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By tailoring the various functional groups along the polymer backbone purchase glycomet 500mg line diabetes diet plate, hydrogels can be designed to be sensitive when subjected to changes in the ambient conditions such as temperature 500mg glycomet diabetic jury duty, pH buy discount glycomet 500mg line diabetes detection dogs australia, electric ﬁeld, or ionic strength. To utilize the environmentally responsive intelligent hydrogel sys- tems over material surfaces for a wide range of applications in the ﬁeld of biomedi- cal engineering, Chirra et al. Nanoparticles, in particular, have been developed for accu- rate, sensitive, and selective biosensing devices due to their unique size-related, ease-of-functionalization, and unique physical properties (electrical, optical, electro- chemical, and magnetic) (39). The immediate follow-up work done by researchers by using the colorimetric system worked on the principle of color change observed when a polymeric network of nanoparticles was formed speciﬁc to the length of the oligonucleotide that aggregated to the biomolecule of interest (5,42). A real-time bioafﬁnity monitoring system based on an angular-ratiometric approach to plasmon resonance light scattering was recently developed by Aslan and colleagues (52). In this strategy, the target molecule induces a conformational change of the detector–ﬂuorophore chain, from arch to stretched form and vice versa, thereby either restoring or quenching the ﬂuorophore for optical detection (Fig. A summary of the recent approaches in the construction of electrochemical biosensors utilizing 100 Chirra et al. When these capture probes are hybridized to matching targets, the binding of the labeled proteins is hindered and is indicated by the decrease in the Au redox sig- nal. This, in turn, establishes a unique Au oxidation wave that can be detected using the electrode (Fig. These devices have an added advantage of low background currents, depending on the type of electrode used (55). This was successfully applied as a biosensor for the amperometric detection of glucose at 0. A similar matrix was used by Tang and colleagues for the detection of carcinoma antigen 125 as represented in various tumors (64). The advantage of this technique is that by controlling the electrochemical parameters of polymer grown on the electrode surface, it is pos- sible to control the various polymer characteristics, such as ﬁlm thickness, perme- ation, and charge transport. Chitosan, a natural polymer exhibiting excellent ﬁlm-forming and adhe- sion ability, together with susceptibility to chemical modiﬁcation, has led to the immobilization of various enzymes over conductive electrodes. The release of these ther- apeutic agents can be triggered by cellular chemical [e. Therapy via Active and Passive In Vivo Targeting The disadvantage of conventional drug administration is that the drug typically does not localize to the target site but is systemically distributed. The success of any in vivo medical application depends on the ability of a nanocarrier to arrive at the targeted tissues after administration into the circulatory system. Passive targeting with these particles, along with radiotherapy, has been used for the treatment of liver cancer, in which the sinus endothelium of liver has openings of 150 nm in diameter. Active targeting, which employs a ligand or antibody functionalized par- ticle, has been successfully used by many researchers to treat certain diseases. Although these ligands are speciﬁc to target receptors, the presence of the parti- cle in the circulatory system provides possibility of normal host immune response. Hepatocyte cell–speciﬁc targeting rendered by the galactose ligand can be potentially used for drug delivery. A plethora of therapeutic delivery systems were developed using the active and passive targeting strategies. The enhanced permeation and retention effect as provided by passive targeting has been used for treating carcinogenic tumors. Nitric oxide was released from water-soluble nanocontainers when a pH stimulus (pH = 3) was given to these drug delivery systems (76). While external stimuli such as pH and temperature prove effective in trig- gered release, internal cellular signals/chemicals can provide an enhanced control on drug release. Gene therapy is the treatment of genetic as well as acquired diseases by the insertion of genes into the cell or tissues. Although an adenovirus vector vehicle for gene delivery has been successfully used for gene therapy, safety issues con- cerned with unpredictable viral cytotoxicity and immune responses have mini- mized viability of gene therapy (90,91). Photoactivated drug release by plasmonically active particles was per- formed by Caruso and colleagues (105,106). A remote-controlled drug delivery strategy based on nanocomposite hydro- gels was developed by West and Halas (107). The triggered release of the proteins by using a laser of wavelength 1064 nm for multiple burst is shown in Figure 14. For most applications, it is critical that the gold surfaces are functionalized in a controlled manner. In addition, recent research activities in applying gold