Arthritis Australia

By S. Dennis. Bob Jones University.

The average peak concentrations of zidovudine in the cerebrospinal fluid were 30% of those observed in plasma buy 10 mg atorvastatin mastercard, but were highly variable between monkeys generic 5mg atorvastatin mastercard, and very little 3′-azido-3′-deoxy-5′-O-α-D-glucopyranosyl- thymidine was recovered from the cerebrospinal fluid (Cretton et al. Perfused human placentas were used to show that zidovudine readily crosses the human placenta and that the passage is bidirectional, with no evidence of active or carrier-mediated transport. No evidence for glucuronide conjugation of zidovudine by the placenta was reported (Schenker et al. When human placental tissue and human trophoblast cells (Jar) were exposed to zidovudine at a concentration of 7. Zidovudine, zidovudine monophosphate and 3′-azido-3′-deoxy-5′-O-α-D-glucopyranosyl-thymidine glucu- ronide were detected in most fetal tissues after administration to pregnant rhesus monkeys (Patterson et al. After exposure of pregnant pigtailed macaques to zidovudine, the fetal:maternal plasma concentration ratio of zidovudine was 0. Zidovudine administered to a baboon in late pregnancy resulted in a fetal:maternal plasma concentration ratio of 0. Nausea was reported by 243 individuals, and others reported vomiting, gastric pain, asthenia and headache. Ten individuals had anaemia and seven had transient increases in the activity of liver enzymes. In the same study, 70% of patients had had to interrupt dosing at least once, and increased haematocrit was observed after dosing cessation in 52% of patients. In later trials at lower doses, the absolute rates of anaemia and neutropenia were considerably decreased: Ippolito et al. A related haematotoxic effect, macrocytosis with decreasing haemoglobin concentrations, was also observed in several studies (Mathé et al. Skeletal muscle myopathy has been observed in up to 27% of patients with a clinical presentation including fatigue, myalgia, muscle weakness, wasting, elevated serum creatine kinase activity and decreased carnitine concentration. In skeletal muscle biopsy samples, accumulation of lipid in muscle fibres, accumulation of mitochondria in the subsarcolemmal space (ragged red fibres) and morphologically abnormal mitochondria have been observed (Mhiri et al. Congestive heart failure, left ventricular dilatation, reduced ejection fractions (7–26%) and morphologically abnormal mitochondria have been demonstrated after prolonged (two years or more) use (Lewis, 1998). The clinical, morphological and bio- chemical manifestations of cardiac and skeletal muscle myopathy improved when zido- vudine use was terminated (Mhiri et al. Analysis of neuromuscular function in a multicentre trial of patients receiving 600 mg/day zidovudine showed that 225 of 2467 patients had ≥ grade 2 peripheral neuropathy or distal symmetrical neuropathy. Of these cases, about 20% were consi- dered to be related to treatment with zidovudine. Patients (7%) receiving zidovudine alone reported muscle weakness and ache, while 37% had difficulty in performing a series of tasks (Simpson et al. Also as in humans, the effects were typically reversible within days to weeks after discontinuation of the drug. Continuous exposure caused greater inhibition of cell growth than a 1-h exposure, and the mouse cells were slightly more sensitive than the human cells to the toxic effects of zidovudine. The animals given bolus doses showed no toxicity, but those given the 24-h infusion had significantly decreased numbers of bone-marrow erythroid progenitor cells. The numbers of bone-marrow myeloid and erythroid progenitors reached the lowest point at five days and had returned to normal within two to five days after exposure. Long-term exposure to zidovudine results in more extensive haematopoeitic effects. In other studies, doses of 25–1000 mg/kg bw zidovudine given to B6C3F1 mice by gavage daily for 13 weeks caused bone-marrow depression and macrocytic anaemia, both of which were reversible when the drug was discontinued (Thompson et al. The 60- and 30-mg doses produced anaemia by days 4 and 13, respectively, and decreased packed red cell volume, bone-marrow hypercellularity and splenic extramedullary haematopoiesis were seen, similar to the effects in humans. After 12 months of dosing, the erythrocyte counts were decreased in rats and those of leukocytes were slightly decreased in monkeys. In the rats, zidovudine was preferentially concentrated in heart and skeletal muscle. In both species, the mitochondria were enlarged with disorganized or absent cristae and abnormal functioning of oxidative phosphorylation. They concluded that zidovudine treatment induces changes in mitochondria that result in diminished contractile capacity of skeletal muscle. No increased risk for premature births, intrauterine growth retardation or newborn asphyxia was found, and 41 of the 45 infants were born at term. Among the 12 newborns who had been exposed to zidovudine during the first trimester, no malformations were reported. There were eight fetal or neonatal deaths, five in the group receiving zidovudine and three in the group given the placebo. None of these deaths was considered by the authors to be attributable to the drug. In order to determine the safety of zidovudine administered during pregnancy, Sperling et al. During the inclusion period of 1991–93, 424 eligible women were randomized to either zidovudine or placebo, and the women were followed through six months post partum, while their infants were followed through 18 months of age. Five women given zidovudine and two given placebo had either a spontaneous abortion or a stillbirth.

