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Doctors have a key role to play in taking this debate forward and this is discussed in Chapter 11 order fluvoxamine anxiety symptoms joints. Summary • For the last half century generic fluvoxamine 50 mg otc anxiety 5 things you can see, prohibition and criminalisation has been the dominant policy for drug control buy fluvoxamine amex anxiety level quiz, both nationally and internationally. Among this latter group of commentators, the lack of research into the effects of criminalising illicit drug use and possession does not, in itself, lead to the position that new or amended regulations are required. Reducing the number of people using drugs by delaying their initiation into drug use and preventing the transition from experimental or recreational drug use to problematic or dependent use has a role to play in drug prevention. At present, strategies that aim to reduce the use of drugs fall broadly under two categories: • reducing the number of people who are dependent on drugs, mainly by means of treatment and other forms of support • undertaking activities to improve people’s knowledge about the risks of using drugs, to influence their attitudes and behaviour and to encourage the development of skills to resist. This chapter will explore the efficacy of interventions that aim to delay the onset of drug use. A focus on young people has been chosen because the volume of research among this population is much larger than for prevention in adults. These are: • primary prevention: where the aim is to avert or delay the initial use of a drug • secondary prevention: where the aim is to minimise hazards, or actual harms, among those who have already begun using drugs. In relation to alcohol use, available evidence suggests that harm-reduction approaches show considerable promise in reducing alcohol-related harm. Most preventative drug interventions, known as universal interventions, are directed at unselected populations. A small minority of target groups are known, or believed, to be at a heightened risk of involvement with drug use; targeted interventions are known as: • selective interventions: these strategies target subsets of the total population who are thought to be at an increased risk of using drugs. These approaches are intended for entire groups of people considered at risk, regardless of the degree of risk for any one individual in the group • indicated interventions: rather than affecting groups, indicated interventions focus on identifying individuals who are exhibiting early signs of drug use. The emphasis is placed on identification, intervention, support and, in some cases, referral. When considering the evidence base for prevention programmes, there are two limitations. Interventions that take place in school-based settings have received the greatest amount of attention, usually because of the ease of conducting research in these settings, compared to community-based or mass media interventions. Drug use at an early age is associated with future drug use, particularly for harmful drugs such as heroin or cocaine, and is correlated with a range of other negative behaviours. These types of interventions can include programmes that address an entire school population through drug education lessons, parents through parenting programmes, or communities through community-wide prevention efforts. The vast majority of universal prevention initiatives take place in an educational setting. This is because schools represent the most systematic and efficient way of reaching a substantial number of young people. Despite the widespread international use of drug prevention programmes in schools, there is limited high-quality evidence about the effect of school-based interventions on drug use. In the 1970s, drug education and prevention interventions in schools were primarily aimed at reducing drug use through giving young people information about the risks associated with drugs. Evaluation of this intervention shows that this approach did not reduce young people’s drug-taking behaviour. The theory behind these interventions is that drug use is caused by lack of self-esteem, as opposed to a lack of knowledge about the adverse effects of drug use. Affective programmes aimed to prevent or reduce the scale of drug use, through enhanced personal and social development. These were based on the hypothesis that drug use stems from direct or indirect social influences from peers and the media. There is little evidence of reduction in the use of illicit drugs as a result of these programmes. Research, including the 2005 Cochrane review,11 has found that these high-quality school-based multifaceted programmes show a marked improvement in young people’s knowledge and skills, which can have a small impact on illicit drug use, and drug behaviour, most notably in delaying the onset of use. Programmes that change the environment of a classroom or school are thought to be more effective than those that try to change individual behaviour. Stronger effects were found in boys who were identified as aggressive and disruptive at a young age. The long-term effects of this intervention appear to