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Over the next 5–10 years order 10mg sarafem otc, additional growth drivers are also expected to become important generic sarafem 20 mg with mastercard, including the first successful outcomes to research into delivery systems for gene therapy buy 10 mg sarafem otc, new targeting systems for anticancer therapies generic 20mg sarafem with visa, and additional sectors including mucosal formulations discount 20mg sarafem fast delivery. For these reasons, it is expected that the advanced drug delivery market will grow at more than 20% per annum to the millennium and beyond. This split between richer and less prosperous markets has been especially noticeable in the regional distribution of the advanced drug delivery market, which was originally characterized by relatively high- priced products, so that its distribution among the main pharmaceutical market regions of the world tended to show disproportionately higher shares among the more prosperous regions—North America, Western Europe and Japan. However, other factors, in particular demographic and epidemiological ones, tend to maintain the differential. New developments in advanced drug delivery always result, at first, in high-priced products which are more affordable in developed economies. This will apply particularly to gene therapy delivery systems and targeted anticancer therapies, because these are expected to command very high prices. At the same time, delivery systems which were revolutionary and high-priced on their first introduction (e. The increasing use of advanced drug delivery technology by generic companies is bringing it more into the realm of everyday medicine. Antihypertensive drugs form the largest product category within this market, accounting for sales of some $20 billion. Some antihypertensives are also used for long-term maintenance in angina, while there is a separate group of drugs used for short-term angina relief. Annual sales of antihypertensive and anti-anginal products using advanced drug delivery technology are estimated to be around $5 billion worldwide at 1995 levels, representing one-sixth or more of all cardiovascular sales. This share will increase in the near term, as sales of older drugs in conventional dosage forms decline. Anti-inflammatory drugs The market for prescription drugs used in the treatment of major inflammatory diseases, including arthritis and rheumatism, is currently valued at $7 billion worldwide. In fact Voltarol is the leading product in this market, with sales around $1 billion, largely contributed by the long-acting version. Most usage is still in the area of cytotoxic drugs, with hormonal therapy growing dramatically in recent years due to the increasing use of drugs such as tamoxifen. Because of their high price, these new products represent an unusually large share of the market; most cytotoxic and hormonal products are mature and relatively low-priced. The main opportunity for advanced drug delivery systems in this market is in the area of targeted drug delivery. Current research is focused on the development of carriers such as liposomes and on the use of monoclonal antibodies as targeting agents (see Sections 5. The eventual market opportunity is considerable—cancer is still one of the commonest fatal diseases, and some of the most deadly forms are resistant to available therapies. The potential market for effective targeting delivery systems may eventually exceed $5 billion. Whether, and how soon, it achieves this figure will depend on the speed with which successful products come to market. Anti-asthma therapies The asthma market is thought to be worth some $6 billion worldwide, and consists mainly of inhaled products—bronchodilators and corticosteroids. It is a growing market because the incidence of asthma is increasing, especially in developed countries. It has been postulated that this increase is partly related to overuse of inhaled bronchodilators, which can mask progression of the underlying inflammatory disease process. The asthma market will almost certainly continue to grow, with increasing use of inhaled therapy, favoring stronger growth of steroids over bronchodilators in the current climate of opinion. However, inhalation products now available go a considerable way towards compensating for the drawbacks of early metered-dose aerosols. The major suppliers (including AstraZeneca, 3M and GlaxoSmithKline) have developed improved delivery devices, as well as dry powder formulations and control of medication particle size to optimize penetration into the lung (see Chapter 10). However, it seems likely that the main factor driving this market upwards in the near term will be the rising prevalence of asthma, fuelling annual market growth in the region of 8–10%. Diabetes Insulin is the only currently effective treatment for the millions of diabetics who suffer from Type I diabetes (also known as insulin-dependent and juvenile onset diabetes). Insulin is a peptide, and if given orally it is broken down by enzymes in the gut (see Section 1. Although manufacturers have introduced user-friendly devices such as insulin pens, an effective, less invasive alternative would be instantly popular.

