Such a diagnosis strongly affected women’s perception of the magnitude of their risk 100mg amantadine with mastercard hiv infection and. hiv disease, and therefore their willingness to undergo a preventive treatment cheap amantadine 100mg overnight delivery antiviral. Or generic 100mg amantadine free shipping antiviral innate immunity, as a Time magazine article put it in 2006: what if doctors had a pill that prevents cancer and nobody wanted to take it? That has pretty much been the situation with tamoxifen, an estrogen-like drug that was proved in 1998 to cut in half the chance of developing breast cancer if taken for fve years by women with increased risk of the malignancy. Craig Jordan and Monica Morrow, „Acceptance of tamoxifen chemoprevention by physicians and women at risk“, Cancer, 2004, 100(9): 1800- 1806. Robert Aronowitz had shown that similar mechanism – display and treatment of an existing dysfunction rather than of hypothetical risk – favored diffusion of other preventive drugs, such as statins. Cronin, „Re- Tamoxifen for prevention of breast cancer“, Journal of the National Cancer Institute, 2002, 94(19): 1504. Here again, the – implicit – conclusion is that women “at risk” should be made aware of anomalies in their breast tissue and therefore more open to possibility of chemoprevention. The majority of drugs have multiple physiological effects, as do nearly all the biologically active substances. Jordan’s article, one may assume, is not alluding to multiple functions of a molecule, but rather to its multiple marketing targets. A drug that was initially developed to reduce bone loss can be prescribed at the same time for the prevention of other conditions as well. A treatment that prevents breast cancer should also be destined to all the women, not only those with known risk factors, because the latter are only a fraction of all the women who develop breast cancer. While the effcacy of raloxifene to diminish incidence of breast cancer has still to be proven, Jordan concluded, “ it is clear that a new era of preventive therapies has arrived”. Victor Vogel, the director of the comprehensive breast program at the University of Pittsburgh and an enthusiastic supporter of medical management of breast cancer risk. Vogel explained that no lifestyle modifcations have yet been proved to prevent or defnitively lower the risk of breast cancer (…) women whose personal risk is high may consider reducing risk by 37 V. Craig Jordan and Monica Morrow, „Raloxifene a a mutifunctional medicine“, British Medical Journal, 1999, 319(7206): 331-332. Craig Jordan, Susan Gapstur and Monical Morrow, „Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis and coronary heart disease“, Journal of the National Cancer Instititue, 2001, 83(19): 1449-1457. Craig Jordan, „The science of selective estrogen modulators: Concept to clinical practice“, Clinical Cancer Research , 2006, 12(17): 5010-5013, on p. The editorial also criticized the presentation of the trial’s data using relative values (50% risk reduction) and not absolute numbers, a presentation that, “is unlikely to help women to make informed decisions, and cynics may argue that there were other motivating forces behind this publicity”. Norman Wolmark declared in the press conference that: today we can tell you that for post menopausal women at increased risk of breast cancer , raloxifene is just as effective , without some of the serious side effects known to occur with tamoxifen. In the last 25 years, partly thanks to activists’ efforts, breast cancer became highly visible in the media and in public discourse. One of the main messages promoted by activists is the rapid extension of “breast cancer epidemics”: one of twelve, one of ten, and now one of eight women will be diagnosed with breast cancer. They pointed to the absence of statistically meaningful differences in side effects induced by the two drugs and to the fact that raloxifene, unlike tamoxifen, did not reduce the number of in situ cancers (although the meaning of prevention of these lesions is unclear). Women treated with tamoxifen complained more often about gynecological problems, vasomotor symptoms, legs cramps and bladder control problems, while those in raloxifene group complained more frequently about muscle and bone pain, painful intercourse and weight gain. It is not surprising that many women elected to leave this trial before the allocated fve years. The new trial, Brenner argued, had all the shortcomings of its predecessor, and an additional one, the absence of a placebo group. Russel Mokiber, “Lilly’s 2nd disappointment,” Mutinational Monitor, 26(11-12), November-December, 2005, p. For many years mammography was presented by the great majority of cancer experts, but also cancer activists as a highly effcient way to lessen the burden of breast cancer, in spite of absence of a convincing proof that this approach saves lives, increases life span, or that its advantages exceed its harms. The sophisticated and apparently successful commercial strategy of AstraZeneca failed to convince women to use Novaldex® to prevent breast cancer, and it seems that – as now – that Eli Lilly was no more successful with Evista®. Tamoxifen was handicapped by the negative image of chemotherapy of cancer, by reports about potentially serious complications of the therapy, and by the fact that this molecule frequently induces bothersome side effects. Raloxifene is not an anti-cancer drug, but its side effects may also reduce the quality of life of its users. Sixteenth report by the Committee on Government Operations, committed to the Committee of the Whole House on the State of the Union, October 0, 1994. Alice in the Wonderland of breast cancer screening“, New England Journal of Medicine, 1997, 336(16): 1180-1183. Ot such an increase is see today by many experts mainly as an artifact of introduction of mammographic screening. They warned women to beware expert’s hype, displayed fnancial interests that linked drug manufactures to trial’s organizers, and put pressure on governmental regulatory agencies. These activities probably played an important role in the rise of a cautious approach to preventive uses of tamoxifen and raloxifene. The combination of women’s spontaneous resistance to chemoprevention of breast cancer, the generalization of