By D. Jared. Hamilton College.
The plasma concentration after administration of 1 mg of Konakion intramuscularly exceeded those after oral administration at all times generic himcolin 30 gm overnight delivery erectile dysfunction doctors in orlando, and after 24 h the median was 444 ng/mL generic himcolin 30 gm line impotence lack of sleep. Physiologically, these concentrations compare with adult endogenous levels of about 0. By 24 days, the concentrations in both groups were mainly within the adult physiological range (0. In this study, however, the plasma concentrations after 24 days were significantly higher after intramuscular injection, consistent with the hypothesis of the depot effect of intramuscular phyllo- quinone (Loughnan & McDougall, 1996; see also section 4. They calculated from published studies that a realistic estimate of the terminal plasma half-time in neonates was 26–193 h (median, 76 h), as compared with 8–22 h (median, 14 h) in adults after intravenous administration (Øie et al. This longer terminal half- time may reflect the poorly developed organ systems of neonates and a reduced capacity to metabolize and excrete vitamin K (Stoeckel et al. The plasma profile of an oral dose of this preparation in five-day- old infants appeared to be similar to that of phylloquinone; after a 4-mg dose, a peak concentration of about 100 ng/mL was achieved after 3–4 h, before declining to about 30 ng/mL by 12 h (Shinzawa et al. The liver has often been assumed to be a major depot for vitamin K because it is the site of synthesis of the vitamin K-dependent coagulation proteins. Measurements of phyllo- quinone in livers obtained at autopsy from 32 adults in the United Kingdom revealed hepatic concentrations ranging from 1. Similar hepatic concentrations of phylloquinone were found in a smaller number of analyses of post-mortem samples from adults in Japan (10 ng/g) (Uchida & Komeno, 1988) and in The Netherlands (11 ng/g) (Thijssen & Drittij-Reijnders, 1996). The distribution of the various forms of vitamin K in the liver is quite different from that in plasma in that the major transport form, phylloquinone, represents the minority of total hepatic stores (about 10%); the remainder comprises bacterial menaquinones, mainly menaquinones- 6–13 (Shearer et al. The pattern of individual menaquinones in the liver varies considerably between individuals (Shearer et al. This proposal is supported by the finding that two menaquinones, -10 and -11, which are major forms in most liver samples (Uchida & Komeno, 1988; Thijssen & Drittij- Reijnders, 1996), are known to be synthesized by Bacteroides species which are predom- inant members of the human intestinal flora (Conly & Stein, 1992); yet menaquinone- 10 and menaquinone-11 do not make appreciable contributions to normal diets (Shearer et al. The concentration in the heart (~5 ng/g) [~10 pmol/g] is comparable to those in the liver, and even higher concen- trations (~13 ng/g) [~25 pmol/g] are found in the pancreas, but lower concentrations (< 1 ng/g) [< 2 pmol/g] were detected in brain, kidney and lung. These tissues do not appear to contain appreciable concentrations of menaquinones except for the short- chain menaquinone-4. Particularly high concentrations of menaquinone-4 relative to phylloquinone are present in the kidney, brain and pancreas. Although these and other tissues contain the enzymes of the vitamin K epoxide cycle (see Figure 1) and carry out vitamin K-dependent carboxylation of protein precursors, this would not appear to account for the tissue-specific accumulation of menaquinone-4 and may suggest a hitherto unrecognized physiological role for menaquinone-4 in certain tissues (Shearer, 1992; Thijssen & Drittij-Reijnders, 1996). Indeed, menaquinone-4 may arise by tissue synthesis from phylloquinone itself (Davidson et al. Osteocalcin is a major vitamin K-dependent bone protein synthesized by osteo- blasts and therefore requires a source of vitamin K for γ-glutamyl carboxylation. Both trabecular and cortical bone contain ample reserves of vitamin K, with phylloquinone predominating and smaller amounts of shorter-chain menaquinones (Hodges et al. With the absence of the typical hepatic forms menaquinones- 10–13, the vitamin K content of bone resembles that of other extrahepatic tissues. The endogenous stores of vitamin K in the liver of the newborn differ both quantitatively and qualitatively from those of adults because the concentrations and total reserves of phylloquinone are lower than those of adults (Shearer et al. The carboxylation reaction is driven by a vitamin K-dependent carboxylase activity (1) coupled to vitamin K- epoxidase activity (1) which simultaneously converts vitamin K quinol to vitamin K 2,3-epoxide. Vitamin K 2,3-epoxide is reduced back to the quinone by vitamin K epoxide reductase (2A). The cycle is completed by the reduction of recycled vitamin K quinone by vitamin K reductase activity (2B). The activities of both vitamin K epoxide (2A) and vitamin K reductase (2B) are dithiol-dependent (dithiol and disulfide denote reduced and oxidized dithiols) and are inhibited by coumarin anticoagulants such as warfarin. The median hepatic con- centration of 1 ng/g in term infants is equivalent to a total liver pool of about 0. Hepatic phylloquinone concentrations may remain elevated for several weeks after injection: in two infants known to have received 1 mg phylloquinone by the intramuscular route and who survived 13 and 28 days, the total hepatic stores were 24 and 15 μg, respectively (Shearer et al.
