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Elimination rate constant (K) a constant representing the fraction of drug removed per unit of time -1 (in units of reciprocal time order viagra plus 400mg without a prescription, usually hr ) 400 mg viagra plus sale. Extraction ratio (E) the fraction of drug removed from plasma by one pass through an organ viagra plus 400mg otc. Organs that are very efficient at eliminating a drug will have an extraction ratio approaching 1 (i. First-order elimination occurs when the amount of drug eliminated from the body in a specific time is dependent on the amount of drug in the body at that time. A straight line is obtained from the natural log of plasma drug concentration versus time plot only for drugs that follow first-order elimination. First-pass effect drug metabolism by the liver that occurs after absorption but before the drug reaches the systemic circulation. Half-life (T1/2) the amount of time necessary for a plasma drug concentration to decrease by half. Kinetic homogeneity describes the predictable relationship between plasma drug concentration and concentration at the receptor site. Model a simplified mathematical simulation of physiologic processes used to predict the time course of drug concentrations or effect in the body. Model-independent parameter a pharmacokinetic parameter, such as clearance, that can be calculated without the use of a specific model. Model-independent pharmacokinetics pharmacokinetic calculations using parameters that do not require the use of specific compartmental models (e. Pharmacodynamics the relationship between drug concentrations at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects. Pharmacokinetics the relationship of drug dose to the time course of drug absorption, distribution, metabolism, and excretion. Plasma the fluid portion of blood (including soluble proteins but not formed elements). Receptor a structure on the surface of a cell to which a drug binds and causes an effect within the cell. Serum the fluid portion of blood that remains when the soluble protein fibrinogen is removed from plasma. Steady state the point at which, after multiple doses, the amount of drug administered over a dosing interval equals the amount of drug being eliminated over that same period. Therapeutic range the plasma concentration range that is effective and safe in treating specific diseases. Volume of distribution (V) an important indicator of the extent of drug distribution into body fluids and tissues, V relates the amount of drug in the body to the measured concentration in the plasma. Studies of drug regulation are of course nothing like a blank territory in the history of science, medicine and technology. Among the industrial goods, pharmaceuticals are certainly This is the path taken by the marketing of Thalidomid in Brasil. The pictogram of a crossed-out pregnant woman on the package however evoked contradictory associations by each consumer. One reason for the pervasiveness of the idea of regulation in the case of pharmaceuticals is certainly that therapeutic agents are not goods as any other. Their sale and purchase constitute a very peculiar market whose control and surveillance in order to protect “public health”, meaning avoid poisoning as well as the creation of monopolies that might threaten reasonable conditions of access, has been considered a duty of the state since the early days of the transformation of pharmaceutical craft into a profession in the early 19th century. As a consequence of this situation, the historiography of drugs has given regulatory issues a rather institutional meaning. Within this perspective, the words “drug regulation” are usually employed with a narrow understanding, which focuses on the actions taken by the government or other political bodies in order to control the activities of drug makers. Studies then focus on the administrative features that have been used to tame the market or safeguard production, i. Industrial drug making as it developed within the large capitalistic corporations of is the focus of analysis approaching the 20th century highly visible conficts between frms, physicians and public authorities caught within a web of market forces and public health defense. Daemmerich have accordingly highlighted the affairs, controversies and public debates, which have reshaped the agency, enlarging its responsibilities if not its power, shifting pre-marketing evaluation from a mere control of composition to an assessment of toxicity and in the second half of the 20th century an assessment of effcacy. As the above mentioned example of Contergan suggests, this form of state administration has been associated with or superimposed on other forms of collective management, of “regulation”, which did not only target sales and commercialization, but the entire trajectory of drugs, i. The perspective adopted for the workshop that provided the background for the essays assembled in this preprint was therefore that the historiography of science, technology and medicine needs a broader approach of regulation. Contemporary studies of science and technology have often made the point that the production and uses of knowledge are interactive, undetermined, and complex processes. This must also be Without making any attempt to offer a bibliography of drug trajectories or even a selection of existing studies on drugs and regulation, we simply invite the reader to take the beneft of the references included in the individual papers of the collection. In the last two centuries, drugs have become central elements in complex health systems. It is the belated product of a long-term transformation, which began in the second half of the 19th century when the industrialization of drug making coincided both with the rising infuence of experimental sciences and laboratory practices in medicine, and the emergence of hospitals as the place where insurance-based health care accessible to the working class would be routinely provided. Although, state and professional forms of regulation can be traced back to the early 19th century, this conjunction deeply affected – diversifed – regulatory practices, setting the pace for new forms of control emphasis standards, homogeneous protocols or statistical effcacy. Our contention is also that various levels of comparison must be chosen in order to explore the relations between research, therapeutic intervention, and commercialization. Given the emphasis placed on administrative and legal tools of regulation, it is not surprising if comparisons between national settings have – up to the present - had the highest priority. The assays gathered in this preprint add to such cross-national perspective comparisons between periods, cultures, institutions, and therapeutic agents. One additional remark is that although the case studies gathered in this volume all take into account the multiplicity of actors and dispositifs constituting the 20th century regulatory systems, they do not simply stress the novelty, the importance or the benefts of such diversity but recognize the unequal abilities of actors to shape situations and to control the fate of drugs. Power gradients are at the very center of drug regulation and must be considered for their own sake. It is a general feature of the construction of economic markets that it cannot proceed without state and administrative interventions, which built the terrain upon which capital can be invested and goods traded.