critique of use of female sex hormones as preventive drugs, and the intervention of activists were a powerful—and initially unsuspected – mix. Le Women’s Health Movement et les tranformations de la médecine aux Etats Unis”, Travail, Genre et Societés, November, 2005, 14, 89-108. Ilana Löwy and Jean Paul Gaudillière, «Médicalisation de la ménopause, mouvements pour la santé des femmes et controverses sur les thérapies hormonales», Nouvelles Questions Féministes, 2006, 25(2). Aronowitz “Situating Health Risks: An Opportunity for Disease Prevention Policy”, In: Charles Rosenberg, Rosemary Stevens & R. Burns (eds), American Health Care, History and Policy, Berkeley, University of California Press, 006. Even with these contributions, the heterogeneity of diagnostic subtypes has confounded the translation of the substantial scientifc activity to pinpoint defnitive biological mechanisms that can contribute to the development of an effective targeted therapeutic agent. This has raised issues for those regional regulatory committees responsible for making these drugs accessible (i. The contrast between standards of scientifc critical appraisal set by regulatory authorities, evidence-based health technology assessors, clinical researchers and the patient demand for these treatments provides a telling portrait of regulatory issues beset by consumer demands, pharmaceutical marketing and clinician judgements. Statistically signifcant effcacy in clinical trials does not easily translate into effectiveness in the wider population, nor to clinically meaningful treatment effects. The licensing decisions of national regulatory authorities depend on sound scientifc evidence that the products meet the highest standards of safety, effcacy and quality. The decisions of local appraisal committees to fund these treatments are based both on the science and a balancing of the harms, benefts and economic costs, often in light of wider opulation data subsequent to the initial licensing. Although it is always maintained that fnal decisions are based on the science, differences in interpreting the science result in dramatically different conclusions. If individuals are driven to act according to “norms of appropriateness and legitimacy” and not just their own self-interest,1 citing March and Olsen 1984, then the construction and legitimization of what is appropriate in the authoritative structures requires some unpacking before regulation will be recognized to “work” in a more effective decentred and pluralistic manner. A concerted research effort at various sites around the world was launched in the early 1980s to unravel the aetiology of these disorders and to establish the prevalence and incidence rates for dementia and its differential sub-types, in particular, Alzheimer’s disease.
In rats safe 100 mg amantadine hiv infection in korea, dogs and monkeys purchase amantadine 100mg amex onion antiviral, the disappearance of intravenously administered [14C]- mitoxantrone from plasma was rapid cheap 100 mg amantadine otc naproxen antiviral, followed by a slow terminal elimination phase (James et al. Extensive tissue binding was indicated, with 50, 25 and 30% of the dose still retained 10 days after intravenous administration in rats, dogs and monkeys, respectively. In beagle dogs, tri- exponential elimination from plasma was reported, with a very rapid initial distribution phase with a half-time of 6. Extensive tissue retention was again reported, the higher concentrations 24 h after dosing being found in the liver, kidney and spleen. Two metabolites were detected, accounting for 30% of the radiolabel in plasma and 50% in urine, but were not identified (Lu et al. A rapid distribution and a slow elimination phase were also observed in mice, with retention in body tissues, particularly liver and kidney (Rentsch et al. A naphthoquinoxaline metabolite of mitoxantrone has been reported in rats and pigs, resulting from the oxidation of the phenylenediamine substructure (Blanz et al. In general, mitoxantrone is believed to be active in mammalian cells in vitro in the absence of exogenous metabolic activation; however, inhibition of cyto- chrome P450 mixed-function oxidase by metyrapone in HepG2 hepatoxic cells and rat hepatocytes blocked the cytotoxic activity of mitoxantrone, suggesting that conversion to reactive species might be important (Duthie & Grant, 1989; Mewes et al. Leukopenia is the main dose-limiting effect, the lowest leukocyte counts typically being found 10–14 days after a single dose, with recovery by day 21. In a large European trial, seven of 264 patients experienced cardiac abnormalities (3%). Risk factors that may be predictive of the cardiotoxicity of this drug are previous anthracycline therapy, mediastinal radiotherapy and a history of cardiovascular disease (Crossley, 1983). The number of cardiotoxic events increases with cumulative doses of mitoxantrone > 120 mg/m2 in patients who have previously been treated with anthra- cyclines, and > 160 mg/m2 in patients who were not previously treated. The cumulative dose at which a patient has a 50% probability of having to discontinue treatment because of cardiotoxicity was estimated to be 182 mg/m2, representing approximately 13 courses of treatment. Other toxic effects seen with standard doses of mitoxantrone (12–14 mg/m2) include nausea and vomiting (in approximately 50% of patients), diarrhoea (15%), stomatitis and mucositis (20%) and alopecia (50%), although these effects are usually mild and transient (Crossley, 1983). As the drug is an intense blue colour, discolouration of urine and skin is not uncommon. With higher doses (40–90 mg/m2 or 12 mg/m2 on days 1–3), the toxic effects are typically more severe, and hepatotoxicity has been reported (Feldman et al. After intraperitoneal dosing, peritonitis is the dose-limiting toxic effect (Alberts et al. Many of the studies of the toxicity of mitoxantrone have focused on its cardiac effects, particularly in comparison with doxorubicin, another anthracycline known to be toxic to the heart. At doses > 2 mg/kg bw, mito- xantrone induced cardiovascular and renal toxicity in rabbits (Hulhoven et al. Two cats died of complications that may have been attributable to mitoxantrone: one of cardiomyopathy and the other of pulmonary oedema (Ogilvie et al. She had received