compare well with the best school- based programmes aimed specifically at drug prevention. Research has demonstrated that factors that predict development of a drug problem are also predictive of school failure, social isolation, aggression and other problems. It should be noted that, despite this limited evidence base, large amounts of pupil and staff time are invested in these types of intervention. This guidance also states that all schools should have a drug policy that sets out the school’s role in relation to all drug matters, which includes the content and organisation of any drug education programme. Box 7 – Combating the psychological attractiveness and social acceptance of drugs As identified in Chapter 4, heavy exposure to substance use in popular media may influence drug use. Universal interventions aimed at reducing the use of drugs may need to be rethought by policy makers. These lessons take place for finite number of hours a year, with information on health behaviours such as drug use often competing with other modules. Over the same time period, the average person is likely to be exposed to a larger number of hours of drug-promoting references in film, television, popular music, video games and the internet. This large disparity between the exposure to drugs in popular media, and interventions to reduce the use of illicit drug use, may result in the efficacy of interventions to reduce the use of drugs being diluted by the widespread exposure to drug imagery. Appendix 7 explores current and possible policy options to counter the psychological attractiveness and social acceptance of drug use within popular media. The Home Office’s Blueprint drugs education programme,19 which ran from 2003 to 2007, was the largest drugs education programme that has ever been run in Britain. The programme provided drug education lessons to school children aged 11 and 12 years, across 23 different schools in England. It aimed to equip pupils with the knowledge and experiences necessary to make informed choices about drug use. Those who had never taken drugs were more likely to say that lessons had helped them to avoid drugs, and to think about what to do if they were offered drugs. The guidance also advises that drug testing should be placed within the wider context of educating children about the risks, effects and consequences of drug use. Since the publication of this guidance in 2004, the uptake of drug testing in schools has been limited. Research has demonstrated that drug use does not differ between schools with and without drug testing. In 2006, the Cochrane Collaboration published a systematic review of interventions for the prevention of drug use delivered to young people in non-school settings. The lack of research in this area meant the authors were unable to carry out a meta- analysis and pool results across similar interventions. It was suggested that further high-quality research was needed before any conclusions could be made on the efficacy of non-school-based prevention strategies. Significant effects on reducing drug use were detected for individual family interventions. Education and skills training were found to have little effect on reducing drug use. Mass media and social marketing approaches Mass media campaigns are commonly used as part of universal strategies to reduce drug use.

If of any material purchase fluvoxamine 100 mg otc anxiety 6 months pregnant, including components fluvoxamine 100 mg otc anxiety disorder key symptoms, hand jewelry cannot be removed cheap 100 mg fluvoxamine visa anxiety helpline, it dietary supplements, and contact sur- must be covered by material that is faces used in the manufacture, pack- maintained in an intact, clean, and aging, labeling, or holding of a dietary sanitary condition and that effectively supplement. Such measures include the protects against contamination of following: components, dietary supplements, or (1) Excluding from working in any contact surfaces; operations that may result in contami- (5) Maintaining gloves used in han- nation any person who, by medical ex- dling components or dietary supple- amination, the person’s acknowledge- ments in an intact, clean, and sanitary ment, or supervisory observation, is condition. You must keep the organisms, filth, or any other extra- grounds of your physical plant in a neous materials, including perspira- condition that protects against the tion, hair, cosmetics, tobacco, chemi- contamination of components, dietary cals, and medicines applied to the skin. Each person who is identified to parking lots so that they do not con- perform quality control operations stitute a source of contamination in must be qualified to do so and have dis- areas where components, dietary sup- tinct and separate responsibilities re- plements, or contact surfaces are ex- lated to performing such operations posed; from those responsibilities that the (3) Adequately draining areas that person otherwise has when not per- may contribute to the contamination forming such operations. The plumbing in your and adequate under the conditions of physical plant must be of an adequate use. Guard or guide for use in bathrooms or hand-washing