Mark Corson

By P. Makas. University of Maryland Eastern Shore.

The virus certainly may have been present for much longer malegra fxt 140mg on-line erectile dysfunction and diabetic neuropathy, but new diag- nostic procedures buy discount malegra fxt 140 mg line impotence vasectomy, increased technology in virology order 140mg malegra fxt overnight delivery erectile dysfunction uti, and recognition of the virus and its pathophysiology have heightened awareness of this disease. One word of caution, however— throughout the United States in the 1980s in endemic individual sick cows with septic mastitis, septic metritis, form in beef and dairy cattle. The virus apparently does not infect alveolar macrophages but may damage physi- cal defense mechanisms of the lower airway, such as mucociliary transport, and may lead to antigen-antibody complexes that subsequently engage complement and result in damage to the lower airway. Although experi- mental reproduction of the clinical disease has not been consistently successful in challenge studies, there have been recent studies that help explain the pathogenesis of Figure 4-33 the disease further. This cow had respiratory distress and of inflammatory cytokines (tumor necrosis factor, inter- severe subcutaneous emphysema over the chest, back, leukin 6, and interferon); these are thought to help pro- and face (notice indentation of the halter on the face). In any and rales (usually as a result of secondary bacterial bron- event, interstitial pneumonia, secondary bacterial pneu- chopneumonia) have been described. However, the relative defi- agement and have not purchased new cattle, shipped cit of airway sounds fits the existing pathology because and returned existing cattle, or stressed animals in any pneumothorax and/or diffuse interstitial edema and em- apparent way. Where did the infection come from in physema compress the small airways and cause the lungs these herds? Was it latent in a recovered animal, or was to be quieter than one would expect (Figures 4-34, A to it introduced by regular visitors to the farm? This is the same phenomenon that occurs thought to be the reservoir, but it has not yet been in proliferative pneumonia in which the alveoli and shown how or why the virus activates, replicates, and small airways are obliterated or reduced in size. Dyspnea will be severe in such cases, and virus, or serologic confirmation when acute epidemics affected animals usually show open mouth breathing of respiratory disease occur in cattle. Despite the high high morbidity in the affected group within several days fevers and respiratory distress, affected cattle frequently to 1 week. The first stage or phase of the disease is ple increased respiratory rate (40 to 100 breaths/min) characterized by mild or more serious signs as described to open mouth breathing; and in all but the most mild above. The affected animals apparently improve over the outbreaks, a percentage of the affected cattle will have next few days only to develop peracute severe respiratory subcutaneous emphysema palpable under the skin of the distress several days to several weeks after their initial dorsum, especially near the withers (Figure 4-33). Because these animals initially appeared cultation of the lungs in acute cases may reveal a wide to have mild disease and responded to treatment, this range of sounds. These signs are rarely seen in calves younger than 6 weeks, but calves aged 2 to 6 months seem to be most commonly affected. Auscultation of the lungs in acute cases may be helpful if the lungs sound diffusely quiet despite obvious severe dyspnea. Any se- vere pneumonia (especially other interstitial pneumo- nias or severe consolidating bronchopneumonia) can also cause subcutaneous emphysema because the only C remaining normal lung tissue (dorsal or caudal lung fields) is overworked to the point at which emphysema and interstitial edema are likely. Baker and Frey emphasize that antibody titers show reasonable patience when requesting confirmation may increase early after acute infection and often peak of viral diseases. Therefore collection of se- the laboratory, explain the seriousness of the outbreak, rum on day 1 and day 14 is very important when evaluat- provide appropriate samples, and ascertain the appro- ing seroconversion. Necropsy otics are indicated to counteract or discourage bacterial specimens may be very helpful in establishing a diagno- bronchopneumonia and should be initiated following sis. This is especially true if death has been acute and collection of tracheal wash samples from acutely in- secondary bacterial pneumonia has not yet developed to fected calves or cattle. In addition, focal firm bacterial therapy may be instituted if bacterial patho- areas of pneumonia will be palpable throughout the en- gens are isolated. Subsequent laboratory procedures may identify the ity reaction, should receive antiinflammatory medication causative virus, but viral cultures often lag behind bacte- in addition to broad-spectrum antibiotics. Despite the clinical frustra- onset and extreme dyspnea exhibited by these animals is tions and economic consequences, the veterinarian must usually fatal; therefore heroic therapeutic measures are indicated. Several drugs may be indicated, and clinical judgment will determine which drugs will be