no other treatment and had not taken hormones or oral contraceptives. Measurement of lutein- izing hormone, follicle-stimulating hormone and oestradiol in her blood showed that their concentrations were in the menopausal range (Shenkenberg & Von Hoff, 1986). Three weeks later, she received mitoxantrone at 12 mg/m2 for three days in combination with cytarabine. The pregnancy continued, with normal fetal growth, for 60 days when she had complete remission. It should be noted, however, that this trans- location occurs in nearly all cases of de-novo acute promyelocytic leukaemia. The therapy for the primary leukaemia included induction with cytarabine and mitoxantrone, two consolidations with cyta- rabine, daunorubicin and etoposide and then cytarabine and amsacrine followed by maintanence therapy with 6-mercaptopurine and cytarabine. Pedersen-Bjergaard and Philip (1991) reported a balanced translocation involving chromosome band 21q22 in a case of acute myeloid leukaemia that followed mito- xantrone-containing therapy. These strand breakage effects could be enhanced in T-47D human breast cancer cells by prior stimulation with oestrogen. Mitoxantrone was highly effective in causing chromosomal aberrations in cultured Chinese hamster cells and in human peripheral blood lymphocytes in tissue culture. These effects were reduced when an exogenous metabolic activation system was added to the cells. It also induced mutation and somatic recombination in the Drosophila white–ivory test for somatic mutation and in the wing spot test. Mitoxantrone induced primarily small colony mutants at the Tk locus in mouse lymphoma L5178Y cells, in the presence or absence of exogenous metabolic acti- vation. Small colony mutants in L5178Y cells are generally considered to be caused by chromosomal mutations (DeMarini et al. Some discrepancies with regard to the activity of mitoxantrone have been found in various assays. The culture media and conditions differed between the two laboratories, and serum levels and types of media affect apoptosis (Ferguson & Baguley, 1996). Mitoxantrone-induced apoptosis was demonstrated in cultured B lymphocytes from a patient with chronic lymphoblastic leukaemia (Bellosillo et al. Mitoxantrone-induced polyploidy was demonstrated by cytogenetic techniques in Chinese hamster ovary cells by Sumner (1995). Although not directly studied for induction of aneuploidy, mitoxantrone inhibited the polymerization of microtubule assembly (Ho et al. A clinical preparation of mitoxantrone weakly induced sex-linked recessive mutation, but the response failed to reach statistical significance (Frei et al. Similarly, assays for dominant lethal mutation in male and female Sprague-Dawley rats showed signs of reduced pregnancy rates but no clear statistical trend in dominant lethal events in either sex. Most of the mutational events reported in mammalian cells, including point mutations, chromosomal deletions and exchanges and aneuploidy, can be explained by this activity. Instead, it has two other activities that may be responsible for other types of mutation. It possesses readily oxidizable functions: Oxidation of the substituted anthra- quinone skeleton leads to biotransformation of mitoxantrone (Mewes et al. Nevertheless, none of the mutations seen with mitoxantrone is of the type usually associated with oxygen radicals. The second possibility for the role of mito- xantrone in causing translocations is that it selects for cells that already have trans- locations. Chemotherapy has profound effects on the kinetics of the bone marrow; it causes cell death, forcing many bone-marrow stem cells to divide, which might select for the rare stem cells with a translocation (Knudson, 1992). It is used mainly in the treatment of advanced breast cancer, non-Hodgkin lymphoma and certain leukaemias. Case reports of acute myeloid leukaemia developing in patients treated with mito- xantrone are compatible with the association found in the cohort study. The drug is rapidly taken up by blood cells and is extensively distributed in body tissues. The pharmacokinetics of mitoxantrone is linear up to 80 mg/m2 (standard dose, 12 mg/m2).
With such systems 100 mg amantadine fast delivery hiv infection rates ukraine, it has been shown that drug flux can be increased proportionately over that achievable using a simply saturated solution cheap 100mg amantadine with amex antiviral quiz. Furthermore order 100mg amantadine with visa antiviral uk, it appears that this strategy can also induce Supersaturation of the drug in the stratum corneum. The idea is attractive as it appears to be driven only by thermodynamics, without obvious perturbation of the barrier per se. The principal concerns relate to stability and shelf life of a product based upon Supersaturation; however, creative packaging (i. This route of administration involves a reproducibly adhesive and occlusive system, which covers post-application a specific, unchanging site of pre-determined area. The anatomic choices for administration are pre-set and identified on the approved labeling for the system. Usually, the drug is present in the patch throughout the application period at unit, or at least constant, thermodynamic activity, resulting most typically in a significant period of approximately zero-order drug delivery. Administration is possible from once-a-day to once-a-week; again, the application time is a key feature of the patch labeling. For the systems currently marketed, there is an established relationship between the plasma concentrations achieved and the therapeutic effect desired. Bioequivalency between different devices containing the same drug is based upon matching of plasma concentration versus time profiles. Transdermal drug delivery almost certainly results in local skin tissue levels of the drug which are significantly higher than those achieved by more conventional routes of administration. For this reason, particular attention must be paid to questions of skin irritation and sensitization. Finally, it is important to note the beneficial contributions of transdermal drug delivery after nearly 20 years of commercialization. It has been possible to achieve blood level profiles of a drug quite distinct from those produced using other, more conventional dosage forms (e. These distinct plasma concentration