Internet Pharmacies in Middle- and High-Income Countries Disorganized medicines retail is not confned to developing countries 30 gm himcolin otc erectile dysfunction from alcohol. The previous section describes the large gray market for medicines in ba- zaars and unlicensed drug shops in low- and middle-income countries generic 30gm himcolin with mastercard erectile dysfunction after stopping zoloft. The internet serves the same purpose, but mostly in middle- and high-income countries. Illegitimate internet pharmacies are similar to unlicensed drug shops both in the quality of the products they stock, which is poor, and in the lack of offcial oversight of their operations (Crawford, 2003). And, because the internet facilitates easy international sales, online drug stores have spread the problem of falsifed and substandard drugs “from small, unproftable, markets in developing nations to the [drug] industry’s most lucrative markets” (Lybecker, 2007, p. The program aims to improve access to pharmacy services in rural or remote regions and includes a variety of initiatives to improve recruitment and retention of rural pharmacists. The program also increases pharmacy students’ exposure to rural work during their training. Australian pharmacy students work in com- munity or hospital pharmacies as part of their studies. The program also supports students from rural backgrounds to pursue pharmacy degrees. Another successful initiative to improve retention is the program’s emer- gency locum service. Figure 5-6 shows the geographic breakdown of the 30 countries that have legislation on the operation of internet pharmacies. A few countries have an accreditation process for their own internet pharmacies, but internet commerce is transnational. Perhaps concern about the practicality of enforcing laws against internet drug sales prevents countries from passing them. It may also seem futile to ask internet drug sellers to observe the same stan- dards registered pharmacies do, such as requiring doctor’s prescription for controlled medicines, when “national rules banning the sale of drugs with- out a prescription can be easily overcome” (Levaggi et al. Just as often, restrictions and quality controls for online pharmacies are not, in fact, violated because many internet pharmacies operate out of countries that have no such restrictions. Although regulatory agencies can ask foreign governments to close online drug stores, it is diffcult to prevent them from reopening at a different address (Ivanitskaya et al. Because the products are sent through courier or postal services, customs and border offcers may also stop the imported drugs at the port of entry (Ivanitskaya et al. The Attraction of Internet Pharmacies Some of the more reputable-looking internet drug sellers keep up the pretense of having patients complete a health questionnaire before buying drugs, but many do not (Ivanitskaya et al. Bostwick and Lineberry proposed four main categories of customers at internet pharmacies: bargain hunters, the poor or elderly, the “life- style libertines” who prefer to self-prescribe, and drug addicts (Baert and De Spiegeleer, 2010; Bostwick and Lineberry, 2007). Of these groups, ad- dicts are the least likely to purchase prescription drugs online (Inciardi et al. Internet drug stores cater to people who like to buy drugs with- out, or even against, a physician’s advice (Levaggi et al. Table 5-3 shows other perceived advantages and disadvantages of online pharmacies. Other online shoppers seem motivated by a belief, sometimes a mis- taken one, that internet pharmacies sell cheaper drugs. On average, the investigators paid more for the drugs that never arrived than for those that arrived (€0. Investigators cited other hidden costs, including ship- ping and customs fees, as well as the cost of time spent waiting for the slow transactions to process (Levaggi et al. More importantly, of the 13 pharmacies that flled orders, only two were not of substandard quality (Levaggi et al. They criticized the false economy of online drug sellers in part because the products they bought sell for less in Italian regulated, storefront pharmacies (Levaggi et al. A 2001 study of Parkinson’s disease medications found on- line drug stores offered substantial savings off U. A Forbes magazine contributor explained, “My wife needs the meds to stave off a recurrence of cancer, so avoiding [online pharmacies] is not an option” (Wasik, 2012). The risks of online purchases are, especially in the United States, inextricable from larger questions of affordable drug pricing (Financial Times, 2012). Every year more Americans, and others accustomed to using the internet for bargain shopping, import “incremental amounts” of medicines to their countries though gray market internet purchases (Laven, 2006; Shepherd, 2007b). Distinguishing Rogue Pharmacies from Legitimate Ones In late September 2012, Interpol, an intergovernmental organization for police cooperation, organized an international raid of online pharmacies A GlaxoSmithKline ad campaign about the dangers of online pharmacies purporting to sell Canadian medicines.