used. For an adult cow with this form of the disease, drugs that may be considered and their dosages follow: 1. Nebulization with corticosteroids and anti- capable of infecting the bovine respiratory tract and pre- biotics can be helpful, but a bronchodilator should be disposing infected animals to more severe pneumonia administered either before beginning the nebulization when subsequently exposed to bacterial pathogens such or at the same time. After experimental inoculation, the ipratropium and/or aminophylline (2 to 4 mg/kg every virus infects the upper and lower airways of calves with 12 hours) as a constant rate infusion can be used. In subsequent damage to ciliated epithelial cells, mucus animals that develop pneumothorax, evacuation of free layer, mucociliary transport, and infection of alveolar air from the pleural space can offer significant improve- macrophages. The complete mediastinum of cattle often con- purulent exudate fills some small airways. Therefore culture of the organism from acutely infected calves via tracheal wash, nasopharyn- geal swabs, or necropsy specimens is necessary to iden- tify this organism. Paired serum samples also are help- ful because humoral antibody production is anticipated following infection. Isolation attempts may be fruitless if samples are not collected early in the course of the disease. Fatal cases usually are complicated by secondary bacte- rial pneumonia—especially M. Therefore the lated from the lower airway and alveolar macrophages of results are devastating if a cow or group of cows acutely infected cattle. Naive cattle exposed quickly from severe pneumonia that necropsy identifies to type 2 strain may develop severe interstitial pneumo- bacterial pneumonia as the cause of death. Other cattle may show no other signs—no diarrhea, no mu- management-related stresses, transportation, pen reorga- cosal lesions—and merely appear depressed and febrile nization, poor ventilation, and so on may also contribute at 106. Type 1 strains are commonly isolated posed bacterial infection develops, clinical pneumonia from the lower airway and more recently pulmonary may not occur. Naive cattle infected with the type 2 strain may die with severe interstitial Other Viruses pneumonia. Coronavirus is commonly Although naive or susceptible cattle fully recover im- found in outbreaks, either acute or endemic, but can mune function following the development of adequate also be commonly found in healthy animals.

It was postulated that their seafood- rich diet containing high amounts of long-chain polyunsaturated fatty acids had an important role order malegra fxt 140 mg with visa erectile dysfunction causes heart disease. There is currently a large amount of both biochemical and clinical data on these long-chain fatty acids cheap malegra fxt 140 mg online diabetes and erectile dysfunction health. Chapter 6 / Complementary and Alternative Therapies 93 The polyunsaturated fatty acids are categorized as n-3 or omega-6 (n-6) fatty acids based on the biochemical structure of the compounds safe malegra fxt 140mg erectile dysfunction treatment protocol, specifically, the location of the double bond proximal to the methyl terminus. Both n-3 and n-6 fatty acids are essential fatty acids that cannot be synthesized by the body and therefore must be obtained through the diet. The n-3 fatty acids have anti-inflammatory and anti-thrombotic properties, whereas the n-6 fatty acids are proinflammatory and prothrombotic. Unfortunately, the modern human diet contains much more n-6 fatty acids as a result of consumption of vegetable oils high in n-6 fatty acids (such as corn, safflower, sunflower, and cottonseed oils) and meats from land animals. In addition to fish, seeds, and oils (canola oil, flaxseed oil, walnut oil), green leafy vegetables, and beans contain n-3 fatty acid in the form of -linolenic acid (25). A relative increase in n-6 fatty acids and reduction in n-3 fatty acids promote a proinflammatory state, including pain, swelling, warmth, redness, and loss of function. These effects can reduce the function of antigen-presenting cells and, consequently, decrease pathogenic T cells mediating inflammation (26). The n-3 fatty acids have also been shown to inhibit enzymes involved in chronic joint inflammation and cartilage destruction. However, all of the studies have involved relatively small number of subjects (N = 16–67). All of the trials in the meta-analysis were randomized, double-blind, placebo-controlled. Although n-3 fatty acids have anti-thrombotic effects, there have been no documented cases of abnormal bleeding caused by fish-oil supplementation even in combination with other anticoagulant medications (38). Although there have been prior concerns of fish oil worsening hyperglycemia, a recent meta-analysis concluded that fish-oil supple- ments in the range of3gto18gperdayhadnostatistically significant effect on 96 Part I / Introduction to Rheumatic Diseases and Related Topics glycemic control. Furthermore, fish-oil supplements are essentially free of mercury and other contaminants that may be present in fish (42). However, fish and seafood are a major source of human exposure to methylmercury, polychlorinated biphenyls, dioxins, and other environmental contaminants. Larger, older, predatory fish tend to have higher