profiles have been obtained from patches of quite different design, from which drug is released by more than a single mechanism. The absolute blood level of a transdermally delivered drug can be manipulated in a linear fashion by changing the active surface area of the patch. Because the transdermal route of administration largely avoids the first-pass effect, ratios of metabolites different from those seen after oral dosing are produced (usually with beneficial reduction in side-effects). Transdermal delivery has found application in diverse therapeutic areas, and has demonstrated an ability to provide sustained drug input for periods of 0. Not infrequently, the drugs delivered transdermally have proven difficult to formulate for other routes of administration. And last, but not least, transdermal delivery has resulted in a 214 significant improvement in the potential for better patient compliance and drug utilization. Thus, despite the challenges of moving drugs across the skin, transdermal administration has established itself as a successful and feasible route of absorption. Further advances in the technologies of enhancement, and the design and development of more potent therapeutic agents, can only increase the applications and usefulness of this unique and sophisticated technology. A full-text version of this chapter with supplementary information and illustrations can be found at: http:// pharmal. Describe the structure of the skin with reference to the key physiological features. Describe the basic physical chemistry which may be used to model transdermal drug transport. Describe the advantages and disadvantages of transdermal drug delivery over other routes of drug delivery. Using appropriate examples, describe the importance of rate-control in transdermal delivery. List five examples of commercially available drugs that are delivered by transdermal delivery systems. This is another example of local delivery since the lining of the nose was the intended site of action for the study. The nasal cavity may also be exploited as a route of entry into the systemic circulation, either because the absorption profile of the drug is appropriate to its clinical application, e. These molecules are unlikely to realize their full clinical potential unless the patient can easily and conveniently self-administer the drug and hence this goal has led to the investigation of various transmucosal routes for drug delivery including the buccal, pulmonary, rectal and nasal routes. So far, nasal delivery has been the most successful of these alternative routes, with nasal sprays for buserelin, desmopressin, oxytocin and calcitonin already available commercially. Extensive research is currently being carried out in this area and the potential of the nasal route for systemic drug delivery comprises the focus of this chapter. The lining of the vestibule changes from skin at the entrance, to squamous epithelium and then to ciliated columnar secretory epithelium at the turbinates. The area from the anterior ends of the turbinates to the anterior portion of the nasopharynx constitutes the main nasal passage. Here the walls of the nasal septum are folded to create the turbinates and meatuses (air spaces). The olfactory region of the nose is located towards the roof of the nasal cavity and is lined with non-ciliated neuro-epithelium. The remainder of the main nasal passage is lined with pseudostratified columnar secretory epithelium consisting of basal cells, goblet cells and columnar cells which may be ciliated or unciliated (Figure 9. Microvilli are found on the columnar cells which increase the surface area available for absorption. The nasal mucosa is highly vascular; superficial and deep layers of arterioles supply the lamina propria and between the venules and capillaries there are numerous sinuses or venous lakes which are linked to erectile tissue, particularly in the middle and inferior turbinates, which enable the airways to widen or narrow. This autonomically controlled vasculature of the nasal tissue, in combination with its rich supply of secretory cells, is of importance in the modification of inspired air. A: nasal vestibule; B: inferior turbinate; C: middle turbinate; D: superior turbinate; Hatched area: the olfactory region 9. The olfactory region of the nose, a small patch of tissue containing the smell receptors, is located towards the roof of the nasal cavity and is lined with non-ciliated neuro-epithelium. Approximately 20% of the air flowing through the nasal cavity is directed upwards to the olfactory region. Here, bipolar neurones react to inspired air and initiate impulses in the olfactory nerves. The anatomy of the nose permits intimate contact between the inspired air and the mucosal surfaces enabling the air to be warmed and humidified by the vasculature and secretions of the epithelium. Inspired air of 23 °C and 40% relative humidity can be brought to 32 °C and 98% relative humidity upon inhalation via the nose. An additional form of air-conditioning is concerned with the removal of particulates, such as dust, microorganisms and allergens, from the inspired air. The large cross-sectional area of the nasal cavity and relatively low air velocities are ideal for particle deposition, as is the turbulence caused beyond constrictions where changes in air flow direction occur. The efficiency of particle removal from the air-stream is dependent on a number of factors including the aerodynamic diameter of the inhaled particles: • Particles greater than 10 µm are generally filtered out by the vibrissae at the nostrils.
