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Improve- ment of large intestinal absorption of insulin by chemical modifcation with palmitic acid in rats accutane 5mg with amex. Development of oligoarginine-drug conjugates linked to new peptidic self-cleavable spacers toward effective intestinal absorption quality 20 mg accutane. Bioorg Med Chem Lett 2007;17:5129–5132; (b) Takayama K, Suehisa Y, Fujita T, Nguyen J-T, Futaki S, Yamamoto A, Kiso Y, Hayashi Y. Oligoarginine-based prodrugs with self-cleavable spacers for intestinal absorption. The third helix of the Anten- napedia homeodomain translocates through biological membranes. Recent advances in the use of protein transduction domains for the delivery of peptides, proteins and nucleic acids in vivo. Adaptive translocation: the role of hydrogen bonding and membrane potential in the uptake of guanidinium-rich transporters into cells. Adv Drug Deliv Rev 2005;57:529–545; (f) Futaki S, Suzuki T, Ohashi W, Yagami T, Tanaka S, Ueda K, Sugiura Y. An abundant source of membrane-permeable peptides having potential as car- riers for intracellular protein delivery. Oligoarginine vectors for intracellular delivery: design and cellular-uptake mechanisms. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Binding of oligoarginine to membrane lipids and heparan sulfate: struc- tural and thermodynamic characterization of a cell-penetrating peptide. Possible existence of common internalization mechanisms among arginine-rich peptides. Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement. Blood–brain barrier genomics and proteomics: elucidating phe- notype, identifying disease targets and enabling brain drug delivery. Transendothelial permeability changes induced by free radicals in an in vitro model of the blood–brain barrier. Delivery of therapeutics agents to the central nervous system: the problems and the possibilities. Antinociceptive structure-activity studies with enkephalin-based opioid glycopeptides. Relationship of octanol/water partition coeffcient and molecular weight to rat brain capillary permeability. Distribution and analgesia of [3H][D-Pen2, D-Pen5]enkephalin and two halogenated analogs after intravenous administration. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Extremely rapid degrada- tion of [3H] methionine-enkephalin by various rat tissues in vivo and in vitro. Passage of a δ-opioid receptor selective enkephalin, [D-penicillamine2,5] enkephalin, across the blood–brain and the blood-cerebrospinal fuid barriers. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood–brain barrier. Rate of 59Fe uptake into brain and cerebrospinal fuid and the infuence thereon of antibodies against the transfer- rin receptor. Jiang C, Koyabu N, Yonemitsu Y, Shimazoe T, Watanabe S, Naito M, Tsuruo T, Ohtani H, Sawada Y. In vivo delivery of glial cell-derived neurotrophic factor across the blood–brain barrier by gene transfer into brain capillary endothelial cells. In vivo protein transduction: delivery of a biologically active protein into the mouse. Laboratory invest tigations for the morphologic, pharmacokinetic, and anti-retroviral properties of indinavir nanoparticles in human monocyte-derived macrophages. PregnaneXreceptor up-regulation of P-glycoprotein expression and transport function at the blood–brain barrier. Modulation of P-glycoprotein at the blood–brain bar- rier: opportunities to improve central nervous system pharmacotherapy. Increasing volume of distribution to the brain with interstitial infu- sion: dose, rather than convection, might be the most important factor. Nasal route for direct delivery of solutes to the central nervous system: fact or fction? The frst attempt at radioisotopic evaluation of the integrity of the nose-brain barrier. Glucagon-like peptide-1: the basis of a new class of treatment for type 2 diabetes. Telavancin, a mul- tifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Monitoring of benzylpenicillin decomposition in gastric contents by capillary zone electrophoresis.

