmaceutical market of Kazakhstan is the largest and most structured in the Central Asian region, despite the strong growth dynamics, it is based on a relatively low base. Strong economic growth in the country in recent years, caused by the rapid development of oil and gas and mining industries, provided a significant impetus to the growth of sales of pharmaceutical and health care costs. Foreign producers were able to establish a dominant position in competition with local producers, which are limited by relatively low technology and production capacity. To review the pharmaceutical market for the promotion of domestic product of the Republic of Kazakhstan. At the beginning of 2016 in Kazakhstan registered 78 pharmaceutical manufacturers, of which 20-25 of them are active. However, only three companies produce the majority (70%-75%) production: Chimpharm (acquired by the group in Polpharma 2011), Globalpharm, Nobel. Among other pharmaceutical manufacturers republic: a manufacturer of plant-based Phytochemistry, start Karaganda Pharmaceutical Factory; Pharmaceutical company Romat - Pavlodar manufacturer, Kyzylmay and Dosfarm (manufacturers of Over- the-Counter products) and small producers generic products - Lekos and Elias. On June 1, 2015, according to official data of the Registry "national center of examination of medicines, products of medical purpose and medical equipment" the Ministry of health and social development of the Republic of Kazakhstan registered in the territory 7315 drugs represented 67 countries. Nearly half of all the registered medicines occupy solid drugs fractions with 41% (different types of tablets, capsules, granules). The second place is occupied by the liquid dosage forms with a share of 23%, which includes tinctures, syrups, alcoholic solutions for outdoor use, etc. Injection solutions in vials and infusions occupy the third position with a share of 15%. Among other products of domestic manufacturers are registered such dosage forms like sprays, ointments, gels, lotions, 233 suppositories, powder medicines, powders and lyophilizates for the preparation of solutions for injection. Injection solutions in vials and infusions occupy the third position with a share of 15%.

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Clinically important drug interactions • Drug that increases effects/toxicity of lamotrigine: valproic acid 100 mg kamagra gold fast delivery. Editorial comments: Dosage of lamotrigine is complicated by the enhancement of its metabolism by several antiepileptic drugs (phenytoin buy 100mg kamagra gold overnight delivery, phenobarbital effective kamagra gold 100mg, primidone) and its half-life prolongation by valproic acid. Awareness of these interactions is vital to the proper administration of this drug. Mechanism of action: Inhibits dihydroorotate dehydrogenase, resulting in inhibition of pyrimidine synthesis; also has antipro- liferative effect on T cells as well as antinflammatory actions. Contraindications: Pregnancy, significant liver disease, serology positive for hepatitis B or C. Patients with bone marrow sup- pression, severe immunodeficiency, or severe infection. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Adverse reactions • Common: hypertension, diarrhea, nausea, headache, rash, res- piratory infection. Clinically important drug interactions • Drugs that increase effects/toxicity of leflunomide: folic acid, rifampin. The following method has been suggested to promote elimination of leflunomide in the event of severe toxicity: (1) discontinue leflunomide; (2) take 8 g of cholestyramine t. Mechanism of action: Drug acts as a cofactor in the biosynthesis of purines and pyrimidines which is blocked by folic acid antag- onists such as methotrexate, trimethoprim, and pyrimethamine. Leucovorin is an active metabolite of folic acid and should therefore be com- patible. Contraindications: Pernicious anemia, megaloblastic anemia secondary to vitamin B12 deficiency. Clinically important drug interactions • Leucovorin decreases effects/toxicity of trimethoprim–sulfa- methoxazole, barbiturates, phenytoin, primidone. Treatment should con- tinue until methotrexate plasma level is less than 5 × 10–8 M. Editorial comments • Parenteral leucovorin is advised for treatment of megaloblas- tic anemia due to folic acid deficiency when it is not feasible to use oral therapy. Mechanism of action: Inhibits synthesis of estrogen and andro- gens in the ovaries and testicles, thus reducing serum and tissue levels of these hormones. Should not be given to women of childbearing potential who might become pregnant during leuprolide therapy. Advice to patient • Do not stop medication without first consulting with physician. Clinically important drug interactions: Leuprolide increases effects/toxicity of antineoplastic drugs: megestrol, flutamide. Editorial comments • Leuprolide is used as palliative treatment of advanced prostate cancer when alternatives such as orchiectomy and estrogen administration are unacceptable to the patient. Mechanism of action: Relaxes bronchial smooth muscles of the bronchioles by stimulating β2-adrenergic receptors. Properties are similar to those of albuterol, and levalbuterol offers no specific advantages according to The Medical Letter. Mechanism of action: Restores depressed immune function: stimulates antibody formation, activates T cells and macro- phages. Dosage of fluorouracil is 450 mg/m2/d for 5 days, then 450 mg/m2 weekly after with 4-week break, together with 3-day course of lev- amisole starting 21–34 days following surgery. Advice to patients • Inform treating physician if you experience flu-like symptoms. Adverse reactions • Common: nausea, vomiting, diarrhea, constipation, dermatitis, alopecia, fatigue, fever, arthralgia, myalgia. Clinically important drug interactions • Drugs that increase effects/toxicity of levamisole: alcohol (disulfiam-like reaction). Parameters to monitor • Stomatitis and diarrhea during the initial administration of flu- orouracil. If these conditions develop, discontinue the regimen prior to giving full 5 doses. Editorial comments • Before instituting therapy with levamisole, the patient should be out of the hospital, ambulatory, and fully recovered from postsurgical complications.