concentrations of these contaminants. Thus, it is important for consumers to be aware of both the advantages and risks of fish consumption, especially women and children who may be at increased risk of mercury intoxication. In summary, there are a number of potential benefits of n-3 fatty acid supple- ments. Furthermore, n-3 fatty acids have favorable cardiovascular benefits through anti-thrombotic properties. As discussed in the fish-oil section, n-3 fatty acids are anti-inflammatory and n-6 fatty acids are for the most part pro-inflammatory. However, certain n-6 fatty acids derived from plant seed oils have predominantly anti- inflammatory effects. In reports that showed benefit, the results became apparent after 3 to 4 months of supplementation. The study size was small with 19 subjects in the treatment group and 18 subjects in the placebo control group. Although no patients withdrew from the study because of adverse effects, a 28% withdrawal rate was observed in each group, perhaps because of the large number of capsules administered. There was no statistically significant improvement in the primary end point of fatigue. Secondary end points of dry eyes, dry mouth, pain, results on Schirmer tear test, van Bijsterveld score, unstimulated whole sialometry, the use of artifical tears or analgesics did not improve significantly (48). Consumption of borage seeds is not recom- mended during pregnancy and lactation due to potential contamination with liver-toxic pyrrolizidine alkaloids (45). Vitamins Vitamins are organic compounds that are required in small amounts for normal metabolism. The human body does not synthesize vitamins, except for vitamin D; therefore, vitamins must be ingested in the diet. Various syndromes and diseases have been linked to vitamin deficiencies such as scurvy, osteoporosis, neuropathy, anemia, osteomalacia, and cancer. Therefore, vitamin supplementation has been promoted for good health and as a preventive measure against certain ailments. The evidence for vitamin supplemen- tation in rheumatic conditions is reviewed in the following section. Vitamin C is important for the growth, development, and enzymatic reactions of bone and cartilage. Vitamin C acts as an antioxidant in facili- tating the hydroxylation of proline and lysine to hydroxyproline and hydroxylysine in procollagen. These products are essential to the maturation of collagen molecules and, thus, to the construction of the extracellular matrix of cartilage. This may be related to alterations in enzymatic activity or reduc- tions in proline hydroxylation or both (52). It was hypothesized, because animals receiving higher doses had higher cartilages weights, that vitamin C protected against cartilage loss by stimulating collagen synthesis (53). However, more recent work has suggested that long-term exposure to vitamin C supplementation might have deleterious effects (54).

While the overall budget spend by healthcare systems around the world on orphan drugs is small compared to more mainstream products such as cardiovascular or anti-inammatory treatments buy malegra fxt 140 mg line erectile dysfunction drug, and the rare diseases that those drugs treat are oen serious and View Online Denitions discount 140 mg malegra fxt amex erectile dysfunction just before intercourse, History and Regulatory Framework for Rare Diseases and Orphan Drugs 25 life-threatening generic 140 mg malegra fxt mastercard erectile dysfunction treatment food, there does appear to be increasing scrutiny of orphan drug pricing. The key evidence for successful orphan drugs in the future will more than ever be safety and above all efficacy. This will be especially true in disease classes where multiple products exist, and one could envisage a system of ‘risk sharing’ in which a sponsor will be required to lower the cost of a drug treatment if it is shown to have less than expected efficacy. More accurate data of rare disease prevalence and genetic causal links will become available. Translational data sets to rene the targeting of small patient populations and measurement of meaningful clinical biomarkers to assess outcome measures as reliable indicators of drug efficacy will evolve. These resources bridge existing data gaps to complete the necessary studies to provide pre-clinical and clinical data required for regulatory purposes. Of particular interest are the translational research programmes offered by the National Center for Advancing Translational Sciences, the National Cancer Institute, The National Institute of Allergy and Infectious Diseases, The National Heart, Lung, and Blood Institute, and the National Institute of Neurological Disorders and Stroke. Although similar in many respects, there are differences in each of the translational research programmes, including the application and review processes. Some institutes make the traditional grants and contracts available for clinical trial planning and implementation. To avoid confusion with the different processes, it is advisable to identify those institutes with a research portfolio that includes aspecic disease interest. These activities within the translational research programmes are expected to complement or supplement the existing biopharmaceutical industry efforts and not to replace the exten- sive activities related to rare disease research