dogs are allowed in some areas of your facilities. You must dispose dogs will not result in contamination of sewage into an adequate sewage sys- of components, dietary supplements, or tem or through other adequate means. You must provide your (2) You must take effective measures employees with adequate, readily ac- to exclude pests from the physical cessible bathrooms. The bathrooms plant and to protect against contami- must be kept clean and must not be a nation of components, dietary supple- potential source of contamination to ments, and contact surfaces on the components, dietary supplements, or premises by pests; and contact surfaces. You must migants, fungicides, or rodenticides, provide hand-washing facilities that unless you take precautions to protect are designed to ensure that an employ- against the contamination of compo- ee’s hands are not a source of contami- nents, dietary supplements, or contact nation of components, dietary supple- surfaces. You must convey, not become a component of the dietary store, and dispose of trash to: supplement. You must position decision, reprocessing, or are assign one or more employees to super- awaiting disposal after rejection; vise overall sanitation. Each of these (3) Separating the manufacturing, supervisors must be qualified by edu- packaging, labeling, and holding of dif- cation, training, or experience to de- ferent product types including dif- velop and supervise sanitation proce- ferent types of dietary supplements dures. Any physical plant you use in the (d) Be designed and constructed in a manufacture, packaging, labeling, or manner that prevents contamination of holding of dietary supplements must: components, dietary supplements, or contact surfaces. Your physical plant must have, where they may contaminate compo- and you must use, separate or defined nents, dietary supplements, or contact areas of adequate size or other control surfaces; systems, such as computerized inven- (iv) Equipment that controls tem- tory controls or automated systems of perature and humidity, when such separation, to prevent contamination equipment is necessary to ensure the and mixups of components and dietary quality of the dietary supplement; and supplements during the following oper- (v) Aisles or working spaces between ations: equipment and walls that are ade- (1) Receiving, identifying, holding, quately unobstructed and of adequate and withholding from use, components, width to permit all persons to perform dietary supplements, packaging, and their duties and to protect against con- labels that will be used in or during the tamination of components, dietary sup- manufacturing, packaging, labeling, or plements, or contact surfaces with holding of dietary supplements; clothing or personal contact. I (4–1–10 Edition) equipment must be located and oper- Subpart D—Equipment and ated in a manner that minimizes the Utensils potential for microorganisms and par- ticulate matter to contaminate compo- §111. You must calibrate: (iii) Made of nontoxic materials; (1) Before first use; and (iv) Designed and constructed to (2) At the frequency specified in writ- withstand the environment in which ing by the manufacturer of the instru- they are used, the action of compo- ment and control; or nents or dietary supplements, and, if (3) At routine intervals or as other- applicable, cleaning compounds and wise necessary to ensure the accuracy sanitizing agents; and and precision of the instrument and (v) Maintained to protect compo- control. When partment; and the surfaces are wet-cleaned, they (ii) Must have an automated device must be sanitized, when necessary, and for regulating temperature or an auto- thoroughly dried before subsequent mated alarm system to indicate a sig- use. When use to measure, regulate, or record cleaning and sanitizing is necessary, temperatures, hydrogen-ion concentra- you must clean and sanitize all contact tion (pH), water activity, or other con- surfaces before use and after any inter- ditions, to control or prevent the ruption during which the contact sur- growth of microorganisms or other face may have become contaminated. If contamination must be: you use contact surfaces in a contin- (i) Accurate and precise; uous production operation or in con- (ii) Adequately maintained; and secutive operations involving different (iii) Adequate in number for their batches of the same dietary supple- designated uses. In your tions are consistently met; documentation, you must: (b) Determine the suitability of the (i) Identify the instrument or control equipment by ensuring that your calibrated; equipment is capable of operating sat- (ii) Provide the date of calibration; isfactorily within the operating limits (iii) Identify the reference standard required by the process; used including the certification of ac- (c) Routinely calibrate, inspect, or curacy of the known reference standard check the equipment to ensure proper and a history of recertification of accu- performance. Your quality control per- racy; sonnel must periodically review these (iv) Identify the calibration method calibrations, inspections, or checks; used, including appropriate limits for (d) Establish and use