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All other parameters of the ‘Cluster Molecules’-component were kept at their default values buy 400mg viagra plus visa. From each cluster 400mg viagra plus for sale, at least one compound was selected based on predicted solubility 400 mg viagra plus, calculated LogP, and a measure similar to ligand efficiency in docking: the score divided by the number of heavy atoms. To explore the top hits further, ten additional (diverse) compounds were selected that had a score equal or better than the lowest scoring reference compound but that were not part of the top 1,800 highest scoring compounds. Filters were washed three times with ice-cold buffer and placed in scintillation vials. Filters were washed three 169 Chapter 5 times with ice-cold buffer and placed in scintillation vials. Filters were washed three times with ice-cold buffer and placed in scintillation vials. Patterson in Symbolic and Quantitative Approaches to Reasoning with Uncertainty; Lecture Notes in Computer Science; Springer Berlin / Heidelberg, 2005; Vol. This method consists of several iterative cycles of structure generation, evaluation and selection. In addition, three support vector machine models based on molecular fingerprints were developed for the other adenosine receptor subtypes (hA2A, hA2B and hA3) and applied as negative objective functions, to aim for selectivity. Six of these were selected for actual synthesis and subsequently tested for activity towards all adenosine receptors subtypes. Interestingly, two compounds revealed micromolar and submicromolar affinity for the adenosine receptors, namely 4. To further investigate our evolutionary design method, we performed systematic modifications on one of these two scaffolds. A core objective of our computational research program is to automate the drug design process as much as possible to present only the most suitable candidates for a biological target to the chemist. Recently, we reported a user-friendly, fully automated 6 desktop application for de novo design, the ‘Molecule Evaluator’. An important feature of this software is that, in contrast to many de novo design programs, it is an interactive tool for exploring novel chemical structures, while at the same time taking into account the expertise of the medicinal chemists on the fly. The consideration of multiple bioactivities, here considered in a multi-objective optimization routine, is important for both achieving the desired 9 10 efficacy as well as for avoiding off-target effects and it is in line with current 11 approaches of designing also ‘selectively unselective’ drugs, instead of only hitting single targets thought to be involved in the disease under consideration. A schematic drawing of the multi-objective evolutionary method is provided in Figure 1, and a detailed description is reported in the Experimental Section. Our multi- objective evolutionary design procedure consists of an iterative cycle of structure generation, evaluation, and selection of candidate structures. The evolutionary loop starts by generating new candidate molecules with the Molecule 6 Commander program (Figure 1). Like the Molecule Evoluator, this command-line program creates new structures by randomly modifying or combining a set of input molecular fragments by, e. In addition, simple chemical rules are applied to avoid generation of improbable structures (see experimental section for details). In addition, the program calculates a set of physicochemical properties on the fly, which are used to limit output to structures with desired properties. This served merely as a proof of concept at this stage, and more extensive or proprietary toxicity predictors could readily extend or replace this component. For energy 179 Chapter 6 calculation, the minimized energy of a single 3D conformer was used (note that until this point, only the topology (‘graphs’) of the molecules was considered). Occurrence of high-energy structures, which were weeded from the total compound library, is a consequence of the random modification of the molecular graph, which may result in less feasible molecules. Flow chart of the evolutionary optimization loop (see Experimental for detailed explanation). After the initial generation and filtering phase, the ‘fittest’ molecules were selected to serve as parents for the subsequent generation. We 180 Multi-Objective Evolutionary Ligand Design chose to replicate this pharmacophore model because it proved successful for the design of novel ligand chemistry with sufficient specificity. Visual representation of the pharmacophore model used to search for 13 A1 ligands, based on a previously reported pharmacophore. The aromatic core is represented by three spheres F5, F7, and F9, and three spheres that indicate the direction of the normal of the aromatic feature, F6, F8, and F10. At least one of the aromatic features with normal projection should be occupied by a corresponding aromatic feature in the molecule. A hydrogen bond acceptor and donor region are represented by F1 and F3, respectively. The grey dots indicate the inclusion volume, the volume into which the molecules generated need to fit for not being subject to a fit penalty. The reason for this is that for the adenosine A1 receptor the binding features needed to be defined as specific as possible, while for the other three subtypes (selectivity score) a broad range of possible ligand features had to be detected to ensure selectivity. Property ranges were defined, 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.

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Mean elimination half- of 750 mg in this study buy 400 mg viagra plus, peak serum concentra- life was 19 buy viagra plus 400 mg with mastercard. Te elimination epileptic patients who had been receiving a half-life ranged from 17 to 25 hours in drug-free constant dose of primidone for at least 2 months buy viagra plus 400mg lowest price. Tere Data were compared in two groups: 10 elderly was no evidence for a glucuronide conjugate. Te rate of metab- group, than the young (575 ± 206 mg/day olism to phenobarbital showed wide variation and 422 ± 115 mg/day, respectively). In the (25-fold) among children, which, although not elderly and young, respectively, the mean half- infuencing the overall elimination rate constant life of primidone was 12. Differences between phenytoin had no detectable efect on half-life the two groups were not statistically significant, or serum concentrations of phenobarbital. Of indicating that half-life and total clearance of the total primidone daily dose, approximately primidone were unaltered in elderly patients. Te administered primidone was studied in 12 chil- shortest half-lives for primidone (8–11 hours) dren (age, 7–14 years) undergoing long-term were detected in two neonates whose mothers (> 3 months) treatment for epilepsy, and were had been treated with phenytoin in addition to assumed to be in steady state. Serum concentrations and elimina- were taking primidone only, and eight were tion rates varied among neonates, and during the also taking phenytoin. Mean recovery of the adminis- neonatal metabolism of primidine, and rate of tered dose in the urine within 24 hours was 92% 196 Primidone elimination increased afer a few days in some increase or decrease in pharmacologically active babies (Nau et al. Primidone is frequently used in combi- Analyses of maternal milk of four of the nation with such substrates (e. Because of breastfeeding, all compounds faster, and total body clearance was increased, were also detected in neonatal blood (Nau et al. In a study of seven neonates, whose mothers were treated for epilepsy throughout (iii) Liver disease pregnancy, the shortest half-lives for primidone Te disposition of a single oral dose of 500 mg were reported in two neonates whose mothers of primidone was studied in seven patients with had been treated with both phenytoin and prim- acute viral hepatitis and in seven healthy subjects idone (Nau et al. Afer oral adminis- plasma concentrations of primidone (at most tration of primidone (at a dose of 50 mg/kg bw), doses and time points) were consistently higher 198 Primidone (approximately double) and half-lives greater (b) Chromosomal damage (two- to fvefold) in females than in males. Additional in-vitro plasma of female rats at 15 and 30 minutes, and studies showing no induction of sister-chro- plasma concentrations of phenobarbital, for a matid exchange in Chinese hamster ovary cells, given dose, were consistently higher in males or chromosomal