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It carries the connotation of Illicit drug use quality 40 mg accutane, though alcohol discount accutane 20 mg with mastercard, nicotine, and caffeine are the substances most frequently used in combination with others in industrialised societies (Polysubstance use). The category is also used when the exact identity of some or even all of the substances being used is uncertain or unknown, since many multiple drug users often do not know themselves what they are taking. Polysubstance use The concurrent use of an Illicit drug or Drugs and alcohol, tobacco (nicotine) or caffeine. For statistical purposes, the definitions and methods of calculation differ from country to country. Prohibition Policy under which the cultivation, manufacture, and/or sale (and sometimes the use) of a Psychoactive drug are prohibited under criminal law (although pharmaceutical sales are usually permitted). This term and its equivalent, Psychotropic drug, are the most neutral and descriptive terms for the whole class of substances, licit and illicit, of interest to Drug policy. The term encompasses acute Intoxication, Harmful use, Dependence syndrome, withdrawal state, withdrawal state with delirium, psychotic disorder, and amnesic syndrome. For a particular substance, these conditions may be grouped together as, for example, cannabis use disorders, stimulant use disorders. Psychoactive substance use disorders are defined as being of clinical relevance; the term ‘psychoactive substance use problems’ is a broader one, which includes conditions and events not necessarily of clinical relevance. Psychopharmacology The actions of Drugs, and their effects on mood, sensation, cognition and behaviour. Receptor A structure or site on the surface of a cell that can bind a chemical substance that will then induce a change in the cell. In the context of Psychoactive drugs, binding of a drug to a specific receptor on nerves in the brain can induce a psychological effect by either mimicking or blocking the action of a specific natural neurotransmitter. Recreational use Use of a Drug, usually an Illicit drug, in sociable or relaxing circumstances, by implication without Dependence or other problems. The term is not favoured by those seeking to define all Illicit drug use as a problem. This usually includes improved family and social relationships, living in appropriate housing and being gainfully employed. It is likely to be achieved by treatment to reduce or eliminate dependence on Illicit drugs. Recovery capital The ‘breadth and depth of internal and external resources that can be drawn upon to initiate and sustain Recovery’ from Substance use. Examples of regulated products are over-the-counter drugs, prescription drugs, alcohol and tobacco. Rehabilitation In the field of Substance use, the process by which an individual with a substance use disorder achieves an optimal state of health, psychological functioning, and social wellbeing. Rehabilitation follows the initial phase of treatment (which may involve Detoxification and medical and psychiatric treatment). It encompasses a variety of approaches, including group therapy, specific behaviour therapies to prevent relapse, involvement with a mutual-help group, residence in a therapeutic community or half- way house, vocational training, and work experience. Relapse A return to drug use after a period, of abstinence or controlled use, often accompanied by reinstatement of Dependence symptoms. Some distinguish between relapse and lapse (‘slip’), with the latter denoting an isolated occasion of alcohol or drug use. This can be pharmacological (eg naltrexone-maintained abstinence from opioid use), or a psychosocial intervention such as cognitive-behavioural therapy, which focuses on helping users to identify situations where they are most vulnerable to drug use and to develop coping skills to deal with these situations. In the context of Illicit drug use, it can refer to a period of abstinence or controlled use, or to a period of freedom from the Craving associated with Dependence. Residential rehabilitation Prolonged residential treatment in a home, hostel or hospital unit, for Dependence, usually on a Psychoactive drug. There is a positive and highly structured drug-free environment with strict rules, where residents are expected to participate in a programme of Rehabilitation, based on self-help and mutual support. Substitution treatment Treatment of Dependence on a Psychoactive drug with a substitute drug with cross-dependence and cross-Tolerance. The goal is to reduce or eliminate use of the original drug and/or to reduce harm from a particular method of administration. Therapeutic community A structured environment where individuals with Substance use disorders live, to achieve Rehabilitation. Such communities are often specifically designed for individuals with Dependence on Psychoactive drugs, are run according to strict rules, based on self-help and mutual support, and are often geographically isolated. They use a hierarchical model with treatment stages that reflect increased levels of personal and social responsibility. Peer influence, mediated through a variety of group processes, is used to help individuals learn and assimilate social norms and develop more effective social skills. Increased doses of alcohol or other drugs are required to achieve the effects originally produced by lower doses. Physiological and psychosocial factors may contribute to the development of tolerance, which may be physical, behavioural or psychological.