structures (speciﬁcally nanopar- ticles) in diagnostic and therapeutic applications were presented. Gold has a long history of applications at the nanoscale, but only recently applications in medical ﬁelds have grown exponentially in part due to the development of novel methods for functionalization. The history is long, but only the surface of potential applica- tions in nanomedicine has been scratched. Scanning electron microscopic images of the capsules (D) before laser irradiation and (E) after irradiation. Gold nanoparticles: Assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nan- otechnology. Selective colorimetric detection of polynu- cleotides based on the distance-dependent optical properties of gold nanoparticles. Controlled nucleation for the regulation of the particle size in monodisperse gold suspensions. A study of the nucleation and growth processes in the synthesis of colloidal gold. Synthesis of thiol-derivatised gold nanoparticles in a two-phase liquid-liquid system. Synthesis of poly(styrene) monolayers attached to high surface area silica gels through self-assembled monolayers of azo initiators. Surface-conﬁned photopolymerization of pH- responsive acrylamide/acrylate brushes on polymer thin ﬁlms. Polymer brushes by living anionic surface initi- ated polymerization on ﬂat silicon (SiOx) and gold surfaces: Homopolymers and block copolymers. Homopolymer and block copolymer brushes on gold by living anionic surface-initiated polymerization in a polar solvent. Surface-initiated anionic polymerization of styrene by means of self-assembled monolayers. Synthesis of gold nanoparticles coated with well- deﬁned, high-density polymer brushes by surface-initiated living radical polymeriza- tion. Nanocomposites by surface-initiated living cationic polymerization of 2-oxazolines on functionalized gold nanoparticles. Preparation of poly(N-isopropylacrylamide)- monolayer-protected gold clusters: Synthesis methods, core size, and thickness of monolayer. Preparation of poly(styrene-co-N-isopropylacrylamide) micelles surface-linked with gold nanoparticles and thermo-responsive ultraviolet-visible absorbance.
View Online The Challenges of Conducting Clinical Trials in Diseases with Small Target Populations 77 33 buy 500 mg glycomet with mastercard diabetes diet yoga. Turner and American Heart Association Statistics Committee and Stroke Statistics Subcommittee purchase glycomet online diabetes symptoms age 30, Circulation generic glycomet 500 mg amex diabetes symptoms urinary frequency, 2012, 125,e2–e220. Kang, View Online The Challenges of Conducting Clinical Trials in Diseases with Small Target Populations 79 E. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals For Registration of Pharmaceuticals for Human Use, Choice of control group and related issues in clinical trials E10, http://www. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 85 Table 4. Each period outlines tremendous growth in output to a peak at the end of the period. In addition, the second and third periods are characterised by a nadir at the beginning, resulting from a fall-oﬀ in output from the preceding period’s peak due to macro-level market factors, aer which the growth uptick restarts. This paradigm and associated trends, conrmed based on updates with more recent output data, are illustrated in Table 4. Key points to highlight from this three-stage distribution of orphan drug development market output include the importance of market shocks resulting from a fall-oﬀ in output from the previous peak (i. Indeed, among therapeutic areas, oncology represents a majority share of new orphan disease therapies that come to market (i. Current estimates indicate that there are 5000–8000 rare diseases in the world for which Orphanet, a European organisation, has done systematic identication and classication. Many orphan diseases are characterised by a tight-knit community of patients, care-givers and treating healthcare professionals, which shares information among members on symptoms, disease characteristics, treatment options and new therapies being investigated, including potential clinical trials to participate in. Quite oen, these communities are built on the backbone of formal organisations (i. The degree of community ‘stickiness’ for many orphan diseases will inuence many of the key factors that underpin overall product development approaches for new orphan drugs. Orphan drugs, with current global revenues of $83 billion, have become an increasingly large and important part of the global pharmaceutical market, for which global sales in 2012 amounted to $645 billion. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 89 Figure 4. View Online 90 Chapter 4 The following sections will explore orphan drug product development, commercialisation, investment and economics, as well as the future outlook for this rapidly developing and exciting sector within the biopharmaceutical industry. Second, orphan drug clinical programme strategy and execution is further challenged by uncertainties in the selection and characterisation of appropriate trial end points and treatment durations, paucity of robust biomarkers, recruiting the right patient populations and identifying qualied investigators. Special attention must be paid to ensure that the small patient populations for orphan diseases are characterised appro- priately, given biological and pharmacological heterogeneity/variability, as well as geographical distribution and scarcity. Additionally, for many orphan diseases, the lack of regulatory ‘precedent’ presents a challenge in itself. The scientic basis, level of evidence required, and context for biomarker use are areas to clarify. Accordingly, regulatory success oen requires robust and frequent inter- actions with regulatory agencies to gain alignment on key programme design elements including trial design, patient population requirements, clinical end points (e. The next few sections will discuss tradi- tional and emerging orphan drug product development platforms. A key example is bluebird bio, a gene therapy company focused on rare diseases, which uses its non-replicating lentiviral vector View Online 92 Chapter 4 Table 4. Monoclonal Immunoglobulins: based on Many Iniximab, antibodies specicity for antigenic rituximab epitopes 4. Gene therapy Vector-delivered gene sequences: 1 Alipogene replace decient/aberrant tiparvovec gene products 7. Pharmacological Small molecules: stabilize and/or 0 N/A chaperones reshape misfolded proteins aSmall molecules are low molecular weight (<900 Daltons) organic compounds and have been the main molecule platform for drug development. Large molecules (naturally occurring, recombinant, synthetic) comprise a broad cross-section of compound classes (e. LentiGlobin, which uses a similar vector but replaces beta-globin, is being evaluated for the treatment of beta thalassaemia major and sickle cell disease. Alipogene tiparvovec’s approval, based on clinical data from 27 patients, restricts prescribing to the subset of lipoprotein lipase deciency patients who have suﬀered repeated pancreatitis, and requires ongoing monitoring by the company, to demonstrate long-term eﬃcacy and safety. There are a number of arguments for the proposed price: high pharmaceutical R&D costs in general, and alipogene tiparvovec’s high-cost development programme in particular (i. Interestingly, uniQure has proposed an ‘annuity’ approach to charging health systems for alipogene tiparvovec (e. Duchenne’s, an X-linked disease characterised by progressively debilitating natural history disease stages, has a spectrum of manifesta- tions with important implications for selecting clinical end points and trial design, on a background of a wide array of exon-deletion abnormal- ities. Thelattertwostages,aﬀecting teenagers and older patients, exhibit more debilitating disease aﬀecting cardiac, pulmonary and upper limb function. Prosensa’s exon-targeting therapeutic approach, which would create a ‘menu’ of therapies for each exon-deletion abnormality, is inuenced by the decreasing prevalence of the target exon (e. Based on this background, the clinical development and regulatory approach will probably pursue a full devel- opment programme for compounds addressing the most prevalent target exon mutations (e. Chaperones bring about therapeutic eﬀect downstream of translation by ‘protecting’ their target proteins (e. Amicus Therapeutics, arguably the company with the broadest portfolio of small molecule pharmacological chaperones, is leveraging its technology platform to develop orally bioavailable therapies to address lysosomal storage disorders including Fabry, Gaucher and Pompe diseases. More so, orphan drug reim- bursement, by private or public payer, has traditionally been generous, aﬀording most patients in the small orphan disease communities with access to medicines, which are oen life-saving and/or provide signicant quality of life attributes. Some of these payer management tools, approaches and tactics include the use of restrictive tiers, prior authorisation, step therapy, increased patient coinsurance and/or co-payment, genetic testing (i. Creative risk-sharing schemes, in addition to traditional patient access programmes and manufacturer discounts, are increasingly playing an important role in the provision of orphan drugs to patients. This concept is taken further with performance-based risk-sharing agreements for ultra-orphan therapies, where price reductions can be entertained or negoti- ated if clinical outcomes are suboptimal or not compelling, which provides an approach to address the uncertainty regarding the long-term eﬀectiveness of costly ultra-orphan drugs. 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.