appropriate accuracy and precision of instruments controls for automated, mechanical, and controls when calibrating; and electronic equipment (including (v) Provide the calibration reading or software for a computer controlled readings found; process) to ensure that any changes to (vi) Identify the recalibration meth- the manufacturing, packaging, label- od used, and reading or readings found, ing, holding, or other operations are if accuracy or precision or both accu- approved by quality control personnel racy and precision limits for instru- and instituted only by authorized per- ments and controls were not met; and sonnel; and (vii) Include the initials of the person (e) Establish and use appropriate con- who performed the calibration and any trols to ensure that the equipment recalibration. These controls must be ap- inspections, and checks of automated, proved by quality control personnel. The peti- with dietary supplements must be safe tion must set forth the scientific ra- and suitable for its intended use and tionale, and must be accompanied by must not be reactive or absorptive or the supporting data and information, for proposed alternative testing that otherwise affect the safety or quality will demonstrate that there is no mate- of the dietary supplement. To do so, you must tions to provide sufficient assurance either: that the product you receive is ade- (i) Conduct appropriate tests or ex- quately identified and is consistent aminations; or with your purchase order. In such a case, you must may adulterate or that may lead to document why, for example, any com- adulteration of the finished batch of ponent and in-process testing, exam- the dietary supplement. To do so: ination, or monitoring, and any other (1) You must select one or more es- information, will ensure that such ex- tablished specifications for identity, empted product specification is met purity, strength, composition, and the without verification through periodic limits on those types of contamination testing of the finished batch; and that may adulterate or that may lead (2) Your quality control personnel to adulteration of the dietary supple- must review and approve the docu- ment that, if tested or examined on the mentation that you provide under finished batches of the dietary supple- paragraph (d)(1) of this section. No fin- product that you receive for packaging ished batch of dietary supplements or labeling as a dietary supplement may be released for distribution unless (and for distribution rather than for re- it complies with §111. I (4–1–10 Edition) (5) Documentation for why any com- identity, purity, strength, or composi- ponent and in-process testing, exam- tion of a dietary supplement; ination, or monitoring, and any other (b) Reviewing and approving the doc- information, will ensure that a product umentation setting forth the basis for specification that is exempted under qualification of any supplier; §111. To do so, quality control per- must include: sonnel must perform operations that (a) Reviewing and approving all lab- include: oratory control processes associated (a) Approving or rejecting all proc- with the production and process con- esses, specifications, written proce- trol system; dures, controls, tests, and examina- (b) Ensuring that all tests and exami- tions, and deviations from or modifica- nations required under §111. I (4–1–10 Edition) modifications to the master manufac- ensure that specifications established turing records; under §111. I (4–1–10 Edition) (c) You must quarantine components (c) You must quarantine packaging before you use them in the manufac- and labels before you use them in the ture of a dietary supplement until: manufacture of a dietary supplement (1) You collect representative sam- until: ples of each unique lot of components (1) You collect representative sam- (and, for components that you receive, ples of each unique shipment, and of of each unique shipment, and of each each unique lot within each unique unique lot within each unique ship- shipment, of packaging and labels and, ment); at a minimum, conduct a visual identi- (2) Quality control personnel review fication of the immediate containers and approve the results of any tests or and closures; examinations conducted on compo- (2) Quality control personnel review nents; and and approve the results of any tests or (3) Quality control personnel approve examinations conducted on the pack- the components for use in the manufac- aging and labels; and ture of a dietary supplement, including (3) Quality control personnel approve approval of any treatment (including the packaging and labels for use in the in-process adjustments) of components manufacture of a dietary supplement to make them suitable for use in the and release them from quarantine. I (4–1–10 Edition) (1) Identify specifications for the erence to the physical location of the points, steps, or stages in the manufac- actual or representative label; turing process where control is nec- (h) Written instructions, including essary to ensure the quality of the die- the following: tary supplement and that the dietary (1) Specifications for each point, supplement is packaged and labeled as