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Critically generic sarafem 10 mg amex, given the compound mode of action buy 20 mg sarafem with amex, analysis of blood samples for evidence of non- selective read-through of stop codons was also undertaken by looking for extended length marker proteins order sarafem 20mg otc. Although the drug was well tolerated and this latter result was encouraging cheap sarafem 20 mg with mastercard, it was not statisti- cally signicant order 20mg sarafem visa, and the study was discontinued. Further- more, the confounding activity in the rey luciferase assay was conrmed. The assay protocol was validated using ataxia-telangiectasia as a disease model, and in separate experiments also established that the treatment of mdx cells with the compounds resulted in the restoration of dystrophin expression. Although a detailed evaluation of the compound’s pharmacokinetics was not reported, bioanalysis of 11. Interestingly no parent compound was detectable in plasma at any time point following intraperi- toneal injection, although levels up to around 3 mM were detected in most muscles sampled, including the heart. This observation is of particular relevance for a muscular dystrophy therapeutic where cardiac muscle has historically proven difficult to target with drugs. Based on the in vitro cellular data, compound levels of between 2 and 10 mM would be predicted to increase dystrophin levels by around 1–3%, and indeed this is what was Figure 11. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 287 observed when various types of muscle were analysed for dystrophin-positive bres. More importantly, these positive histological data translated to functional benet following treatment with 11. Although these data are clearly encouraging, it is important to place this project in context. A more detailed analysis of the compound/class pharmacokinetics will be essential, as well as concomitant delineation of structure–activity relationships in order to translate the intraperitoneal dosing regimen into (ideally) an orally delivered agent. There are also functional groups within the compound that may raise concern, for example the nitrophenyl motif, as well as the iminothiazolone ring, because these types of functionalities have been commonly associated with both assay interference and poor drug proles in the past, and so appropriate replacements and/or safety assessments will be critical. For reasons that are not yet clear, utrophin expression decreases signicantly with maturity during foetal development, and is replaced almost exclusively by dystrophin. As well as having structural similarity, utrophin has been established as playing a functionally equivalent role to dystrophin, this having been conclusively demonstrated by Davies et al. Although the proof-of-concept murine experiments were conducted using transgenes, alternative strategies using pharmacological approaches can be envisaged, and are potentially attractive as a small-molecule drug can in principle be delivered orally, would be relatively inexpensive compared to a biologic agent, and should be systemi- cally available, thereby having the potential for treating all muscles, including the difficult to target cardiac tissue. The potential of both biologics and low molecular weight biochemicals to upregulate the production of utrophin has good precedent, with agents such as heregulin128 and L-arginine129 having been shown to ameliorate the dystrophic phenotype when dosed to mdx mice. Heregulin is thought to work by activation of the utrophin A promoter, with the mode of action of L-arginine being postulated as being through activation of the nitric oxide pathway, indirectly activating utrophin. Although providing a critical proof-of-concept for the approach, none of these agents represents a viable drug therapy at this stage, because many questions remain unanswered, particularly how an appropriate dosing regimen can be established, as well as whether or not there are any longer- term compound-associated toxicological consequences. A number of companies, including large pharmaceutical organisations as well as biotechnology companies, are seeking to develop small-molecule upregulators of utrophin, including BioFocus and Summit plc, and the View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 289 therapeutic approach has been reviewed recently by Khurana et al. It was discovered during a collaborative programme with scientists from the University of Oxford’s Chemistry, Physiology, Anatomy and Genetics Departments. The medicinal chemistry hit discovery and lead optimisation work for this project has been published recently. Following hit conrmation, a more straightforward lead optimisation approach was undertaken, based on evaluating the structure–activity relationships of a series of hit compounds. The initial assay used for primary screening of the compound libraries was conducted in H2K cells, which had been engineered to express the utrophin A promoter linked to a luciferase reporter construct. Accordingly, any compounds that interacted with and activated the respective utrophin promoter would be easily detected and quantied using a luminescent readout. Since that time additional utrophin promoters have been identied, and therefore it is possible that this screen would not necessarily identify all compounds that are potentially able to upregulate the production of utrophin using this or a related mechanism. View Online 290 Chapter 11 considerable optimisation, because they were described as suffering from rapid metabolism in mouse liver microsomes and having poor physico- chemical properties. Moreover, both contained functional groups that were felt to be unsuitable for progressing the compounds further, including anilines and phenols. The aniline motif contained within both examples was felt to be a particular liability, because it is known to be a potent toxicophore in some cases. The latter liability was conrmed in vivo when preliminary assessment of exposure levels was made by dosing lead molecules orally in mice, and plasma levels of compound were found to be very low.