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Staffng shortages at the regulatory authority are a particularly serious problem in India and China buy discount glycomet on-line diabetes for kids, two main pharmaceutical producing nations with massive industries to oversee order 500mg glycomet with visa diabetic diet 2500 calories. China has a comparatively more manageable 3 cheap glycomet 500mg without a prescription diabetes diet guidelines after your visit,500 companies, down from roughly 5,000 in 2004; the reduction is partly the result of heightened enforcement in the wake of a series of drug contamination scandals (Reuters, 2008). In contrast, the top 10 innovator pharmaceutical companies control about 42 percent of the international market (Sun et al. Inspecting and licensing so many factories would be an overwhelming task for a well-funded regula- tory agency with suffcient staff. In both China and India, the understaffed provincial authorities oversee licensing and inspecting manufacturers, with uneven results. In 2007 a Chinese provincial regulator issued 67 forged manufacturing licenses for a bribe (Liu, 2010). Indian regulators sometimes approve medicines without trials or valid expert review and authorize ir- rational, even dangerous, fxed-dose formulations of multiple active com- pounds (Vaidyanathan, 2012). Drugs that neighboring countries ban are often available in India because the regulatory agencies cannot enforce bans or execute recalls (Shaji and Lodha, 2010). Figure 4-4 shows the number of agencies out of the 26 surveyed that can perform drug regulatory functions. Governments in low- and middle-income countries need a strategy to act against falsifed and substandard medicines. Any viable solution will include strengthening the drug regulatory system, including building the inspectorate, enforcing quality standards, and licensing in accordance with international standards. Without a competent regulatory authority to in- spect wholesalers, distributors, and manufacturers, opportunities to corrupt the drug supply abound. Box 4-6 describes a patient safety disaster follow- ing the disbanding of the Pakistani national regulatory authority. A 2012 Institute of Medicine report called for greater international investment in building food and drug regulatory systems in developing countries and for an international training and credentialing system for Copyright © National Academy of Sciences. The drug responsible was Isotab (isosorbide mononitrate, 20 mg), manufactured by Efroze Chemical in Karachi, Pakistan (Arie, 2012). Each Isotab tablet contained isosorbide mononitrate, as well as 14 times the normal dose of the antimalarial drug pyrimethamine. The drug’s packaging did not contain dates of manufacture or expiration, and the drugs were given to patients for free (Arie, 2012). Anonymous sources at the hospital reported signifcant pressure to buy the lowest cost drugs avail- able. Though the government approved an independent drug regulatory authority in 2005, political tensions prevented action (Arie, 2012). In 2010, a con- stitutional amendment further debilitated regulation by abolishing the ministry of health. Provincial governments, many with weak infrastruc- tures, were given sole responsibility for drug regulation. Manufacturers exploited the confused system by rapidly registering thousands of drugs (Khan, 2012). Following the Isotab scandal, the Pakistan Supreme Court ordered action on the independent agency. Doctors have expressed doubts, fear- ing that insufcient regulatory expertise and inefective execution will impede the new agency’s success (Khan, 2012). The new agency’s board includes only one position for an expert in medicine or pharmacy (Khan, 2012). It also recognizes that the magnitude of the task facing these agencies is overwhelming and that governments need to make drug quality a priority, and then empower their regulatory agencies to improve. Recommendation 4-4: Governments in low- and middle-income coun- tries should support their regulatory agencies to develop strategic plans for compliance with international manufacturing and quality-control standards. In the least developed countries, international organizations should support their efforts. International quality standards for drug manufacture depend on the competence of the national regulatory authority. The agencies’ budgets do not allow for im- provements in all these areas, and the scope of the needs can overwhelm the agencies, leading to inaction. It is important for regulators to make strategic decisions about what to invest in frst. A strategic plan can help identify an organization’s priorities and guide activities that advance these priorities (Tominaga, 2012). The committee believes that making a strategic plan is feasible for almost all poor countries. The process of making the plan helps regulators advocate for better support from their ministers and identify places for do- nors to contribute. Agencies in the poorest countries should frst enforce standards in man- ufacturing, wholesale, and retail. Some regulatory agencies in emerging economies have made great progress in a relatively short time. These agencies are well positioned to help their counterparts in other developing countries set out their goals. For example, experts from the Brazilian drug regulatory agency, Anvisa, could work with their counterparts in Mozambique or Angola to help develop realistic plans. A strategic plan for compliance with international standards can help reduce redundant work and fragmentation. For many smaller countries the plan should include a strategy for sharing work and pooling resources. Multilateral agencies, such as development banks, should support the development and implementation of strategic plans for compliance with international standards. The pharmaceutical market is international, and everyone has an interest in promoting