step, or stage in the manufacturing specified in the master manufacturing process where control is necessary to record; and ensure the quality of the dietary sup- (2) Establish controls and procedures plement and that the dietary supple- to ensure that each batch of dietary ment is packaged and labeled as speci- supplement that you manufacture fied in the master manufacturing meets the specifications identified in record; accordance with paragraph (b)(1) of (2) Procedures for sampling and a this section. I (4–1–10 Edition) (4) Approved and released, or re- ment (and for distribution rather than jected, the packaged and labeled die- for return to the supplier); and tary supplement, including any repack- (5) Packaged and labeled dietary sup- aged or relabeled dietary supplement. These precautions in- or dietary supplements, by, for exam- clude: ple: (a) Performing manufacturing oper- (1) Filters or strainers, ations under conditions and controls (2) Traps, that protect against the potential for (3) Magnets, or growth of microorganisms and the po- (4) Electronic metal detectors. You must do (a) You must make and keep records this using any effective means, includ- required under this subpart K in ac- ing the following: cordance with subpart P of this part. You must clearly identify, hold, and control under a quarantine system for (a) You must hold reserve samples of appropriate disposition any packaged dietary supplements in a manner that and labeled dietary supplement that is protects against contamination and de- rejected for distribution. You must identify and quarantine re- (a) You must make and keep records turned dietary supplements until qual- required under this subpart N in ac- cordance with subpart P of this part. Subpart O—Product Complaints You may salvage a returned dietary supplement only if quality control per- §111. For the purposes of this part, the fol- (f) Critical factor means any property, lowing definitions apply: characteristic, condition, aspect, or (a) Aseptic processing and packaging other parameter, variation of which means the filling of a commercially may affect the scheduled process and sterilized cooled product into pre- sterilized containers, followed by asep- the attainment of commercial ste- tic hermetical sealing, with a rility. A Bleeders may serve as a means of re- holding period in a heated section may moving condensate. Persons en- vertical distance between the level of gaged in the production of foods that the product (generally the liquid sur- are to be used in market or consumer face) in the upright rigid container and tests are also included. Tomatoes and tomato prod- shall apply in determining whether the ucts having a finished equilibrium pH facilities, methods, practices, and con- less than 4. Commissioner for giving instruction (r) Scheduled process means the proc- appropriate to the preservation tech- ess selected by the processor as ade- nology involved and who has been iden- quate under the conditions of manufac- tified by that school as having satisfac- ture for a given product to achieve torily completed the prescribed course commercial sterility. This person shall super- be in excess of that necessary to ensure vise only in those areas for which a destruction of microorganisms of pub- school approved by the Commissioner lic health significance, and shall be at identifies the person as having satisfac- least equivalent to the process estab- torily completed training. Subpart C—Equipment (t) Should is used to state rec- ommended or advisory procedures or to §113. Each retort shall be equipped with the scheduled process, the maintenance at least one mercury-in-glass ther- of which vacuum is critical to the ade- mometer whose divisions are easily quacy of the scheduled process. Thermometers shall cock, or other adequate valves used for be tested for accuracy against a known the elimination of air during the vent- accurate standard thermometer upon ing period. I (4–1–10 Edition) thereafter, or more frequently if nec- the retort shell or in a well attached to essary, to ensure their accuracy. Each temperature-recorder Records of thermometer accuracy bulb well shall have a 1⁄16-inch or larger checks that specify date, standard bleeder which emits steam continu- used, method used, and person per- ously during the processing period.

The answer is simply financial—such an approach creates in effect (insofar as the regulatory agencies are concerned) a new chemical entity which must be subjected to the same indepth scrutiny as the “parent” compound buy fluvoxamine paypal anxiety symptoms 6 year old. Under these circumstances order fluvoxamine mastercard anxiety children, most pharmaceutical companies would prefer to invest in the search for a different purchase cheap fluvoxamine on-line relieve anxiety symptoms quickly, orally active analog. The microparticulate species employed include liposomes, niosomes and microemulsions (see chapter 5). Usually, the aim of this strategy is to improve, somehow, the delivery of lipophilic drugs, which have low inherent solubilities in most of the classical formulation excipients. While numerous and expensive liposomal and niosomal-based cosmetic