This concept is taken further with performance-based risk-sharing agreements for ultra-orphan therapies buy generic amantadine 100mg on line hiv infection control at home, where price reductions can be entertained or negoti- ated if clinical outcomes are suboptimal or not compelling cheap amantadine 100 mg on line antiviral eye drops for cats, which provides an approach to address the uncertainty regarding the long-term eﬀectiveness of costly ultra-orphan drugs 100mg amantadine overnight delivery stages of hiv infection wiki. In summary, the key dimensions of commercialisation success around which companies must diﬀerentiate in order to win in the orphan drug market include understanding and exploiting orphan disease market fundamentals (e. There are two key evaluations or reports that have investigated this topic – the Drug Discovery Today article ‘Orphan Drug Development: An Economically Viable Strategy For Biopharma R&D’ (published in 2012), and EvaluatePharma’s ‘Orphan Drug Report’ (published in 2013). This indicates that mean per-year economic values of the orphan and non-orphan drug cohorts were almost equal, which underscores the value-creation viability of orphan drugs. View Online 102 Chapter 4 overall pharmaceutical market (excluding generics), as outlined in Figure 4. A separate analysis, in the same report, demonstrated a statistically signicant greater trend for multi-indication orphan drugs to target initial approval in an orphan vs. When the development plans for individual orphan drugs are being created, the cost, complexity, challenges and high-risk nature of pharmaceutical R&D in general should not be underestimated. The current trends in the orphan drug product development arena provide some interesting themes and an inno- vation imperative for inuencing the evolution of the biopharmaceutical landscape – for orphan drug R&D specically, as well as continual stimula- tion of biopharmaceutical R&D in general. Orphan drug R&D will make important contributions to life sciences research, drug discovery and translational medicine, thereby enhancing therapeutic development approaches (e. Indeed, orphan drug R&D experiences will help to advance the development and use of personalised/stratied medicine approaches and targeted medicines. Orphan drug R&D also has a key role in evolving clinical development paradigms (e. It will be interesting to see the extent to which ‘real world trials’ are included as part of ongoing orphan drug development programme eﬀorts to expand clinical data sets and update the risk–benet prole of orphan drugs. The ‘real world trial’ paradigm, gathering eﬃcacy and safety data across countries where feasible, could help encourage greater use of progressive (not only conditional) regulatory approval approaches for orphan drugs, which could help address concerns regarding the paucity of clinical data available at the time of marketing authorisation. Awareness, education, outreach and marketing approaches, for consumers and prescribers, will also be inuenced by the degree to which orphan drugs embrace social media and community connectivity models. Merkel and Rare Diseases Clinical Research Network, Mol Genet Metab, 2009, 96,20–26. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 109 33. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 111 76. Patient support groups, voluntary health organisations and disease advocacy organisations are just a few of the names by which advocacy and support for rare conditions is known. These organisations run the gamut from simple support for people aﬀected by a condition to full-blown research entities that rival some pharmaceutical companies in nancing and capacity. When specically considering drug development for rare diseases, it is more likely that the organisation lies at the research entity end of the spectrum. In determining what phrase to use to describe these entities, it should also be noted that there is a growing distaste in both umbrella bodies comprised of these organisations as well as among the individuals aﬀected by rare conditions for the term ‘patient’. Much of the lives of these individuals and their families are spent living with a chronic condition, and not in the care of a physician. The word ‘patient’ connotes the less than empowering position of being in the doctor–patient dyad and not in a position of power and participation. Biomedical research, and particularly drug development, lying as it does on the far end of the translational spectrum, requires participation of the individuals, families and communities it will benet. It would perhaps be more precise to say ‘disease research organisations’, but that would limit the discussion unnecessarily, because a substantial part of the acceleration of drug development in rare diseases comes from activity other than direct scientic research. Their participation is uneven and fragmented, thus not easily discernable or measured, although there are certainly extraordinary excep- tions. These organisations span the continuum from providing simple support for aﬀected individuals and families, to creating and operating full-blown for-prot pharmaceutical companies. However, as described in detail in other chapters of this book, there is little incentive for these companies to invest in diseases with low or negligible commercial potential, because this business model is driven by very ambitious revenue and quarterly prot goals. Looking ahead and in the context of a quite generalised economic crisis, the commercial attractiveness of developing drugs for small disease populations is becoming increasingly ‘uncertain’. Indeed six-digit treatment costs per year are less and less likely to remain bearable for strangled health care systems and the ethical pressure of providing access to health care to those suﬀering from rare and oen debilitating diseases is putting strong pressure on treatment pricing. As described elsewhere, it takes up to 18 years, on average, for a drug to move from discovery to commercialisation. Only ve in 5000 compounds that enter preclinical testing make it to human testing, and only one of those ve is ever approved for use. This is not an imaginable or acceptable failure rate for those aﬀected by disease. Estimates for R&D costs for a single new drug (taking into account failed projects) can now range between $800 million to $1. Because successes are scarce, failures are the norm, and costs continue to rise, the pharmaceutical industry is scrambling for answers to reduce the inherent risks of this endeavour and is attempting to shorten the timelines of the R&D process, while minimising attrition through stringent quality controls and de-risking strategies at all levels. Despite all these eﬀorts, the uncertainties and the nancial risks remain high, translating into enormous pressure on pharmaceutical companies. In the last 5 years, most large pharmaceutical companies have cut their staﬀs substantially, most notably within the research workforce, and now focus principally on only the lowest risk