Within the chronological perspective outlined above the mounting importance of the administrative regulation has for instance been correlated with the declining infuence of the profession generic accutane 5 mg line. Although the acceptance of the controlled clinical trial as reference was not only supported by public health authorities but also by elite clinicians generic 30 mg accutane with visa, the generalization of approval negotiations based on standardized tests or trials have nonetheless limited the role and the autonomy of professional bodies, shifting the balance of power between pharmacy and medicine. With all their pragmatic variations and complex history, the emphasis placed here on the production of statistical evidence, on the organization and interpretation of such trials, on the evaluation of their regulatory meaning shows that clinical research was not only turned into a new form of biomedical knowledge, but has also become regulatory science. At stake is less the question of “capture” and the possibility that state agencies act as a smokescreen for the real and invisible industrial regulation than the issue of professional autonomy. Controlling commercial circulation or negotiating prices is not controlling medical practices even if has consequences on them. Moreover – as repeatedly illustrated in this volume – the scenario of a simple historical succession must be qualifed to take into account the mutual construction of the ways of regulating. Even in its glorious time, during the second half of the 19th century, professional regulation was always bound to the state depending on some demarcation work distributing aims, expertise and power of decision between professional and administrative institutions. What is however a reasonable hypothesis is that the late 20th century has seen the emergence of another challenge to the regulation by medical bodies in the form of guidelines issued not by the drug administration but by paying third parties, i. Exploring the relations between the culture of preparation and pharmacological modeling that imprinted the professional regulation up to the middle of the 20th century brings to the fore another set of questions regarding the impact regulatory practices have had on our understanding of diseases. Ways of regulation are bound to ways of knowing in a historical sense, not in an ontological or logical one. This is not to restate the trivial, namely that the early 20th century regulatory landscape was dominated by other categories and tools (mixtures and physiological assays) than ffty years later (pure molecules eventually combined and clinical trials). Following the analysis of use and prescription included in this collection is rather to insist on the interplay the regulatory activities of physicians, frms and state bodies have on the defnition of the normal 13 Jean-Paul Gaudillière and Volker Hess and the pathological. Regulation thus contributed in more than incidental ways in what may count as one of the most important changes of medical practice in Western industrial societies, i. This is powerfully exemplifed by the diagnostic and classifcatory meaning of prescription in such various felds as cardiovascular medicine, obesity treatment, psychiatry, or cancer staging. Another major point surfacing in the papers is the importance of recent changes associated with the demarcation of a public regulation. One aspect outlined above is the fact that users and patients have gained new margins of intervention through court actions, political demonstrations or media campaigns. The public regulation is closely related to the forms of public negotiations that were understood under the label of the “public sphere” since the early 19th century. The case studies gathered here document the capabilities of patients and users organizations to develop alternative forms of expertise challenging the claims of the profession or the industry. Such expertise is often referred to new – and more personal - ways of documenting and discussing the experience of diseases or the quality of care. It is however important not to forget that the knowledge made by the public or within the public sphere is not extraneous to clinical or epidemiological inquiries. Beyond the classical affairs that reshaped drug regulation the visibility of patients in the political, judicial and media arenas is bound to the above-mentioned displacement of medical practices in the direction of chronic diseases management and to the increasing surveillance of what happens after marketing when drugs are massively used in routine conditions differing from the (relatively) controlled worlds of trials. A sure sign of novelty is thus the fact that by then users’ mobilization has resulted in the termination of a drug trajectory either because the industry, confronted with underestimated challenges, makes the decision to withdraw its product or – as shown here – because patients simply stop taking their medicine. Compared to the number of therapeutic agents put on the market or actually consumed such cases are however a tiny minority. The contemporary public regulation is in the frst place a regulation of information rooted in the massive developments of consumer-oriented activities in our post-modern industrial societies. At stake here is not only the fact that what state agencies or pharmaceutical frms do has evolved in order to include all sorts of information management, but the signifcant displacements in the administration and qualifcation of evidence. Beside clinical trials, the favorite tools now include a combination of cost-beneft and risk-safety analysis, which nurture and polarize the mundane work of market construction and post marketing surveillance. Looking at the small number of studies investigating frms, it may seem that – once again - the industrialist acts as an invisible hand. The papers nonetheless offer two approaches to the specifcity of the industrial regulation. The frst one focuses on the older linkage between quality control, standardization, toxicological assessment and side-effect management that was central to the pharmacists’ peculiar positions in frms, gradually creating an autonomous space that became an alternative to the professional regulation of preparations. The second approach echoes the discussion of health risk management, it targets the development of scientifc marketing, of drug 14 Introduction advertisement and pharmaceutical representation has become central in the companies, creating new spaces of interaction with the doctors for defning indications, doses, targeted populations. In conclusion we would like to come back to the administrative and disciplinary understanding of regulation. The discussions refected in these papers defnitely make a case for the idea that regulation is much more than a series of protocols defning the ways of producing, controlling and distributing therapeutic agents. Such protocols are elements in the various ways of regulating but the later are in the frst place ways of determining what are therapeutic agents. They shape them as historically changing objects emerging at the crossroad between knowledge acquisition and evidence making, industrial preparation and technical analysis, consumption and market construction, lobbying and information, at the crossroad between the present form taken by political and the moral economies of industrial societies. At the beginning of the 19th century, this regulatory activity was ensconced in new administrative procedures.

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By substituting the value of k in equation (5) buy 5 mg accutane with visa, we get dC Ds A = (Cs − C dt Vlb thus discount accutane 20 mg, water-soluble drugs will be released faster than the hydrophobic ones. Si-Nang and Carlier (9) modified this equation for drug release from micro- capsules dC Ds A K = (8) dt Vlm where A = internal surface area of coating. In this case, the plot of 3 W versus t gives a straight t line and the value of k can be obtained from the slope. For weakly acidic and basic drugs, the influence of pH on solubility is given by the Handersson-Hasselbach equation: S − S0 For weak acids, pH = pka + log (10) S0 S0 For weak base, pH = pka + log (11) S − S0 where S = saturation solubility of the solute; S0 = intrinsic solubility of the solute. In addition, flux ∝ 1/l; so, as the thickness decreases, flux also increases due to reduced diffusional path length. Other factors include type and amount of matrix material, size and density of the microparticle, presence of additives or adjuvants, extent of polymerization, denaturation, cross-linking or hardening, diffusion temperature, diffusion medium, its polarity, presence of enzymes, etc. Empiric Models of Drug Release Kinetics of drug release from microparticulates can be understood from various models based on their nature. However, simple empiric models are often used in place of complex models, which are discussed in the following text. Exponential Equation Diffusional exponent approach has been given by Peppas and colleagues (11,12). It is applicable for hydrating or eroding systems in which D is not constant, thereby giving anomalous diffusion. Mt n = kt (12) M0 where Mt/M0 = fractional mass of drug released at time t; and n = diffusional expo- nent. The two exponents consist of rapid or burst phase and slow or sustained release phase, respectively. On converting equation (15), we get In Mt 3k1t 1 − =− 2 M0 r which is the equation for a straight line. Nowadays, drug release kinetics are determined and better understood from their nature, depending on whether they are reservoir-, matrix-, or sandwich-type systems. Reservoir-Type Devices (Microcapsules) (14–18) Various equations have been given depending on different situations. Case 1 Assuming that thermodynamic activity of the core material is constant within the microcapsule, which is spherical and has inert homogeneous coating, steady-state release rate is derived from Fick’s first law of diffusion. However, when the ratio of ro to ri is 4, further increase in size will not significantly affect drug release (14). If product is tested immediately after preparation, as fluid takes time to pene- trate and attain concentration gradient, there will a delay or lag time, t1 is given by Crank’s equation as, t = (r − r )2 6D (22) 1 o i This can be used to find D at a particular time, and vice versa, if film thickness is known. If the product is stored for a long period of time before testing or has surface- associated drug, it shows burst effect, leading to the initial overdosage. Thus, the time necessary to reach steady state depends on coating thick- ness and D. The burst time, tb,is 2 (ro − ri) tb = (23) 3D Monolithic Devices (Microparticles) (19–22) Monolithic or matrix systems are those in which the core is uniformly dispersed throughout the matrix polymer. The drug release kinetics will depend on whether the drug is dissolved or dispersed in the polymer. Early stage approximation is given by the Baker-Lonsdale equation (14): 1/2 Mt Dt 3Dt = 6 2 − 2 (24) M∞ r r where M∞ = drug dissolved in the polymer; Mt = drug released at time t; r = radius of particle; and D = diffusion coefficient. Then, the equation will convert to Mt = − 3 (25) M0 Total drug release can be obtained by the integration of the equation: 1/ d(Mt/M∞) D 2 3D = 3 2 t − 2 (26) dt r r This is the equation for a straight line and shows that release is inversely propor- tional to the radius, r, of the microparticles. Later time approximation is given as follows: 2 Mt 6 Dt = 1 − 2 exp 2 (27) M∞ r which is valid for (Mt/M∞) > 0. Inte- gration of the equation gives 2 d(Mt/M∞) 6Dt Dt = 2 exp − 2 (28) dt r r Thus, it shows that later drug release is exponential. Case 2 When the drug is dispersed in the coat, that is, the drug is insoluble in and is uni- formly dispersed throughout the matrix A. The Baker-Lonsdale equation derived from the Higuchi equation for homoge- neous, spherical matrix 1 d(Mt/M∞) 3CmD (1 − Mt/M∞)3 = 2 1 (29) dt roC0 1 − (1 − Mt/M∞)3 where Cm = drug dissolved in the membrane; C0 = initial drug concentration. This is valid when Cm <<< Ctot, that is, not more than 1% of the drug is present in the membrane. This equation assumes that the solid drug is dis- solved from surface layer first and next layer dissolves only after the first layer is exhausted. However, the majority of microparticulate systems are heterogeneous and drug release is complex. The equation implies that drug release is proportional to the square root of time and is simplified to Q = k t1/2 (32) 1 This is the modified Higuchi equation. For planar surface of granular-type matrix having irregular, clustered, or aggre- gated particles, the following equations holds: 1 D ∈ 2 Q = (2Ctot − Cs)Cst (33) where ∈=porosity; = tortuosity; Ctot = total concentration of drug in matrix; and Cs = saturation concentration.

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