and orphan product devel- opment activities. It will also be interesting to see if big pharma, and indeed smaller biotech companies, can be incentivised to work on rare diseases for which there is very little known and take the lead role in driving the basic science behind such diseases. Rare diseases can be staggering if you consider the need for sufficient resources to discover and develop products to diagnose, treat or prevent rare diseases experienced by approximately 6–8% of the population who have one of the more than 6000 rare diseases. Partnering and collaborating with the academic research community is an essential component of R&D efforts for the bio- pharmaceutical and medical device industries to develop a portfolio of potential interventions and diagnostics. The pharmaceutical industry, with its unique product R&D infrastructure and expertise, provides the academic research community with the capability of moving a discovery to the marketplace. Rare diseases do not respect geographical or national borders and offer numerous research and regulatory challenges requiring global efforts as we observe expansion of activities that include the academic research communities from around the world. Numerous academic and government technology transfer programmes are now available to industry. Many of these programmes are formal partnerships between the industry and the academic partners. Both initiatives can lead to products for rare diseases but require a keen understanding of these programmes and the responsible programme staff who provide the links to the existing resources. It is equally important for the academic community to have a clear path to the biopharmaceutical and medical device industries by having knowledge of appropriate contacts and available pro- grammes from the potential industry partners. Many of these arrangements require considerable time for resolution of legal considerations between two or more parties, involving intellectual property and the estimated value of this property, and the milestones associated with drug development. Many of these organisations, such as the Cystic View Online Denitions, History and Regulatory Framework for Rare Diseases and Orphan Drugs 27 Fibrosis Foundation, Pulmonary Hypertension Association, the National Urea Cycle Diseases Foundation, the Parent Project for Duchenne Muscular Dystrophy, and the Progeria Research Foundation, continue to extend their traditional advocacy roles of emphasising rare diseases research and orphan products development and have led to the identication of potentially useful products for their diseases. This new coordinating role has relied upon guidance from the pharmaceutical, biotechnology and medical device industries and contract research organisations. Many of these working relationships advancing to global research investigations are the result of sponsorship and attendance at patient or family and scientic conferences. Many members of the bio- pharmaceutical industry now include active staff liaison and outreach activities between the industry and the patient communities. These activities facilitate the transfer of valuable information about the disease and possible interventions to patients, families, physicians and other healthcare providers, and the public. Each consortia is required to focus on a group of at least three related disorders and receives 5 years of support. More than 15 000 patients have enrolled in studies in the second 5 year period for a total of 22 000 people. A total of 119 studies have been activated since inception and 76 studies activated during the current grant period. With limited resources available, newer models have evolved that utilise the resources available from public–private part- nerships. The rare diseases community recognises and encourages the different multi-organisational approaches to drug discovery View Online Denitions, History and Regulatory Framework for Rare Diseases and Orphan Drugs 29 and development, especially if there is limited or no commercial interest in developing a product for rare diseases. These models also require resources and commitments be made from many private and public organisations to facilitate the development of products. A global approach is required to coordinate research efforts at multiple research sites working under a common protocol and utilising the skills and knowledge from multidisci- plinary research teams. Coordinated and systematic efforts to research and product development require numerous highly motivated global partners utilising the strengths of the individual organisations towards a common goal of developing treatments or diagnostics for rare diseases. United States Congress, Orphan Drug Act, 1983, Public Law Number 97- 414, 96, Stat. National Institute of Health, Office of rare disease research, http:// rarediseases. Department of Health and Human Services, Food and Drug Administration, http://www. Department of Health and Human Services, Food and Drug Administration, http://www. The Committee for Orphan Medicinal Products of the European Medicines Agency Scientic Secretariat, Nat. Department of Health and Human Services, Food and Drug Administration, http://www. University of London, Mitochondrial Neurogastrointestinal Encephalo- myopathy treatment programme, http://www.