aberration in human lympho- than in females. In studies in which rodents were exposed to phenobarbital in vivo, no covalent binding to 4. Phenobarbital did side-efects included nausea, vomiting, dizzi- not increase the frequency of sperm-head abnor- ness, ataxia, and somnolence, and caused early malities in mice, but spermatogonial germ-cell discontinuation of treatment. Further increases in the toin were associated with statistically signif- frequency of chromosomal aberration were found cantly lower incidences of intolerable side-efects in liver foci cells of mice treated with phenobar- than were primidone or phenobarbital. Although tions that were below the reference range when the majority of the test results were negative, the compared with untreated patients and controls. Primidone caused a decrease three large cohort studies of patients with of pteroylpentaglutamates in the liver to less than epilepsy. El-Masri & Portier (1998) carcinogenesis attributable to phenobarbital in have suggested that there is wide inter-individual mice have been reported. Typically, these investi- variation in the metabolic profle of primidone, gations exploited comparison between strains of which may indicate the presence of people who mice that were variously sensitive and resistant produce greater amounts of primidone metabo- to phenobarbital-induced hepatocarcinogen- lites than the general population, and who are esis. Diferences in epigenetic female mice, feed containing primidone caused control (e. Primidone also caused a signifcant increase in the incidence of hepatoblastoma and of thyroid 5. Primidone also caused a small Primidone is a synthetic drug that was used but signifcant increase in the incidence of renal commonly as an oral anticonvulsant, begin- tubule adenoma or carcinoma (combined) in ning in the 1950s. Tere was no signifcant increase in the predominantly for the treatment of essential incidence of any neoplasm in female rats. Te limited to two case–control studies reporting data on genetic toxicity for primidone in tradi- on several types of cancer nested in a cohort of tional assays are limited in scope and amount, epileptic patients in Denmark. Other limitations included incom- absence of metabolic activation only, and at high plete information on exposure to primidone (with concentrations. Alteration of thyroid hormone homeostasis by antie- review suggested that primidone does not induce pileptic drugs in humans: involvement of glucuron- chromosomal changes in vitro or in vivo. Chronic treatment of rats with primidone causes depletion of pteroylpenta- glutamates in liver. Efect of chronic primidone treatment on folate-dependent one-carbon Tere is inadequate evidence in humans for metabolism in the rat. Physiologically based pharmacokinetics model of primidone and its metab- olites phenobarbital and phenylethylmalonamide in humans, rats, and mice. Single-dose pharmacokinetics and anticonvulsant J Chromatogr B Biomed Sci Appl, 718(1):199–204. Pharmacokinetics of anti-ep- Linnebank M, Moskau S, Semmler A, Widman G, Stofel- ileptic drugs in the dog: a review. Environ Sci Pollut level studies of primidone and its metabolites in the Res Int, 19(6):2096–106. Blood and cere- drugs in serum and plasma using ultra-performance brospinal fuid pharmacokinetics of primidone and its liquid chromatography-electrospray ionization tandem primary pharmacologically active metabolites, pheno- mass spectrometry. Sensitive analytical method for serum children of epileptic mothers and the possible rela- primidone and its active metabolites for single-dose tion to maternal anticonvulsant therapy. Antiepileptic treatment and primidone, phenobarbital and phenylethylmalona- risk for hepatobiliary cancer and malignant lymphoma. Results of a nationwide Veterans interactions in epilepsy: general features and inter- Administration Cooperative Study comparing the actions between antiepileptic drugs. Te efect of selected phenobarbital-induced expression changes of genes antiepileptic drugs on the chromosomes of human involved in key pathways in precancerous liver and lymphocytes in vitro. Evidence-based guide- line update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology. Efect of hexamidine on level of spon- taneous mutation in a number of subjects Dokl.