products can be found on sale in every large department store, the use of this technology in pharmaceutical preparations has yet to make a significant impact. These systems are difficult to stabilize, use ingredients which are not cheap, and remain difficult to justify in terms of therapeutic benefit (relative to simpler, cheaper vehicles). Although progress of such formulaics for the parenteral route are showing considerable promise (see chapter 5), their efficient release into and through the skin is not guaranteed. Claims that such colloidal carriers can transport their “pay loads” intact across the stratum corneum have not been substantiated. Given that the space between the corneocytes of the stratum corneum is on the order of 0. Targeting of vesicles to specific appendageal structures, such as the hair follicle, has been discussed and illustrated qualitatively, but the practical utility (and efficiency) of such an effort is still a matter for investigation more than development. In this approach, saturated solutions of drug in miscible cosolvent mixtures of different composition are combined to create a resulting formulation in which the drug is present at n-fold its saturation concentration. This thermodynamically unstable state persists normally for only a short time, before crystallization occurs, and must therefore be stabilized in some way (typically by the addition of a small amount of a polymer such as hydroxypropylmethylcellulose). With such systems, it has been shown that drug flux can be increased proportionately over that achievable using a simply saturated solution. Furthermore, 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 reason for this is that for the adenosine A1 receptor the binding features needed to be defined as specific as possible buy fluvoxamine 50mg with visa anxiety chat room, while for the other three subtypes (selectivity score) a broad range of possible ligand features had to be detected to ensure selectivity cheap fluvoxamine 100mg amex physical anxiety symptoms 24 7. Property ranges were defined purchase fluvoxamine 50mg without prescription anxiety side effects, outside of which molecules were rejected using filters. For this, each property was converted using a desirability function to a value between zero and one, where zero (0) indicates undesirable property values and one (1) that property values are excellent. The use of desirability 15 functions/indices originates from areas such as quality control. This was performed with Pareto selection, which is a method to select the best candidates 16 when considering multiple objectives. In contrast to a simple combination of scores into a single score, Pareto selection considers all three scores simultaneously to select the best candidates. Since evolutionary algorithms have a tendency to focus towards 17 small regions of the chemical search space, diversity of the parent molecules was 18 also taken into account using niching. Niching enforces diversity within populations of candidate solutions by maintaining separated groups, requiring a minimum distance between those groups and a maximum distance between the group members. For each new generation, the number of known structures, the number of structures with known adenosine ligand scaffolds, and the number of structures with high 182 Multi-Objective Evolutionary Ligand Design pharmacophore score were calculated. Chart 1 shows the percentage of compounds that contain known adenosine scaffolds as well as those having a high pharmacophore score. The occurrence of scaffolds also found in adenosine ligands (which were removed) gave us some upfront confidence that the generated structures might indeed be potential adenosine receptor ligands. In general, the number of compounds with a high pharmacophore score is expected to improve over the generations while the number of unknown compounds will increase as well. Although generation of novel compounds is preferred from a medicinal chemistry point of view, a high number of unknown compounds also signals for potential difficulties with synthesis planning or acquisition of starting materials. As visualized by the ‘Scaffolds’ bars in Chart 1, the percentage of scaffolds also found in common adenosine receptor ligands decreases with each generation. The data presented in Chart 1 also suggests that the pharmacophore fit improves with each subsequent generation; the first generated compounds with at least 13 pharmacophore matches first appear in the fifth generation. Percentage of compounds that contain known adenosine ligand scaffolds (“Scaffolds”), and the percentage of compounds with at least 11, 12, or 13 pharmacophore feature hits (“Hits11”/”Hits12”/”Hits13”) per generation (number of generations on X-axis). The generated molecules from all generations were collected and merged into one set (discarding duplicates), resulting in a set of 3. The resulting set of 242 hits was examined for novelty by matching the structures against a set of common adenosine receptor scaffolds and ring systems. These candidates were grouped by scaffold and ranked according to pharmacophore score, as provided in Figure S3 of Supporting Information, to aid