and highest prevalence targets and diseases with proven or plausible commercial potential. That is no longer the major concern – pharmaceutical and biotech companies have begun to see rare diseases as a solution to their woefully stressed business models. They are clearly aware that this is a lucrative business and will draw a substantial audience. Thus registration fees of more than $1000 per attendee are typical, and there is no lack of participation. There has been a great deal of discourse about how to actually impact the translational research system to increase its eﬀectiveness. Many pharmaceutical companies are opening rare disease therapeutic development divisions, hop- ing to capitalise on the generally high prices these drugs can garner, as well as attempting to discover new models to sustain and advance the industry. Mindful of the fact that only about 5% of all rare conditions have treatments, and aware that organisations such as the International Rare Disease Research Consortium16 declare an international goal of 200 new interven- tions by 2020, there is no doubt that a new model or models are critical. There simply is no pathway to accelerate drug development for rare (or any) diseases without transforming the current system. Indirect inuences are at work on the ecosystem or environment, and are perhaps more inuential on the system overall than is direct action. Direct engagements are the processes and activities that involve the nuts and bolts of drug development. Riordan, who were working with the Foundation at the time, discovered the gene that causes cystic brosis. By entering into contractual agreements with its commercial partners, it allows the Foundation to receive nancial returns such as royalties aer approval and/or sale of certain drugs that are developed as a result of the organisation’s funding. This creates a nancially sustainable model where nancial R&D returns are reinvested into R&D to further ght for a cure.
If the catheter remains occluded after 120 minutes buy amantadine 100mg without a prescription antivirus website, a second dose may be administered by repeating the procedure Patients weighing at least 10 kg and less than 30 kg: 1 mg/mL concentration; do not exceed 2 mg in 2 mL Patients weighing at least 30 kg: 2 mg in 2 mL Systemic thrombosis: initial buy 100 mg amantadine otc hiv virus infection youtube, 0 generic amantadine 100 mg mastercard main symptoms hiv infection. Therapeutic levels are not clearly established, but the recommended minimal effective plasma con- centration is 0. Alteplase is metabolized in the liver, with more than 50% of drug cleared within 5 minutes after the infusion has ended and 80% cleared within 10 minutes. Precautions/Warning Alteplase may cause bleeding; concurrent use of heparin or oral anticoagulants may increase bleeding; arterial and venous puncture should be minimized; avoid intramuscular (I. Drug-Drug Interactions Anticoagulants and drugs that affect platelet function may increase the risk of bleeding. Safety of the concurrent use of aspirin or heparin with alteplase within the first 24 hours after the onset of symptoms is unknown and should be considered with caution. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial and/or ventricular arrhythmias. Compatible Diluents/Administration Alteplase must be used within 8 hours of reconstitution. Aminocaproic acid widely dis- tributes through intravascular and extravascular compartments. Forty to 60% of aminocaproic acid is excreted as unchanged drug in the urine within 12 hours. Contraindications Contraindications to aminocaproic acid use are hypersensitivity to aminocaproic acid, disseminated intravascular coagulation, and evidence of 252 P. Precautions/Warnings Use injection form in premature neonates cautiously because of the presence of benzyl alcohol; use aminocaproic acid cautiously in patients with cardiac, hepatic, or renal insufficiency (drug may accumulate in patients with decreased renal function and may require dosage adjustment); use cautiously in patients with hematuria of upper urinary tract origin or in patients at risk for venooc- clusive disease of the liver; a definite diagnosis of primary fibrinolysis must be made before administration. Adverse Effects Adverse effects of aminocaproic acid include hypotension, bradycardia, arrhyth- mias, headache, seizures, rash, hyperkalemia, nausea, vomiting, decreased platelet function, agranulocytosis, leukopenia, myopathy, acute rhabdomyoly- sis, glaucoma, deafness, renal failure, dyspnea, and pulmonary embolism. It is recommended that patients on therapy for longer than 2 weeks and with total doses of greater than 500g should be monitored carefully for renal, hepatic, or muscle toxic- ity. Aprotinin Indication Aprotinin is used in the United States in adults to prevent hemorrhage after coronary artery bypass graft; it has been used in liver transplantation as a 11. Mechanism of Action Aprotinin is a serine protease inhibitor; it inhibits plasmin, kallikrein, and platelet activation; and is a weak inhibitor of plasma pseudocholinesterase. Dosing A test dose should be administered to all patients at least 10 minutes before administration of the routine dose to assess for allergic reaction. Infants and Children: data pertaining to dosage recommendations in this population vary, with no conclusive dosing regimen established. Pharmacokinetics Aprotinin has a rapid distribution and a slow degradation by lysosomal enzymes, with an elimination half-life of 150 minutes and a terminal elimina- tion of 10 hours. Aprotinin is an ingredient in some fibrin sealant products, and this should also be noted. Consider limiting aprotinin use to patients in whom the benefit of reducing blood loss is essential to management. Anticoagulants, Antithrombotics, and Antiplatelets 255 Poisoning Information Carefully monitor patients for the occurrence of toxicity. Compatible Diluents Aprotinin is incompatible with corticosteroids, amino acid solutions, fat emul- sions, heparin, and tetracyclines. Administration All patients treated with aprotinin should first receive a 1-mL test dose at least 10 minutes before the loading dose to assess for a potential allergic reaction; patients who have received aprotinin in the past are at increased rate of anaphylactic reac- tions and should be