Recommendation 5-1: State licensing boards should only license whole- salers and distributors that meet the National Association of Boards of Pharmacy accreditation standards atorvastatin 20 mg visa. Food and Drug Adminis- tration order atorvastatin 20 mg free shipping, in collaboration with state licensing boards, should establish a public database to share information on suspended and revoked wholesale licenses. The committee fnds that peculiarities of the American wholesale sys- tem account for much of the United States’ vulnerability to falsifed and substandard drugs. Limiting the wholesale market to vetted frms would Copyright © National Academy of Sciences. Similar weaknesses plague the wholesale system in developing coun- tries, and action in the American market might give regulators around the world an example and encouragement to tighten controls on the chaotic wholesale and distribution systems. Next, the regulators should design the database and publish the processes for collecting accurate, reliable, and timely information about the suspension or revocation of wholesale licenses. Wholesale Market In the United States, state governments control professional practice, including the practice of pharmacy, which includes medicine distribution and wholesale. Some states have enacted tighter regulations on the market, with unintended spillover effects (Laven, 2006). After the state of Nevada increased oversight of drug wholesale, for example, “some wholesalers simply moved operations across the state line into California” (Flaherty and Gaul, 2003). When unscrupulous businesses can seek out the softest regulatory systems to work in, they do. As the previous section explains, the wholesale trade depends on buying and selling medicines in response to shortages and gluts in different parts of the country. Therefore, the weak- nesses in one state licensing system can become vulnerabilities for the oth- ers. The committee recognizes the authority of states to license wholesalers but believes that public health will be best protected if all businesses adhere to the strict standards laid out by the National Association of Boards of Pharmacy accreditation process. Every state has an interest in promoting high minimum standards for medicine sale and manufacture. The recent fungal meningitis outbreak from an steroid injection compounded under unhygienic conditions at New England Compounding Center in September 2012 is a reminder of the risks of competing state standards (Grady et al. Though the Massachusetts Department of Health registered three complaints against New England Compounding Center, there is no man- datory national system for sharing these complaints (Grady et al. Similarly, there is no way for state authorities to share information on Copyright © National Academy of Sciences. As part of a stronger wholesale system, states should report violations and revocations of wholesale licenses to a national, public database. This will impede unscrupulous wholesalers from moving from state to state and starting over when caught in violation of one state’s rules. The recent tragic meningitis outbreak has brought to light the importance of sharing information on dangerous actors in the drug distribution chain. Although the states have the author- ity to license wholesalers, the nation’s interests are best served by enabling communication among the states. The Wholesale Market in Low- and Middle-Income Countries As the previous section explains, the wholesale market is a common vulnerability in medicines distribution around the world. For example, in 2004 the Chinese drug regulatory authority cut the number of drug wholesalers in the country from 16,000 to 7,445 (Yadav et al. This is still many more than in the United States, Europe, or Japan, but it is an admirable move in a more sustainable direction. Proponents of the current drug wholesale system maintain that a small number of wholesalers cannot serve the drugs market of developing coun- tries. They reason that a system of three or four large primary wholesalers may work in Europe or North America, but in developing countries a few companies could never guarantee fne-mesh distribution (Foundation Strat- egy Group, 2005; McCabe, 2009). Medicine shops in Kenya, for example, report buying from a range of pharmaceutical and general wholesalers both in and outside of the shop’s district, as well as mobile vendors and manu- facturers (Amin and Snow, 2005). Analysis of successful distribution chains, such as the Coca-Cola distribu- tion chain, suggests this is a false dichotomy, however (Yadav et al. ColaLife, a nonproft, has been using Coca-Cola’s fne-mesh distribution chain to bring oral rehydration and zinc supplements to remote areas since 2008 (ColaLife, 2012). Steps toward a more controlled and effcient wholesale market can protect patients in the markets most hurt by bad- quality drugs. A reduction in the number of licensed wholesalers and use of more effcient distribution chains can help the wholesale market around the world. With every transaction on the chain, there is a risk of the drug supply’s being compromised. Crimi- nals take advantage of places where the distribution chain breaks down and medicines depart from documented chain of custody. Drugs that leave the proper distribution system are called diverted drugs; the markets that trade diverted drugs, or more generally, markets that trade with little authorized oversight, are called gray markets. Drug diversion is the means through which medicines approved for sale in one country are sold in others, where they may not be registered. On the surface, drug diversion is not the public health threat that falsifed and substandard medicines are (Bate, 2012).