global standards. Compliance with international standards will demand a wide range of activities, includ- ing research, education, supply chain management, and incentives for the private sector. The regulatory agency alone cannot effect change and will need government support to marshal the involvement of all stakeholders. Developed country governments also need to improve support for their regulatory agencies. At the time this report was prepared, substandard injectable drugs caused a fungal meningitis outbreak in the United States, bringing the topic of drug regulatory oversight to the forefront of the U. In the United States, professional practice, including the practice of medicine and pharmacy, is regulated by the states. Compounding phar- macies, which were traditionally small operations that prepared custom drugs for individual patients, fall under state jurisdiction (Burton et al. Pharmacy councils have long resisted federal interference in their practice, including oversight of compounding pharmacies (Calvan, 2012; Markey, 2012). Large compounding pharmacies are in practice much closer to small manufacturers than pharmacies (Burton et al.
Comparative assessment of the qual- ity control measurements of multisource amlodipine tablets marketed in Nigeria order line glycomet diabetes diet soda. Epidemiological survey of mithicillin resistant Staphylococcus aureus in the community and hospital buy glycomet online now diabet-x daily prevention skin therapy, Gannavaram buy discount glycomet 500 mg diabetes prevention control, Andhra Pradesh, South India. Emergence of artemisinin-resistant malaria on the western border of Thailand: A longitudinal study. Antibiotic use, re- sistance development and environmental factors: A qualitative study among healthcare professionals in Orissa, India. Uterotonic drug quality: An assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana. A cluster of cases of severe cardiotoxicity among kala- azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Mitigating the threat of artemisinin resistance in Africa: Improvement of drug-resistance surveillance and response systems. Infuence of tropical climate conditions on the quality of antihypertensive drugs from Rwandan pharmacies. International study of the prevalence and outcomes of infection in intensive care units. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance. Survey of the quality of antiretroviral medicines circulating in selected African countries. Counterfeit and substandard drugs in Myanmar and Viet Nam: Report of a study carried out in cooperation with the governments of Myanmar and Viet Nam. Countering the Problem of Falsified and Substandard Drugs Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 3 The Magnitude of the Problem It is diffcult to accurately measure the burden of falsifed and sub- standard drugs. As Chapter 2 mentions, some of the understanding of the problem comes from alerts in gray literature, including investigative journalism and industry and association reporting. Although these sources provide some insight, they do not provide an accurate estimate of the true magnitude of the problem. National regulatory authorities and drug com- panies keep records on fraudulent medicines; a broader understanding of the problem comes from peer-reviewed literature. There are few epidemio- logically rigorous, peer-reviewed studies on the prevalence of falsifed and substandard drugs. This chapter presents the results of a cross section of government and industry data and peer-reviewed and gray literature about the global burden of falsifed and substandard drugs. It does not summarize every study, but rather gives an overview of important trends. There was a time when this was a con- scious secrecy, an effort to avoid discrediting the public health system and drug companies, expressed in the Royal Pharmaceutical Society’s 1989 statement “no great publicity [about fake drugs] should be sought because it could damage public confdence in medicines” (Cockburn et al. Food and Drug Administration and Interpol, have taken action against sub- standard and falsifed medicines. Similarly, drug companies, both innovator and generic, may withhold information about falsifed and substandard medicines on the grounds that such stories discourage patient confdence in their products (Cockburn et al. There is a difference between secrecy and appropriate discretion with evidence for pending criminal prosecutions. The committee recognizes that undercover intelligence informs law enforcement agencies’ actions against criminals. Prematurely releasing confdential information about pharma- ceutical crime can compromise an investigation. Too often, however, gov- ernments and industry withhold information years after incidents pass (Cockburn et al. Regulators should be able to access this data so that they can communicate it to the public as appropriate, as it informs consumer safety and can trigger epidemiological research on drug quality. There is also value in sharing information on falsifed and substan- dard medicines internationally. Drug manufacturers source chemicals from around the world, and different factories process ingredients into a fnal formulation that