pretreated with an antihistamine and H2 blocker before administration of the loading dose. Administer the loading dose over 20 to 30 minutes with patient in supine position; no other medications should be present in the same line. Mechanism of Action Argatroban is a direct, highly selective thrombin inhibitor that reversibly binds to thrombin’s active site. Recommendations on dosing have been extrapolated from the adult literature; however, because of 256 P. Neonates and infants, however, may have immature development and function of the liver and require dosing on the more conservative side of the range. The elimination half-life of argatroban is 39 to 51 minutes and can be as long as 181 minutes in patients with hepatic impairment. Contraindications Contraindications to argatroban are hypersensitivity to argatroban or major bleeding. Precautions/Warning Caution should be taken in administering argatroban to patients with increased risk of hemorrhage (e. Poisoning Information A minimum toxic dose of argatroban in humans has not been established. Treatment of possible overdose is symptomatic and supportive, with no specific antidotes available. Monitor for signs of bleeding, vital signs, electrocardio- gram, and renal and hepatic function in symptomatic patients. Discontinue or decrease infusion to control excessive anticoagulation with or without bleeding. Reversal of anticoagulant effects may be longer than 4 hours in patients with hepatic impairment. Hemodialysis may remove up to 20% of the drug; however, this is considered clinically insignificant. Off-label use of aspirin includes the treat- ment of Kawasaki Disease and to prevent thrombosis in patients after single ventricle palliation with a shunt, bidirectional Glenn, or Fontan procedure. Mechanism of Action Aspirin is a salicylic derivative that inhibits both prostaglandin synthesis and platelet aggregation. Dosing Children: Analgesic and antipyretic (oral, rectal): 10 to 15mg/kg/dose every 4 to 6 hours; maximum dose, 4 grams/day Anti-inflammatory (oral): initial, 80 to 100 mg/kg/day in divided doses Kawasaki Disease (oral): 80 to 100 mg/kg/day divided every 6 hours for 2 weeks, then 3 to 5 mg/kg/day once daily for 7 weeks or longer Antiplatelet effects: adequate pediatric studies have not been per- formed, therefore, the dose is not well established. Doses ranging from 3 to 10mg/kg/day administered as a single daily dose have been used; doses are rounded to a convenient amount; maximum, 325 mg/dose Mechanical heart valves: 6 to 20 mg/kg/day either alone or in combina- tion with dipyridamole Blalock-Taussig shunt and endovascular stents:2,11 1 to 5 mg/kg/day Fontan procedure: 5 mg/kg/day Arterial ischemic stroke: 2 to 5 mg/kg/day after discontinuation of anti- coagulants Adults: Analgesic and antipyretic (oral, rectal): 325 to 1000 mg every 4 to 6 hours (up to 4 grams/day) Anti-inflammatory (oral): 2. The immediate-release formulation is completely absorbed, whereas the enteric-coated form is erratically absorbed. The half-life of the active drug is 6 hours with a time-to-peak serum concentration being 1 to 2 hours (this may be delayed with controlled- or timed-release preparations). Patients with asthma, rhinitis, or nasal polyps may be more sensitive to the effects of salicylates. Combination therapy of salicylates and carbonic anhydrase inhibitors, such as acetazolamide, brinzolamide, dichlorphenamide, dorzolamide, and meth- azolamide, has resulted in significant metabolic acidosis in pediatric and adult patients. Nondihydropyridine calcium channel blockers (diltiazem and verapamil) may enhance the anticoagulant effect of salicylates. Salicylates may enhance the adverse/toxic effect of varicella virus-containing vaccines causing Reye’s syndrome, and they may increase serum concentration of methotrexate. Adverse Effects Adverse effects of aspirin use include rash, urticaria, nausea, vomiting, dys- pepsia, epigastric discomfort, occult bleeding, prolongation of bleeding time, leukopenia, thrombocytopenia, hepatotoxicity, bronchospasm, tinnitus, head- ache, dizziness, confusion, metabolic acidosis, and hyperpyrexia. Poisoning Information Salicylate serum concentrations correlate with the pharmacological actions, and adverse effects are observed with serum salicylate levels of approximately 100mg/dL. Patients with mild-to-moderate intoxication may develop fever, tachypnea, tinnitus, respiratory alkalosis, metabolic acidosis, lethargy, mild dehydration, nausea, and vomiting.
Although these notions on role behavior may help in understanding malingering in general cheap amantadine 100 mg otc hiv transmission statistics uk, there is as yet little empirical work which would aid in the prediction of the persons and the circumstances which might combine to produce simulation of psychosis purchase 100 mg amantadine fast delivery antiviral birth control. It is apparent that almost all individuals play different roles cheap amantadine 100 mg without prescription hiv infection after 2 years, and the role played is partly dependent upon who the partner is in the social situation. Block (9) and Block and Bennett (11) have demonstrated that a single subject varies his behavior as the interpersonal situation changes. The complexity of this understanding did not appear to be a function of self and ideal-self discrepancy in a homogeneous sample of college students. However, Gough (35) and Cameron (14) have argued that role-taking ability is related to emotional well-being. Studies by Sarbin and Farberow (78), Sarbin and Hardyck (79), and Sarbin and Jones (80) have tended to confirm that adequate role perception and validity of role enactment are positively related to adjustment. However, in a study by Helfand (40), schizophrenics in remission were found to be more adept at taking the role of a standard stimulus person than were either normals or chronic schizophrenics. Thus, there are somewhat contradictory findings concerning the question of adjustment in relation to skill for enacting a variety of roles. The more specific question of the type of person who will attempt to simulate the role of the psychotic has not been investigated experimentally. From role theory comes the suggestion that the role chosen and played well is the one which is congruent with the nature and organization of the