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Although intermediate equations are used purchase sarafem 20 mg with visa, only the final equation is important to remember sarafem 10mg visa. The first dose produces a plasma drug concentration versus time curve like the one in Figure 4-1 purchase sarafem 10 mg otc. C0 is now referred to as Cmax discount sarafem 10 mg on line, meaning maximum concentration sarafem 20 mg cheap, to group it with the other peak concentrations that occur with multiple dosing. If a second bolus dose is administered before the first dose is completely eliminated, the maximum concentration after the second dose (Cmax2) will be higher than that after the first dose (Cmax1) (Figure 4-2). The second part of the curve will be very similar to the first curve but will be higher (have a greater concentration) because some drug remains from the first dose when the second dose is administered. The only difference is that the actual concentrations may be higher at later doses, because drug has accumulated. Because Ct = C0e at any time (t) after the first dose, it follows that: -Kτ Cmin1 = Cmax1e where Cmin1 is the concentration just before the next dose is given and τ, the dosing interval, is the time from Cmax to Cmin. The plasma drug concentration versus time profile reveals a further increase in the maximum concentration immediately after the third dose, as shown in Figure 4-4. Just as after the first dose: -Kτ Cmin2 = Cmax2e -Kτ -Kτ which, by substitution for Cmax2, equals Cmax1(1 + e )e. Moreover: Cmax3 = Cmin2 + Cmax1 -Kτ -Kτ which, substituting for Cmin2, equals Cmax1(1 + e )e + Cmax1. This simplifies as follows: -Kτ -Kτ Cmax3 = Cmax1[(1 + e )(e ) + 1] -Kτ -2Kτ = Cmax1[e + e + 1] -Kτ 2Kτ = Cmax1[1 + e + e ] As we can see, a pattern emergesafter any number of dosing intervals, the maximum concentration will be: -Kτ -2Kτ -(n-1)Kτ Cmaxn = Cmax1[1 + e + e +. This equation can be simplified by mathematical procedures to a more useful form: where Cmaxn is the concentration just after n number of doses are given. So, if we know Cmax1, the elimination rate, and the dosing interval, we can predict the maximum plasma concentration after any number (n) of doses. It is called the accumulation factor because it relates drug concentration after a single dose to drug concentration after n doses with multiple dosing. This factor is a number greater than 1, which indicates how much higher the concentration will be after n doses compared with the first dose For example, if -1 100 doses of a certain drug are given to a patient, where K = 0. The accumulation factor for two or three doses can also be calculated to predict concentrations before achievement of steady-state. The concept of accumulation factor is discussed in more detail in the section Accumulation Factor later in this lesson. These equations will be used later to predict drug concentrations for given dosage regimens. Clinical Correlate If a drug has a very short half-life (much less than the dosing interval) then the plasma concentrations resulting from each dose will be the same and accumulation of drug will not occur (as shown in Figure 4-5). An example would be a drug such as gentamicin given every 8 hr intravenously to a patient whose excellent renal function results in a drug half-life of 1. With first-order elimination, the amount of drug eliminated per unit of time is proportional to the amount of drug in the body. Accumulation continues until the rate of elimination approaches the rate of administration: rate of drug going in = rate of drug going out As the rate of drug elimination increases and then approaches that of drug administration, the maximum (peak) and minimum (trough) concentrations increase until an equilibrium is reached. After that point, there will be no additional accumulation; the maximum and minimum concentrations will remain constant with each subsequent dose of drug (Figure 4-6). When this equilibrium occurs, the maximum (and minimum) drug concentrations are the same for each additional dose given (assuming the same dose and dosing interval are used). When the maximum (and minimum) drug concentrations for successive doses are the same, the amount of drug eliminated over the dosing interval (rate out) equals the dose administered (rate in) and the condition of "steady state" is reached. Steady state will always be reached after repeated drug administration at the same dosing interval if the drug follows first-order elimination. However, the time required to reach steady state varies from drug to drug, depending on the elimination rate constant. With a higher elimination rate constant (a shorter half-life), steady state is reached sooner than with a lower one (a longer half-life) (Figure 4-7). Steady state is the point at which the amount of drug administered over a dosing interval equals the amount of drug being eliminated over that same period and is totally dependent on the elimination rate constant.

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