When this simplifed weight-band dosing was developed atorvastatin 10mg otc, careful consideration was given to the usual body surface area of children from low- and middle-income countries in that weight band generic 5 mg atorvastatin amex. The primary source of information for the guidance provided is the manufacturer’s package insert. This was supplemented with data from other clinical studies as well as expert paediatric pharmacology consultations. In some cases the dose for a component in a particular weight band may be somewhat above or below the target dose recommended by the manufacturer. This is inevitable given the limitations imposed by a fxed-dose combination, but care was taken to ensure that in no case would a child receive more than 25% above the maximum target dose or more than 5% below the minimum target dose. For simplifcation, Antiretroviral drugs that are no longer considered preferred or alternative options for children such as didanosine and saquinavir are no longer included in the dosing guidance. This dosing annex and the simplifed dosing schedule will be regularly reviewed and updated as further data or newer formulations become available, but national programmes are advised to consider the most recent product labelling for up-to-date information. Additional information can also be found in specifc drug information sheets in the Web Annex at www. Antiretroviral drugs and formulations are available from several companies, and the dose strengths of tablets, capsules and liquid formulations may vary from the information given here. In addition, the listing of a formulation in this annex does not equate to quality assurance of that formulation. National programme managers should ensure that any product procured for use is approved and of appropriate quality and stability. For the current list of antiretroviral drugs approved and tentatively approved by the United States Food and Drug Administration, see www. Developing dosing guidance for new and upcoming formulations of paediatric antiretrovirals in line with Treatment 2. Meeting report, Paediatric Antiretroviral Working Group, Geneva, Switzerland, 25–26 October 2011. Oral liquid or syrup formulations should be avoided where possible, especially if volumes are large – such as above 10 ml. Dispersible tablets (or tablets for oral solution) are the preferred solid oral dosage forms, since each dispersible tablet can be made into liquid at the point of use. In general, young children should be switched to available solid oral dosage forms as soon as they are tolerated. Where children have to use adult formulations, care must be taken to avoid underdosing. Different dosing between morning and evening doses should be avoided where possible. Children have to be weighed at each clinic visit, and dose changes are required as children grow and/or gain weight. Annexes 245 246 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 12. Annexes 247 248 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 12. However, the Paediatric Antiretroviral Working Group recognized that, although a child-specifc formulation may be ideal, a scored adult formulation may be easier to develop as a frst step. As more data are obtained to inform the best use of this drug in young children, sprinkles formulation should be made available in resource limited settings. Going from evidence to recommendations: the significance and presentation of recommendations. Achieving universal access for human immunodeficiency virus and tuberculosis: potential prevention impact of an integrated multi-disease prevention campaign in Kenya. Evaluation of a home-based voluntary counselling and testing intervention in rural Uganda. Responding to intimate partner violence and sexual violence against women: clinical and policy guidelines. Use-effectiveness of the female versus male condom in preventing sexually transmitted disease in women. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. European Journal of Clinical Microbiology and Infectious Diseases, 2012, 31:919–927. Scaling up antiretroviral therapy in resource-limited settings: adapting guidance and meet the challenges. Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines.