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By J. Knut. Silver Lake College. 2018.

This is followed by the second phase cheap dutas 0.5 mg mastercard, in which these low molecular weight fragments undergo phagocytosis or solubilization in the body fluids order dutas 0.5 mg online. Their degradation rate can be enhanced by the addition of additives such as oleic acid and tertiary amines generic dutas 0.5mg fast delivery, which act as catalysts in the chain hydrolysis process. Also, copoly- merization with lactide and glycolide decreases crystallinity, and thus hastens the polymer degradation rate due to its higher water uptake (12,22,23). They could be considered safe because it was observed that (i) there were multinucleate, foreign-body giant cells, which are macrophagic cells present in normal processes of polymer degradation 20 D’Mello et al. Polyanhydrides Biodegradation These hydrophobic and crystalline materials have been shown to undergo erosion by surface hydrolysis, minimizing water diffusion into the bulk of the delivery device (25,26). The monomeric anhydride bonds have extreme reactivity toward water and undergo hydrolysis to generate the dicarboxylic acids (27). Although hydrolysis is catalyzed by both acid and base, an increase in pH enhances the rate of hydrolytic degradation. At low pH, oligomeric products formed at the surface of the matrix have poor solubility; this hinders the degradation of the core. The degradation rate of these polymers can be either accelerated by the incorporation of sebacic acid, a relatively more water-soluble aliphatic comonomer than carboxyphe- noxy propane, into the polymer or reduced by increasing the methylene groups or long-chain fatty acid terminal such as stearic acid into the polymer backbone, thereby increasing the monomeric chain length, its hydrophobicity, and the ero- sion rate (28,29). The branching of poly(sebacic acid) with either 1,3,5-tricarboxylic acid or low molecular weight poly(acrylic acid) results in an increased erosion rate (30). It is also known that aliphatic anhydrides and their copolymers undergo a first-order, self-depolymerization reaction, under anhydrous conditions both in solid state and in solution (31). The rate of depolymerization is found to increase with temperature and the polarity of the solvent. Studies on copolymers of several polyanhydride families have shown that varying comonomer ratios produce ero- sion profiles ranging from days to years (32). Biocompatibility During biocompatibility testing of linear aliphatic polyanhydrides in rats, histopathological examination of tissue specimens that were in direct contact with the polymer device showed mild inflammation, but macroscopically, no swelling or pathological signs were observed (27). In another set of compatibility studies, these polyanhydrides were shown to be nontoxic, nonmutagenic, and nonteratogenic (36). A rabbit cornea bioassay indicated the absence of an inflammatory response with implanted polyanhydrides (37). In a rabbit animal model, blank polyanhy- dride particles did not elicit any inflammatory response; however, when a tumor angiogenic factor was incorporated within the polymer matrix, it resulted in a sig- nificant vascularization response, further proving the innocence of the polymer by itself (38,39). When tested in rats, polyanhydrides based on ricinoleic acid did not show any signs of tissue necrosis 21 days postimplantation, while only minimal Polymeric Nanoparticles for Small-Molecule Drugs 21 subacute inflammation and mild fibrosis were noted (40). Clinical trials in humans with a polyanhydride dosage form, Gliadel r , produced no systemic or central tox- icity, thus demonstrating its biocompatibility and acceptability for human use (41). Polyorthoesters Biodegradation Although polyorthoesters are hydrophobic in nature, their orthoester linkage is acid sensitive and highly unstable in the presence of water. The primary mechanism by which these polymers degrade is hydrolysis, and, depending on the reactants used during the polymer synthesis, the degradation products are a diol, a triol, or a mix- ture of diols and carboxylic acid. This in situ production of acid further catalyzes the breakdown of these orthoester linkages, thus resulting in the bulk erosion of the matrix. The rate of this acid-catalyzed hydrolysis of the pH-sensitive linkage can be controlled by incorporating either acidic or basic salts into the polymer matrix (42). This was demonstrated in experiments with 5-fluorouracil-embedded poly- orthoester nanoparticles – when suberic acid was incorporated as an additive, the acidic excipient accelerated the rate of hydrolysis and caused significantly faster release of the drug (43). Alternatively, when the interior of the matrix is buffered with basic salts, the generated acid is neutralized and hydrolysis can be retarded. In this way, they stabilize the bulk of the matrix but allow the drug to escape from the surface region, thus converting the system into a surface-eroding polymer type. For example, the release of tetracycline from a polyorthoester matrix was found to be extremely rapid; however, the addition of 0. Certain poly- orthoesters containing glycolide sequences exist that undergo hydrolytic degrada- tion by autocatalysis without the use of any excipients (45). The control over the erosion rate can also be extended by altering the amount of catalyst, phthalic anhy- dride, present in the polymer (46). The var- ious parameters that can be externally controlled to yield nanoparticles of desired physicochemical characteristics, drug entrapment efficiency, and drug release rate properties include the nature and solubility of the drug to be encapsulated, polymer type and concentration, its molecular weight, composition of the copolymers, drug- loading concentrations, type and volume of the organic solvent, the water phase volume, pH, temperature, concentration, types of surfactants, and the mechanical speed of agitation. In vitro and in vivo responses from the nanoparticles are influ- enced by their various properties, such as the particle size and size distribution, sur- face morphology, porosity, surface chemistry, surface adhesion, zeta-potential, drug 22 D’Mello et al. Conventionally, nanoparticles can be prepared either by dispersion of the preformed polymers or by the in situ polymerization of the monomers. Laboratory-Scale Production of Nanoparticles Phase Separation in Aqueous System The use of coacervation technique to develop polyester microspheres was first reported by Fong in 1979 (48) and modifications of the same are used today for the production of nanoparticles. This technique depends on the precipitation of the drug-entrapping polymer either by the addition of a third compound to the poly- mer solution or by some other physical means.

The bioavailability of Neoral® capsules and the oral solution are equivalent buy 0.5 mg dutas amex, 43% in children purchase 0.5 mg dutas free shipping, ranging from 30 to 68% generic dutas 0.5 mg. Cyclosporine is metabolized to a lesser extent by the gastroin- testinal tract and kidneys, and clearance is affected by age. The half-life of cyclosporine is 7 to 19 hours in children and 19 to 40 hours in adults. Metabolites are excreted primarily through the bile into feces; approximately 6% of cyclosporine is eliminated in the urine, with 0. Sandim- mune® oral solution may be diluted with milk, chocolate milk, or orange juice. Mix cyclosporine in a glass con- tainer and rinse the container with more diluent to ensure that the total dose is taken. However, many transplant cent- ers administer cyclosporine as divided doses (2–3 doses/day) or as a 24-hour continuous infusion. Patients should be under continuous observation for at least the first 30 minutes of the infusion, and should be monitored frequently thereafter. Pediatric Heart Transplantation 195 Monitoring Parameters Blood/serum drug concentration (trough), renal and hepatic function, serum electrolytes, lipid profile, blood pressure, and heart rate should be monitored. Reference Range The reference range of target serum trough concentrations depends on the time after transplantation. Typically, it is 300ng/mL in the first few weeks, 200ng/ mL over subsequent months, and 100 to 150ng/mL during long-term follow- up. Trough levels should be obtained 12 hours after oral dose (chronic usage), 12 hours after intermittent I. When central venous administration is used, peripheral venipuncture, capillary pin prick, or a double-lumen catheter should be used to draw blood samples for therapeutic drug monitoring. Drug-Drug Interactions Acyclovir, aminoglycosides, diclofenac, amphotericin B, erythromycin, and metoclopramide increase cyclosporine absorption. Ketoconazole, fluconazole, erythromycin, diltiazem, verapamil, and meth- ylprednisolone increase cyclosporine concentration by inhibiting hepatic metabolism. Phenytoin, phenobarbital, carbamazepine, primidone, rifampin, trimetho- prim, and nafcillin decrease cyclosporine concentration by increasing hepatic metabolism. Prednisolone, digoxin, and lovastatin may undergo reduced clearance when used with cyclosporine. Adverse Effects The principal adverse reactions to cyclosporine therapy are renal dysfunction, hypertension, hyperkalemia, tremor, hyperlipidemia, and gingival hyperpla- sia. Forced emesis may be beneficial if performed within 2 hours of ingestion of oral cyclosporine. Tacrolimus Indication Tacrolimus is used as an alternative primary immunosuppressant to cyclosporine in all forms of solid organ transplantation in children. Tac- rolimus seems to be somewhat more potent in preventing acute rejection than cyclosporine. A recent three-arm randomized trial of tacrolimus versus cyclosporine (along with corticosteroids and either sirolimus or mycophe- nolate mofetil as adjunctive therapy) in adult heart transplantation showed lower acute rejection rates in patients treated with tacrolimus. Renal toxicity seems comparable between tacrolimus and cyclosporine in pediatric heart transplantation. Similar to cyclosporine, tacrolimus inhibits T-cell activation by inhibiting cal- cineurin. When renal function is impaired, induction therapy with T-cell-depleting antibodies is generally used with delayed introduc- tion of tacrolimus orally. Pediatric patients clear the drug twice as rapidly as adults, and require higher doses on a milligram per kilogram basis to achieve similar blood concentrations. Tacrolimus is prima- rily eliminated in bile, with less than 1% excreted as unchanged drug in urine. Typical levels are 10 to 15ng/ mL in first few weeks after transplantation, 7 to 10 ng/mL for remainder of first year, and 5 to 7 ng/mL long after transplantation. Drug-Drug Interactions Diltiazem, verapamil, nifedipine, fluconazole, itraconazole, ketoconazole, cimetidine, clarithromycin, erythromycin, methylprednisolone, nefazodone, cisapride, protease inhibitors, and oral clotrimazole increase tacrolimus serum concentrations. Webber Antacids, cholestyramine, sodium polystyrene, sulfonate, carbamazepine, phenobarbital, primidone, phenytoin, rifabutin, rifampin, and St. Pediatric Heart Transplantation 199 immunosuppressive efficacy while reducing organ toxicities associated with single agents used in high dosage. Webber Adverse Effects Hematological: bone marrow suppression, leukopenia, macrocytic ane- mia, thrombocytopenia. Decontamination is with ipecac within 30 minutes or lavage within 1 hour; administer activated charcoal. Alternative dose, 30 to 45 mg/kg/day divided every 12 hours (some pediatric patients require every 8-h dosing because of rapid clearance). Drug-Drug Interactions Antacids containing aluminum or magnesium hydroxide decrease absorption of mycophenolate. Webber Adverse Effects Principal adverse effects are gastrointestinal and hematological and include leukopenia, diarrhea, and vomiting.

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Its purpose is to draw treatment; new approaches to preventing public attention to their opinion that drug drug-overdose deaths buy dutas 0.5 mg otc, involving family prohibition itself is the major cause of drug- members; and contingency management related harm to individuals cheap dutas 0.5 mg with visa, communities to improve treatments to reduce drug use and nations discount dutas 0.5mg with visa. He has made prohibition to be replaced by effective, just contributions to the Department of Health, and humane Government control and Home Office, Royal College of Psychiatrists, regulation. He has received the work of organisations that review project grant support and/or honoraria evidence of effectiveness of drug policy; has and/or consultancy payments from the received research and educational grant Department of Health, National Treatment support or honoraria, consultancy payments, Agency, Home Office, European Monitoring and travelling, accommodation, or Centre for Drugs and Drug Addiction and conference expenses from pharmaceutical United Nations Office on Drugs and Crime. He has measurement of health, and was principal had no support from any organisation for investigator on the Arts and Humanities the submitted work and, other than the Research Council funded project, The Ethics above, no financial relationships with any of Risk. He is a member of the Nuffield organisations that might have had an Council on Bioethics, and the Ethics interest in the submitted work in the Committee of the Royal College of previous three years. Formerly, he was a member of the Gambling Review Body, the Nuffield Council Working Party on the Ethics of Research Involving Animals, and the Academy of Medical Sciences Working Party on Brain Science and Addiction. He is currently advising an interdepartmental government committee on the valuation of life and health. His recent books include Ethics and public policy: a philosophical inquiry (2011) and The human right to health (2012). Desired effect Addictiveness Amphetamine A synthetic drug that Stimulant used for a People can become can easily be ‘buzz’ of alertness dependent on the produced on a small and energy and the psychological effects scale. Relieves amphetamines do or smoked or, less boredom and not create physical frequently, injected. Desired effect Addictiveness Cannabis Naturally occurring A mild hallucinogen There is some plant used as leaves that also has some evidence of physical (‘grass’, ‘ganja’, sedative and dependence ‘marijuana’, ‘weed’), disinhibiting associated with resin (‘hash’, properties. It induces cannabis use, which ‘hashish’) or oil that relaxation and can lead to can be smoked or heightens the senses. It may be many different relieve symptoms in psychologically varieties of varying chronic illnesses like addictive if people strengths. Around multiple sclerosis and depend on it as part 100 varieties have glaucoma are being of a coping strategy high levels of the actively researched. Does not powerful physical produce physical and psychological dependence to the rush of exhilaration same degree as and excitement, heroin, but its alertness, confidence physical effects are and strength within 3 powerful and minutes of ingestion withdrawal creates and the effects last very unpleasant 15-40 minutes. No instant from the morphine depress the nervous dependency, but from the opium system and slow physical dependence poppy. Users used for a number of When pure, it is a experience a rush, a days consecutively, white powder, but it warm sensation and even at relatively is usually brownish- sense of being cut low levels. Can May produce ketamine produce euphoria at psychological hydrochloride, found lower doses, dependence. Usually sold as effects, which may tiny squares of paper, last up to 8-12 often with pictures hours, include on them, but also heightened and found as a liquid or altered perception. Psilocybin Mushrooms growing Hallucinogens, Not addictive, but (magic mushrooms) in the wild. Spice A collection of herbs When smoked, they Not known to induce (synthetic or plant material that produce cannabis- physical dependence. Although tobacco smoke and cannabis smoke are known to contain a similar range of mutagens and carcinogens, actual exposure to these compounds may differ between tobacco and cannabis users in terms of the frequency and duration of use, and because of factors such as the depth of inhalation. Percentage of 16 to 64 year olds reporting lifetime, last year and last month use of individual drugs in Scotland, 2008/2009, by sex Lifetime use Last year use Last month use Men Women Total Men Women Total Men Women Total Any drug 37. Can cause Mannitol nasal irritation Lead Soft, malleable metal Heroin In low dosages lead • Abdominal pain Potentially a by- poisoning can have and cramping product of the use of mild effects. Low doses been reported in • Opisthotonos act as a muscle non-life threatening (holding of body in stimulant quantities, small awkward rigid increases could position) Heroin potentially be fatal Enhances retention of heroin when volatised. Has only been found at non- life threatening quantities Cocaine Reason for inclusion unknown. Liverpool: Centre for Public Health, Liverpool John Moores University; and Jones L, Bates G, Bellis M et al (2011) A summary of the health harms of drugs. This includes the cross-Government organised crime strategy, Local to global: reducing the risk from organised crime, published in July 2011b 3. This includes raising awareness among parents and carers, and targeting young people 2. Any use of drugs must be The 12A category only exists for infrequent and should not be cinema films, where children glamorised or give instructional under 12 must be accompanied detail by an adult to enter. Films classified as 12A are not recommended for children under 12 15 Suitable only for 15 years Drugs may be shown but the and over film as a whole must not promote or encourage drug use. The misuse of easily accessible and highly dangerous substances (for example, aerosols and solvents) is unlikely to be acceptable 18 Suitable only for adults No specific guidance on drugs R18 To be shown only in specially No specific guidance on drugs licensed cinemas, or supplied only in licensed sex shops, and to adults of not less than 18 years Source: British Board of Film Classification (2009) The guidelines. This is because evidence suggests that warning messages displayed ahead of films portraying pro-smoking imagery may mitigate some of the effects these images have in terms of encouraging uptake of smoking. Given that evidence suggests film images can influence drug behaviour, film producers should consider the impact that depicting drug use may have on individuals. To aid in this process, policy makers may wish to consider informing those involved in the production of film of the potential damage done by the depiction of drug use in film.