is packaged, repacked, and sold in many different countries. The chances that a drug quality problem in one country affects that country alone decrease when products travel along global supply chains. The interconnectedness of the drug supply chain makes it imperative that countries share information on falsifed and substandard drugs. These companies share information on illegal phar- maceutical manufacture and trade. Because criminals who make and traffc illegal drugs target a wide range of companies’ products, cooperation and data sharing among companies adds depth to their collective understanding of the problem. The institute maintains a secure database to which members report cases of fraudulent manufacture and mislabeling of drugs, as well as cases of fraudulent packaging. A unique tracking number links every incident to a distinct date, time, place, and product. An analysis of the institute’s data gives an understanding of where law enforcement and regulators are active against the illegal trade and manu- facture of drugs. Some countries with serious problems never appear in incident reports because there is little political will for action. Table 3-1 shows only those countries where government or industry staff found a bad product; many more countries stand to be affected by those products. If a shipment of falsifed pills comes from China to the United States via India, then the incident report names all three countries. Criminal interest in cardiovascular disease drugs is a new trend; only in 2011 did that class 1 Detection means confrming though chemical or package analysis that the product is not what it purports to be. This is consistent with other industry reports that drugs sold and restocked fre- quently are most often targeted (Mukherjee, 2012). In about half of these incidents (n = 810) companies were able to do product and packaging analysis. Investigators found that most samples were fraudulent in both product and packaging (see Figure 3-1). A false product in legitimate packaging was the second most common result; Chap- ter 5 discusses this problem in more detail. The data do not suggest anything about the relative burden of the problem in different countries, however. Indeed, countries with lax enforcement attract illegal manufacturers, and countries with vigorous law enforcement repel them. Admittedly, the Asia category in both fgures includes rich countries such as Australia and Japan (personal communication, Mariam Kahn, Business Monitor Inter- national, October 23, 2012). The higher cost of living, higher incomes, and greater access to medicines in North America and Europe also account for these regions’ large share of pharmaceutical sales. Nevertheless, North America and Europe make up almost two-thirds of the world’s combined pharmaceutical sales but account for only a quarter of global trade in illegal medicines.
Sera and Immunoglobulins Antbodies of human origin are usually termed immunoglob- ulins buy generic glycomet 500 mg online diabetes education services. Because of serum sickness and other allergic-type reactons that may follow injectons of antsera discount glycomet 500mg online diabetes erectile dysfunction, this therapy has been replaced wherever possible by the use of immunoglobulins order glycomet no prescription diabetesorg. Contraindicatons and Precautons Anaphylaxis, although rare, can occur and epinephrine (adrenaline) must always be immediately available during immunizaton. Immunoglobulins may interfere with the immune response to live virus vaccines which should normally be given either at least 3 weeks before or at least 3 months afer the administra- ton of the immunoglobulin. Intravenous injecton; Systemic reactons including fever, chills, facial fushing, headache and nausea may occur, partc- ularly following high rates of infusion. Ant-D Immunoglobulin (Human): Ant-D immunoglobulin is prepared from plasma with a high ttre of ant-D antbody. It is available to prevent a rhesus- negatve mother from forming antbodies to fetal rhesus- positve cells which may pass into the maternal circulaton. The aim is to protect any subsequent child from the hazard of haemolytc disease of the newborn. It should be administered following any potentally sensitzing episode (for example aborton, miscarriage, stll-birth) immediately or within 72 h of the episode but even if a longer period has elapsed it may stll give protecton and should be used. The dose of ant-D immunoglobulin given depends on the level of exposure to rhesus-positve blood. The injecton of ant-D immunoglobulin is not efectve once the mother has formed ant-D antbodies. Anttetanus Immunoglobulin (Human): Anttetanus immunoglobulin of human origin is a preparaton containing immunoglobulins derived from the plasma of adults immunized with tetanus toxoid. It is used for the management of tetanus-prone wounds in additon to wound toilet and if appropriate antbacterial prophylaxis and adsorbed tetanus vaccine. Diphtheria Anttoxin: Diphtheria anttoxin is prepared from the plasma or serum of healthy horses immunized against diphtheria toxin or diph- theria toxoid. It is used for passive immunizaton in suspected cases of diphtheria without waitng for bacterial