further manual inspection. As mentioned above, different structures not known to be adenosine receptor ligands were generated and clustered into different groups (i. We observed that all these scaffolds contained substituents of different nature, at different positions on the scaffold. To investigate the qualities of the multi-objective evolutionary design method, we began with the preparation of six scaffolds (Figure 3), the selection of which was based on ease of synthesis according to a panel of in-house medicinal chemists. Moreover, we were interested in the influence of the suggested substituents; therefore, we began with simple substitution (methyl groups) if any on these six scaffolds. Chemical structures of selected scaffolds generated using the multi- objective evolutionary design method: [1,2,4]Triazolo[4,3-a]quinazolin-5-one (1), 4-Aza-5[H]-phenanthridin-6-one (2), 2-Methylpyrimido[1,2-a]benzimidazol- 4(10H)-one (3), 3,5,6,7-Tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin- 4-one (4), 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (5). The 6:6:5 fused heteroaromatic system [1,2,4]triazolo[4,3-a]quinazolin-5-one (1) was 20 synthesized as previously reported, by the cyclization of 2-hydrazinoquinazolin-4- 21 one in formic acid. Compound 2 was synthesized using a slightly modified reported 185 Chapter 6 22 method, starting from the synthesis of the 2-(N,N- 23 diisopropylcarboxamido)phenylboronic acid, which was then used in a Suzuki- Miyaura cross-coupling reaction with 2-amino-3-bromopyridine under microwave conditions. Subsequently, cyclization of 2-(2-aminopyridin-3-yl)-N,N- diisopropylbenzamide using lithium diisopropylamide yielded the desired compound 2. The 6:5:6 fused heteroaromatic system 2-methylpyrimido[1,2-a]benzimidazol-4(10H)- one (3) was obtained by heating a mixture of 2-aminobenzimidazole and ethyl acetoacetate in the presence of phosphoryl chloride and phosphoric acid. Cyclization of 2-amino-5,6-dihydro-4H- cyclopenta[b]thiophene-3-carbonitrile and 2-amino-4,5,6,7-tetrahydro-1- benzothiophene-3-carbonitrile in formic acid at 110 °C yielded compounds 4 and 5, respectively Compound 6 was synthesized starting from the commercially available 3,4-dimethylphenylisocyanate, which was reacted with hydrazine hydrate to obtain the corresponding semicarbazide, and was subsequently condensed with cyclohexanecarboxaldehyde to afford the corresponding semicarbazone. Finally, alkaline potassium ferricyanide oxidation of this semicarbazone yielded the desired compound 6. Schemes showing the synthesis path and reaction conditions are in the Supporting Information (Schemes S1-S5). Initially, all compounds were screened at a single concentration of 10 µM on all four receptor subtypes. For compounds that inhibited radioligand binding for more than 30% at one or more receptor subtypes the K values were subsequentlyi determined (Table 1). Compound 3 appeared active on all four adenosine receptor subtypes, also in the micromolar range. We were happy with the 33% ‘hit rate’, but concluded at the same time that the evolution of chemistry towards A1 receptor selectivity was only partially successful. Inspection of the generated molecules that contained this 10H-pyrimido-[1,2-a]- benzimidazol-4-one scaffold, revealed that the insertion of a simple alkyl chain at the 187 Chapter 6 3 R position of the scaffold lead to high-scoring molecules. Therefore, we replaced the methyl group on scaffold 3 by different alkyl groups (Figure 4) and investigated the influence thereof on adenosine receptor affinity. A series of compounds were synthesized (3a-3k) by reacting the corresponding 2-aminobenzimidazole with the appropriate β-keto-ester under microwave conditions (see Supporting Information). For those derivatives that gave more than 50% displacement at 1 µM concentration, whole displacement curves were recorded to determine the K value ofi each compound. A linear propyl group at the R position (3b) also improved the Ki value compared to compound 3, but less so than the iso-propyl substituent. These findings prompted us to synthesize the cyclohexyl derivative 3c, which provides an 3 even bulkier substituent at the R position, yet not aromatic. As listed in Table 2, 3 inserting a phenyl ring at the R position lead to compound 3d with highest affinity on the A1 receptor, with a K value of 0. Interestingly, introducing methyl groups on both 188 Multi-Objective Evolutionary Ligand Design 1 2 R and R positions decreased interaction with the adenosine receptors (Table 2). Therefore, the 3 1 2 combination of R = i-Pr and R = R = Me yielded the most selective compound of this series. Interestingly, compound 3g was also directly suggested from the de novo design procedure, indicative of the predictive power of the method. Affinities or % displacement of compounds 3a-3k in Radioligand Binding Assays at human Adenosine Receptors. This method provides the user with a fast and automated generation of best candidate structures and close analogues thereof. Significant micromolar affinity was obtained with two (out of six) scaffolds that were generated in the design process, 4.

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