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Changes in trace-metal concentrations have been studied at length with regard to the ageing process order dutas 0.5 mg otc. To determine the extent of elements present in ‘crude oil’ by virtue of the fact that some of these may poison the catalysts used in the cracking-process e discount dutas 0.5 mg overnight delivery. Substantiate your explanation based on the en- ergy-level diagrams for an ‘atom’ and a ‘molecule’ purchase dutas 0.5 mg with amex. With the help of a neat-labeled circuit diagram explain the following : (a) Direct Current Arc (b) Alternating Current Arc Discuss their procedural steps, merits/demerits explicitely. Differentiate the plus and nega- tive aspects encountered in : (a) Photographic Detector ; and (b) Photomultiplier Detector, briefly. How would you identify the ‘frequencies’ and the ‘intensities’ of emission spectra by the help of : (a) Littrow type spectrograph, (b) Ebert-mounting spectrograph. Enumerate the various applications of ‘Emission Spectroscopy’ with respect to the following entities : (i) analysis of alloy, (ii) analysis of elements in tissues, (iii) analysis of elements in blood samples, (iv) analysis of Zn in pancreas tissue, and (v) elements present in ‘crude oil sample’. Quite a few such gaseous metal atoms are usually raised to a particular high energy level that enables them to allow the emission of radiation characteristics features of the metal : for example-the characteristic flame colourations of metals frequently encountered in simple organic compounds such as : Na-yellow, Ca-brick-red ; Ba-apple-green. It is quite evident that a relatively large proportion of the gaseous metal atoms shall remain in the ground state i. It has been observed that such ground-state atoms shall absorb radiant energy pertaining to their own particular resource wavelength. Therefore, when a light having the same resonance wavelength is made to pass through a flame consisting of such atoms, a portion of the light shall be absorbed accordingly. Furthermore, the extent or degree of absorption would be directly proportional to the total number of ground-state present in the flame. The emission spectrum thus obtained is made up of a number of lines that actually originate from the resulting excited atoms or ions ; and these steps may be shown diagrammatically as represented in Fig- ure 25. The resulting neutral atoms are excited by the thermal energy of the flame which are fairly unstable, and hence instantly emit photons and eventually return to the ground state (i. Boltzmann Equation : The fraction of free atoms which are excited thermally, or in other words, the relationship between the ground-state and the excited-state quantum is exclusively represented by the Boltzmann equation given below : N /N = (g /g ) e–∆E/kT......... Form equation (d) it may be observed that : • Fraction of atoms excited (N1) solely depends upon the temperature of the flame (T), and • Ratio N1/N0 is dependent upon the excitation energy (∆E). These two typical instruments shall be discussed briefly here highlighting their various components and procedural details. In general, Flame Photometers are designed and intended mainly for carrying out the assay of elements like : Sodium, Potassium, Calcium, and Lithium that possess the ability to give out an easily excited flame spectrum having sufficient intensity for rapid detection by a photocell. Procedure : The compressed and filtered air (A) is first introduced into a Nebulizer (E) which creates a negative pressure (suction) enabling the liquid sample (C) to gain entry into the atomizer (E). Thus, it mixes with the stream of air as a fine droplet (mist) which goes into the burner (G). The fuel gas (D) intro- duced into the mixing chambers (F) at a given pressure gets in touch with the air and the mixture is ignited. Consequently, the radiation from the resulting flame (H) is made to pass through a convex lens (I) and ultimately through an optical filter (J) that allows specifically the radiation characteristic of the element under examination to pass through the photocell (K). Finally, the output from the photocell is adequately amplified (L) and subsequently measured on an appropriate sensitive digital-read-out device. A = Inlet for compressed Air, B = Drain outlet (to maintain constant pressure head in the mixing Chamber), C = Liquid sample (sucked into the Nebulizer), D = Inlet for Fuel-Gas to the Laminar-Flow-Burner, E = Nebulizer to atomize the liquid sample, F = Mixing Chamber for Fuel Gas, Compressed Air, and Atomized Liquid Sample, G = Burner, H = Flame, I = Convex lens, K = Optical filter to transmit only a strong-line of the element, and L = Amplifier to amplify the feeble electrical impulse and a built-in direct read-out device. I = A calibrated potentiometer, J1 = Lines due to the ‘sample’ J2 = Lines due to the Internal Standard ‘Lithium’, and K1 & K2 = Photocells to convert light-energy to electrical impulse. The use of an internal standard flame photometer not only eliminates the visible effects of momentary fluctuations in the flame characteristics produced by variations in either the oxidant or under full pressures, but also the errors caused due to differences in surface tension and in viscosity are minimised to a great extent. Procedure : In this particular instance ‘Lithium’ is employed as an internal standard and an equal concentration is added simultaneously to the sample and the standard solutions. The sample (C) solution having the internal standard (Lithium) is sucked in by an atomizer and a fine spray is thereby introduced into the flame (D). The radiation thus emitted is subsequently passed through a filter (F) and then collected by a mirror (E). The emitted radiation reflected from the mirror is split up into two parts : the first part is caused due to the internal standard (Lithium), whereas the second part arises due to the element under examination. Both these lines J1 and J2 are passed through the respective photocells K1 and K2 whereby the light energy is transformed into the electrical impulses. These electrical impulses are usually very weak and feeble and hence, they are duly amplified by a suitable amplifier (G) individually and are subsequently introduced into the common detecting device (H) i. In short, an internal-standard flame photometer provides a direct and simultaneous result with respect to the ratio of intensities. Procedure (a) Preparation of working curves : Transfer 5 ml of the appropriate radiation buffer to each series of 100-ml volumetric flasks.