confrmaton of the infecton. Diphtheria anttoxin is not used for prophy- laxis of diphtheria because of the risk of hypersensitvity. Rabies Immunoglobulin (Human): Rabies immunoglobulin is a preparaton containing immu- noglobulins derived from the plasma of adults immunized with rabies vaccine. It should be administered as soon as possible afer exposure without waitng for confrmaton that the animal is rapid. The site of the bite should be washed with soapy water and the rabies immunoglobulin should be infltrated round the site of the bite and also given intramuscularly. Dose Intramuscular injecton Adult and Child- Following birth of a rhesus- positve infant in rhesus-negatve mother: 250 µg immediately or within 72 h. Following any potentally sensitzing episode like amniocentesis, stll birth, up to 20 weeks gestaton: 250 µg per episode, afer 20 weeks: 500 µg immediately or within 72 h. Following Rho (D) incompatble blood transfusion: 10 to 20 µg/ml transfused rhesus-positve blood. Precautons See introductory notes; cauton in rhesus- positve patents for treatment of blood disorders; cauton in rhesus-negatve patents with ant-D antbodies in their serum; patents should be observed for 20 min afer injecton. Rubella vaccine may be administered in the postpartum period at the same tme as ant-D immunoglobulin injecton, but only using separate syringes and separate contralateral sites. If blood is transfused, the antbody response to the vaccine may be inhibited and a test for antbodies should be performed afer 8 weeks and the subject revaccinated if necessary. Adverse Efects See introductory notes; local pain and tenderness, fever, headache; cutaneous reacton; tachycardia, hypotension. For freeze dried preparaton: Store protected from light in a colourless glass cotainer at a temperature not exceeding 30⁰C. Anttetanus Immunoglobulin (Human)* Pregnancy Category-C Indicatons Passive immunisaton against tetanus as part of the management of tetanus-prone wounds. Dose Intramuscular injecton Adult and Child-250 units, increased to 500 units if wound older than 12 h or there is risk of heavy contaminaton or if patent weighs more than 90 kg. Second dose of 250 µg given afer 3 to 4 weeks if patent is immunosuppressed or if actve immunisaton with tetanus vaccine contraindicated. If schedule requires tetanus vaccine and anttetanus immunoglobulin to be administered at the same tme, they should be administered using separate syringes and separate sites. Diphtheria Anttoxin* Indicatons Passive immunisaton in suspected cases of diphtheria. Dose Intramuscular injecton Adult and Child- 10,000 to 30,000 units in mild to moderate cases; 40,000 to 1,00,000 units in severe cases. Both intramuscular and intravenous injecton For doses more than 40,000 units, a porton should be given by intramuscular injecton followed by the bulk of the dose intravenously afer an interval of 0. Precautons Inital test dose to exclude hypersensitvity; observaton required afer full dose [epinephrine (adrenaline) and resuscitaton facilites should be available]; history of asthma. Adverse Efects Anaphylaxis with urtcaria, hypotension, dyspnoea and shock; serum sickness up to 12 days afer injecton; fever, respiratory distress. Rabies Immunoglobulin* Pregnancy Category-C Indicatons Passive immunisaton either post-exposure or in suspected exposure to rabies in high- risk countries in unimmunised individuals (in conjuncton with rabies vaccine). Dose Intramuscular injecton and wound infltraton Adult and Child- 20 units/kg (half by intramuscular injecton and half by wound infltraton). Contraindicatons See introductory notes; avoid repeat doses afer vaccine treatment initated; intravenous administraton. If schedule requires rabies vaccine and rabies immunoglobulin to be administered at the same time, they should be administered using separate syringes and separate sites. Adverse Efects See introductory notes; soreness at injecton site; fever; chest pain; tremor; dyspnoea. Local efects include pain, swelling, bruising and tender enlargement of regional lymph nodes. Spontaneous systemic bleeding, coagulopathy, adult respiratory distress syndrome and acute renal failure may occur. Snake antvenom sera are the only specifc treatment available but they can produce severe adverse reactons. They are generally only used if there is a clear indicaton of systemic involvement or severe local involvement or, if supplies are not limited, in patents at high risk of systemic or severe local involvement. Spider bites may cause either necrotc or neurotoxic syndromes depending on the species involved. Supportve and symptomatc treatment is required and in the case of necrotc syndrome, surgical repair may be necessary. Spider antvenom sera, suitable for the species involved, may prevent symptoms if administered as soon as possible afer envenomaton. Dose 60-100 ml in 5% dextrose or normal saline intravenously over one hour; start at 1 ml of diluted soluton per minute initally, watch- ing for reacton. Skin sensitvity test is not recommended; In hemotoxic snake bites, may repeat a second dose at 6 h. Precautons Resuscitaton facilites should be immediately available; anthistamine and treatment for anaphylactc shock should be kept ready.