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Thus a prodrug of a drug cheap kamagra gold 100 mg visa, because of its increased lipid solubility buy discount kamagra gold 100mg, may demonstrate enhanced membrane permeability in comparison to the parent drug cheap kamagra gold 100 mg on-line. Enzymatic or chemical transformation converts the inactive prodrug to the pharmacologically active drug, after absorption has taken place. A further important point, discussed in detail in the next section, is that lipid solubility must be considered in the context of the degree of ionization of the drug. Therefore the pH of the solution will affect the overall partition coefficient of an ionizable substance. For ionizable drugs log P is pH dependent and hence log D, the log distribution coefficient of the drug at different pHs, is usually employed instead of log P, as an estimation and/or prediction of absorptive potential. The pH at which the log D is measured should be reported but values normally correspond to determinations carried out at a physiological pH of 7. Log D is effectively the log partition coefficient of the unionized form of the drug at a given pH. The relationship between the observed overall partition coefficient and the distribution coefficient is given by the equation: where α is the degree of ionization of drug. The interrelationship between the dissociation constant and lipid solubility of a drug, as well as the pH at the absorption site, is known as the pH-partition theory of drug absorption. Accordingly, rapid transcellular passive diffusion of a drug molecule may be due to: • a high proportion of unionized molecules; • a high log P (high lipophilicity); • or a combination of both. The extent of ionization of a drug molecule is given by the Henderson-Hasselbalch Equation (Box 1. In contrast, a very low percentage is unionized in the small intestine, which suggests unfavorable absorption. Strong acids, such as cromoglycate, are ionized throughout the gastrointestinal tract and are poorly absorbed. The reverse is true 22 for weak bases (with pK ′s in the range 5 to 11), which are poorly absorbed, if at all, in the stomach sincea they are largely ionized at low pH, but are well absorbed in the small intestine, where they are unionized. Strong bases, such as mecamylamine, are ionized throughout the gastrointestinal tract and are therefore poorly absorbed. Although the pH-partition hypothesis is useful, it must be viewed as an approximation because it does not adequately account for certain experimental observations. For example, most weak acids are well absorbed from the small intestine, which is contrary to the predictions of the pH-partition hypothesis. These discrepancies arise because the pH-partition hypothesis does not take into account the following: • the large mucosal surface area of the small intestine, which compensates for ionization effects; • the relatively long residence time in the small intestine, which also compensates for ionization effects; • even the ionized form of a drug displays limited absorption; • charged drugs, such as quaternary ammonium compounds, may interact with organic ions of opposite charge, resulting in a neutral species, which is absorbable; • bulk transport of water from the gut lumen to the blood, or vice versa, can drag water-soluble molecules with it, resulting in an increase or decrease in the absorption of water-soluble drugs respectively. A more complex relationship pertains for more complex and organized structures such as lipid bilayers, but again, drug diffusivity is inversely proportional (probably by an exponential relationship) to the molecular volume. This means that drug diffusivity across membranes is sensitive to molecular weight, since molecular volume is determined by a number of factors, including the molecular weight of the molecule. Therefore, in general, large molecules will diffuse at a slower rate than small molecules. However, molecular volume is also determined by: • the overall conformation of the molecule; • the heteroatom content that may be involved in inter- and intramolecular hydrogen bonding. Thus molecules which assume a compact conformation will have a lower molecular volume and thus a higher diffusivity. An important consequence of this property is that even if such molecules have a high molecular weight (i. Molecular size and volume also have important implications for the paracellular route of drug absorption. It would appear that tight junctions bind cells together very efficiently and can block the passage of even relatively small molecules. Gap junctions are looser and molecules up to 1,200 Da can pass freely between cells. Larger molecules cannot pass through gap junctions, suggesting a functioning pore size for the connecting channels of about 1.