Contraindications: Hypersensitivity to statins generic 400mg viagra plus with mastercard, active liver dis- ease or unexplained persistent elevations of serum transaminase order viagra plus 400mg line, pregnancy buy viagra plus 400mg visa, lactation. Warnings/precautions • Use with caution in patients with renal insufficiency, history of liver disease, alcohol abusers. These should be obtained prior to and periodically after treat- ment begins to ascertain drug efficacy. It may be advisable to take a liver biopsy if transami- nase elevation persists after drug is discontinued. Warnings/precautions • Use with caution in patients with the following conditions: seizures, glaucoma, history of urinary retention, cardiovascu- lar disorders. Sit at the edge of the bed for several minutes before standing, and lie down if feeling faint or dizzy. Male patients with orthostatic hypotension may be safer urinating while seated on the toilet rather than standing. Adverse reactions • Common: extrapyramidal reactions, drowsiness, constipation, dry mouth. Clinically important drug interactions • Drugs that increase effects/toxicity of loxapine: β blockers, antacids (aluminum and magnesium types), antidiarrheals. Alternatively, administration of diphenhydramine and benztropine may be indicated. Editorial comments • Tardive dyskinesia, a neuroleptic-induced movement disorder, if it occurs will become apparent after several months or years after treatment. Mechanism of action: Inhibits tubular resorption of water and electrolytes, increasing urine output. Onset of Action Peak Effect Duration Lowering intracranial pressure 15 min 30–60 min 3–8 h Lowering intraocular pressure 30 min No data No data Food: Not applicable. Contraindications: Severe renal disease, dehydration, pulmonary edema, hypersensitivity to mannitol or its components. Warnings/precautions • Use with caution in patients with severe heart failure, severe pulmonary congestion, active intracranial bleeding. Adverse reactions • Common: headache, nausea, vomiting, dizziness, blurred vision, urinary frequency. Clinically important drug interactions • Mannitol decreases effects/toxicity of lithium. Editorial comments • Overdose with mannitol is manifested as hypotension and car- diovascular collapse. In such circumstances, infusion should be discontinued, supportive measures used, and, if necessary, hemodialysis initiated. When mannitol is administered for oliguria, the rate at which it is given should be titrated to pro- duce a urine output of 30–50 mL/h. Mechanism of action: Inhibits uptake of glucose and other nutri- ents by parasitic helminths. Warnings/precautions: Use with caution in patients with liver disease, ulcerative colitis, Crohn’s ileitis. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Clinically important drug interactions: Drugs that decrease effects/ toxicity of mebendazole: phenytoin, carbamazepine, cimetidine. Have patient swab peri- anal area each morning using transparent tape and bring to your office. Cellophane tape swabs should be taken prior to and starting 1 week after treat- ment to detect ova in the perianal area. Editorial comments • Patient and family members should be taught how to avoid reinfestation with these worms. The following measures should be undertaken to avoid reinfection: (1) perianal area should be washed thoroughly; (2) hands and fingernails should be cleaned before meals and after defecation; (3) undergarments and bedclothes should be changed daily. Mechanism of action: Inhibits impulses from vestibular system to the chemoreceptor trigger zone. Parameters to monitor • Patients with motion sickness: nausea and vomiting prior to and 60 minutes after drug is taken. Editorial comments: Discontinue meclizine if the vertigo does not respond in 1–2 weeks. If previously estrogen primed, the dose is 10 mg/d for 10 days, beginning on day 16 of menstrual cycle. Contraindications: Hypersensitivity to progestins, history of throm- bophlebitis, active thromboembolic disease, cerebral hemorrhage, liver disease, missed abortion, use as diagnostic for pregnancy, known or suspected pregnancy (first 4 months), undiagnosed vaginal bleeding, carcinoma of the breast, known or suspected genital malignancy. Warnings/precautions • Use with caution in patients with respiratory infection, history of depression, epilepsy, migraine, cardiac disease, renal disease, diabetes. Advice to patient • Weigh yourself twice a week and report to treating physician if there are any unusual changes in weight. Adverse reactions • Common: irregular or unpredictable menstrual bleeding (spotting), amenorrhea, breakthrough bleeding, infertility for up to 18 months. Clinically important drug interactions: Drugs that decrease effects/toxicity of progestins: aminoglutethimide, phenytoin, rifampin. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Pregnancy: Category D Lactation: Another drug from this class (medroxyprogesterone) is considered compatible by American Academy of Pediatrics. Contraindications: Hypersensitivity to progestins, history of thrombophlebitis, active thromboembolic disease, cerebral hem- orrhage, liver disease, missed abortion, use as diagnostic for pregnancy, known or suspected pregnancy (first 4 months), undi- agnosed vaginal bleeding, carcinoma of the breast, known or suspected genital malignancy. Warnings/precautions • Use with caution in patients with respiratory infection, history of depression, epilepsy, migraine, cardiac disease, renal disease, diabetes.