self (77). This would tend to support those writers who feel that malingering of psychosis is a symptom of a serious personality defect, if not a psychosis in itself. This position is most clearly taken by Ossipov (69) who feels that the person who simulates a psychosis is accentuating his own latent characteristics. Moreover, several authors have pointed out that malingering may be used to -280- conceal an actual psychosis, and that which was at first considered malingering may show up as a grave disorder later (13, 22, 34, 47, 58). Eissler (22) explains this as an attempt to hold a psychosis in abeyance by acting as if the behavior is under control and not something one is submitting to. Furthermore, on recovery from psychosis, a person may claim he was malingering because it may be too humiliating to have others know that that he was suffering from a psychiatric disorder (22, 58). Thus, regardless of the problem of who is best at taking roles, the disturbed or the integrated individual, there are many who would hold that the choice of a specific role, that of the psychotic, usually indicates serious psychopathology. However, others argue that while the malingerer may be emotionally upset, there are also many normals and near normals who malinger under extreme circumstances (22, 23, 29, 30, 41, 58, 88, 91). As MacDonald (58) and Ossipov (69) indicate, the simulation of mental incompetence is more frequent when there is danger of loss of life. Certainly the malingerer does not expect to be punished more severely for having committed a murder and feigning psychosis than for having committed a murder without feigning psychosis, if through simulation there may be a chance of avoiding punishment. The person may see himself in a role conflict, and failure to resolve the conflict may cost him his life. He is occupying two positions simultaneously, and the role expectations of the one are not compatible with the other. As a loyal soldier he is expected by his country to withhold information which would aid the enemy. As shown by Gullahorn (38), a person who is placed in a situation where incompatible demands are placed upon him because of his role relationships in two groups will try to retain both positions and find a way of satisfying them both. Toby (84) in his analysis of role conflict situations suggests that illness is an excuse by which a person in role conflict may avoid performing an obligation or duty of a role, without relinquishing the position and without suffering sanctions for failing to perform the duty. Thus illness, and particularly mental illness, would allow the prisoner to escape the role dilemma, and since illness is such a widespread excuse, special personality characteristics may not be necessary for selecting this role under extreme circumstances. Furthermore, if one conceives of malin- -281- gering as antisocial behavior (Szasz, 83), then there is much evidence to indicate that many people are dishonest at one time or another (15, 17, 39, 51, 59). This is one way of interpreting the rather consistent finding that poor students who are having difficulty maintaining their roles as students are more likely to cheat (15, 17, 39). This also seems to be congruent with the finding that a person will take a particular role if it is seen as satisfying an important need (66). As pointed out by several writers, the person who simulates is an actor who portrays an illness as he understands it (8, 58, 69). It would appear that the characteristics and behaviors which are perceived as crucial to the role are acquired through experience and observation. Personal experiences may have occurred with friends or relatives who were psychotic. In the two cases described by Atkin (4), the role perceptions necessary for the malingering were built up by confinement in mental hospitals at eariler times. The cultural stereotype of the deranged person also seems to be used as a basis for role enactment. Observations made of criminal cases being psychiatrically evaluated prior to trial tend to support this. Many Negro patients who are thought to be malingering tend to play the part of a slow, somewhat confused and defective person who understands little of what is going on around him. Like members of other oppressed minorities, some Negroes have adopted a mask of dullness and unawareness when interacting with the Caucasian majority (5). The cultural determination of the ingredients Which are perceived as comprising the psychotic -282- role is also evident in the work of Benedict (6). Her investigation of trancelike states in primitive cultures led her to conclude that the content of the hallucinations experienced is relatively constant within groups but highly variable between groups. This suggests that the role of the person in trance is learned from interaction with his own group. As she states, "Even in trance the individual holds strictly to the rules and expectations of his culture, and his experience is as locally patterned as a marriage rite or an economic exchange" (6, p. Sarbin (76) gives a similar interpretation to the behavior of the hypnotized subject which can also be approximated through simulation. This principle appears central to the indices of malingering which are reported in the literature. Although the simulator may have some understanding of psychosis, his understanding is usually spotty. He fails to appreciate the underlying disturbance and portrays isolated symptoms instead (19, 87). Thus, he may complain of hallucinations or delusions but not show any of the formal characteristics of schizophrenic thought. Often he presents symptoms which are exceedingly rare, existing mainly in the fancy of the layan (8). This symptom is very unusual in true psychosis, but is used by a number of simulators (19). In schizophrenia, the onset tends to be gradual, delusions do not spring up full-blown overnight; in simulated disorders, the onset is usually fast and delusions may be readily available (47, 69). The feigned psychosis often contains many contradictory and inconsistent symptoms, rarely existing together (8, 47, 69, 87). The malingerer tends to go to extremes in his portrayal of his symptoms: he exaggerates, overdramatizes, grimaces, shouts, is overly bizarre, and calls attention to himself in other ways (8, 19, 47, 55, 69, 87).