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Two minor urinary metabolites discount kamagra gold 100mg otc, 9-carboxymethoxy- methylguanine and 8-hydroxy-9-(2-hydroxyethyl)guanine 100mg kamagra gold with mastercard, have been reported to constitute 8–14% and about 0 100 mg kamagra gold free shipping. Active renal clearance occurs by glomerular filtration and renal tubular secretion, with a half-time of 2–3 h (Laskin, 1983; O’Brien & Campoli-Richards, 1989) and a clearance rate of 3. In patients with renal impairment, the mean elimi- nation half-time can be extended to 20 h, and the total body clearance rate can be decreased 10-fold; it is therefore necessary to reduce the dose accordingly (de Miranda & Blum, 1983; Rogers & Fowle, 1983; Brigden & Whiteman, 1985; O’Brien & Campoli-Richards, 1989). Transplacental pharmacokinetics A 39-year-old pregnant woman, presumed to be at 30 weeks of gestation, was treated with aciclovir (350 mg, or 15 mg/kg bw) intravenously every 8 h throughout the remainder of gestation. Beginning at week 38 of gestation and continuing until delivery, seven women were treated orally with 200 mg aciclovir every 8 h and eight with 400 mg aciclovir every 8 h. The drug appears to be taken up efficiently by many tissues, including the brain and skin (de Miranda et al. Like humans, dogs, rats and rhesus monkeys show a biphasic decline in the plasma concentration of aciclovir, indicating a two-compartment open model, with a half-time of 1–3 h (de Miranda et al. Gastrointestinal absorption was poor in the 8-week-old rats, with a bioavailability of 7. Absorption of aciclovir in the gastrointestinal tracts of the young rats was shown to occur by an efficient passive diffusion process, which apparently becomes inefficient at the time of weaning (Fujioka et al. Beagle dogs given 20 mg/kg bw aciclovir had a mean peak plasma concentration of 42 μmol/L (10 mg/L) by 1. The body clearance was similar to the glomerular filtration rate, indicating the absence of active tubular secretion (de Miranda et al. Skin absorption occurred by a first-order process which resulted in excretion of about 0. When aciclovir is given orally, the doses are typically low and serious adverse events are extremely rare (Goldberg et al. Oral dosing is less frequently neurotoxic but was reported to induce acute disorientation in four patients, three of whom had renal insufficiency (MacDiarmaid-Gordon et al. Renal dysfunction is not an absolute requirement for aciclovir-induced neurotoxicity; but, apart from age and neurotoxic medications (Rashiq et al. The neurotoxicity induced by aciclovir manifests primarily as tremor (28–30%), myclonus (30%), confusion (30–43%), lethargy (17–30%), agitation (27–33%) and hallucination (20–26%) (Rashiq et al. Less frequent manifestations (3–17%) include dysarthia, asterixis, ataxia, hemipares- thaesia and seizures (Ernst & Franey, 1998). Neurotoxicity typically occurs during the first 24–72 h of drug administration, and discontinuation of the drug results in a complete return to normal by about 15 days (Rashiq et al. Haemodialysis has been shown to attenuate aciclovir-induced neurotoxicity effectively in symptomatic patients (Krieble et al. In patients receiving high doses of aciclovir, reversible increases in serum creatinine concentrations can occur (Kumor et al. The existence of compromised renal function, use of other nephrotoxic drugs, rapid infusion of large doses, advanced age and dehydration can all contribute to aciclovir-induced nephrotoxicity (Rosenberry et al. Like aciclovir-induced neurotoxicity, the nephrotoxic effects are typically transient and rapidly ameliorated by haemodialysis (Whitley et al. Topical adminis- tration may be associated with pain, burning or rash (Rosenberry et al. The main effect observed is related to kidney function but is dependent on dose, animal strain and route of administration. Wistar rats given three subcutaneous injections of 15 mg/kg bw aciclovir per day for five days (a total of 45 mg/kg bw per day) showed no significant changes (Hannemann et al. Obstructive nephropathy, caused by crystalline precipitation of the drug in the renal tubules and collecting ducts, was observed in Long-Evans rats given intravenous injections of 20, 40 or 80 mg/kg bw aciclovir daily for three weeks. These changes were accompanied by increased water consumption, urine output, blood urea nitrogen concentration and kidney weight (Tucker et al. All of the nephro- toxic effects of aciclovir resolved within two weeks after drug discontinuation. In Sprague-Dawley rats given 50, 150 or 450 mg/kg bw aciclovir per day by gavage for 25 months, no treatment-related toxic effects were observed (Tucker et al. Taken together, these studies suggest that nephrotoxicity is much more likely to result from intravenous than from oral dosing with aciclovir. Parallel clinical observations support the notion that oral dosing is less toxic than intravenous infusion in humans.

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