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Barau K purchase 0.5 mg dutas amex, Thirion X cheap dutas 0.5 mg with visa, Micallef J et al (2001) Comparison of methadone and high dosage buprenorphine users in French care centres discount dutas 0.5mg with amex. Auriacombe M, Fatséas M, Dubernet J et al (2004) French field experience with buprenorphine. Amato L, Minozzi S, Davoli M et al (2011) Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Gossop M, Stewart D, Browne N et al (2003) Methadone treatment for opiate dependent patients in general practice and specialist clinic settings: outcomes at 2-year follow-up. Taylor D, Paton C & Kapur S (2009) The Maudsley prescribing guidelines in psychiatry (10e). National Institute for Health and Clinical Excellence (2011) Alcohol dependence and harmful alcohol use. Minozzi S, Amato L, Vecchi S et al (2011) Oral naltrexone maintenance treatment for opioid dependence. Volume 1: A study of effectiveness and financing of public and private drug treatment systems. Strang J, Manning V, Mayet S et al (2007) Does prescribing for opiate addiction change after national guidelines? Methadone and buprenorphine prescribing to opiate addicts by general practitioners and hospital doctors in England 1995-2005. Marsden J, Eastwood B, Bradbury C et al (2009) Effectiveness of community treatments for heroin and crack cocaine addiction in England: a prospective, in-treatment cohort study. Bell J, Trinh L, Butler B et al (2009) Comparing retention in treatment and mortality in people after initial entry to methadone and buprenorphine treatment. Bell J, Butler B, Lawrance A et al (2009) Comparing overdose mortality associated with methadone and buprenorphine treatment. Strang J, Griffiths P, Powis B et al (1999) Which drugs cause overdose among opiate misusers? Zador D & Sunjic S (2000) Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995. Williams A, Reed K, Groshkova T et al (2010) Training family members and carers of opiate users in overdose management and naloxone administration: a randomised trial. Strang J, Darke S, Hall W et al (1996) Heroin overdose: the case for take-home naloxone? Neale J, Tompkins C & Sheard L (2008) Barriers to accessing generic health and social care services: a qualitative study of injecting drug users. Barnaby B, Drummond C, McCloud A et al (2003) Substance misuse in psychiatric inpatients: comparison of a screening questionnaire survey with case notes. Kouimtsidis C, Reynolds M, Hunt M et al (2003) Substance use in the general hospital. Ryrie I & Ford C (2001) The primary care treatment of drug users: is shared care really the best approach? McCambridge J & Strang J (2004) The efficacy of single-session motivational interviewing in reducing drug consumption and perceptions of drug-related risk and harm among young people: results from a multi-site cluster randomized trial. Marijuana Treatment Project Research Group (2004) Brief treatments for cannabis dependence: findings from a randomized multisite trial. National Institute for Health and Clinical Excellence (2007) Drug misuse: opioid detoxification. Bell J (2010) The global diversion of pharmaceutical drugs: opiate treatment and the diversion of pharmaceutical opiates: a clinician’s perspective. Blackwell J (1988) The saboteurs of Britain’s opiate policy: overprescribing physicians or American-style ‘junkies’? National Institute for Health and Clinical Excellence (2011) Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. Sikdar S (1998) Physical dependence on zopiclone: prescribing this drug to addicts may give rise to iatrogenic drug misuse. Reed K, Bond A, Witton J et al (2011) The changing use of prescribed benzodiazepines and z-drugs and of over-the-counter codeine-containing products in England: a structured review of published English and international evidence and available data to inform consideration of the extent of dependence and harm. Schweitzer E & Rickels K (1998) Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management. Royal College of Psychiatrists (1997) Benzodiazepines: risks, benefits or dependence: a re-evaluation. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (4e). Vandrey R & Haney M (2009) Pharmacotherapy for cannabis dependence: how close are we? Darke S & Hall W (2003) Heroin overdose: research and evidence-based intervention. Strang J, McCambridge J, Best D et al (2003) Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow-up study. Williams A, Reed K, Groshkova T et al (2010) Training family members and carers of opiate users in overdose management and naloxone administration: a randomised trial.

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