By H. Bengerd. Pacific Lutheran University. 2019.
Receptors plotted above or below the diagonal have different average distance to the other receptors between trees buy super levitra with mastercard. For instance effective 80mg super levitra, consider a delta-delta plot that plots a substructure tree along the x-axis and a sequence tree along the y-axis purchase super levitra 80 mg on line. If a receptor is plotted above the diagonal, the mean distance of that receptor to the other receptors is larger in the sequence tree than the substructure tree; for receptors plotted below the diagonal, the opposite is true. A molecule from the left-out class is a hit when it is predicted to belong to one of the closest classes in sequence space. The closest classes in sequence space are found using the distance matrix from the multiple sequence alignment. Prediction of the class of a molecule is based on the Euclidean distance in substructure space. This distance is calculated as follows: for each substructure, the square of the difference between the relative frequency in a class and the molecule is calculated. The relative frequency of a substructure in a molecule is either 0 for absence, or 1 for presence of the substructure. The square root of the sum of all squared differences is the Euclidean distance between a molecule and a class. This table related all generated substructures with all molecules in which they occurred. Substructures that had a frequency just above the support threshold in the left-out class were not considered when analysis was performed for molecules of this class. Funding: This work was supported by the Dutch Top Institute Pharma, project number: D1-105. G protein-coupled receptor drug discovery: Implications from the crystal structure of rhodopsin. High- Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein Coupled Receptor. Chemogenomic data analysis: Prediction of small-molecule targets and the advent of biological fingerprints. Chemogenomic approaches to drug discovery: similar receptors bind similar ligands. A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Definition of the G Protein-Coupled Receptor Transmembrane Bundle Binding Pocket and Calculation of Receptor Similarities for Drug Design. Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off-Target Effects from Chemical Structure. The selectivity of -adrenoceptor antagonists at the human 1, 2 and 3 adrenoceptors. Allosteric site on muscarinic acetylcholine receptors: identification of two amino acids in the muscarinic M2 receptor that account entirely for the M2/M5 subtype selectivities of some structurally diverse allosteric ligands in N-methylscopolamine-occupied receptors. The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Dopamine receptors for every species: Gene duplications and functional diversification in Craniates. Subfamilies are color-coded according to ligand type whereby the 17 broad ligand types applied by in Gloriam et al. Legend: red – receptor with aminergic ligands; pink – peptide ligands; green – lipid ligands; dark blue – purinergic P2Y ligands; light blue – adenosine ligands; brown – melatonin ligands. Description: The complete set of plotted scores of identified ligands per number of closest neighbors (sequences). For each plot, receptors are ordered along the x-axis (labeled “Number of included receptors”) in order of increasing distance in sequence space to the receptor under study. The y-axis (labeled “Ligands identified”) indicates the cumulative number of retrieved ligands, normalized linearly to the interval [0;1]. The red curve indicates the number of active ligands that are retrieved when including all (closest) receptors that are listed along the x-axis up to that point. The blue diagonal illustrates recovery of ligands when performance is equal to random prediction. The best model in statistical terms was subsequently applied to large-scale virtual screening of a commercial vendor library. This hit rate is quite comparable to that of the referenced target-based virtual screening study, while both approaches yield new, non-overlapping sets of ligands. Members of this family respond to a variety of extracellular stimuli, such as ions, small molecules, 1 peptides, proteins, and even photons. Selective A2A antagonists, on the other hand, may prove of value to block 14,15 immunosuppressive pathways that hinder antitumor immunity. Preventing this inhibition using 16 selective A2A antagonists is actively explored as treatment for Parkinson’s disease. These studies yielded high hit rates (41% and 35%); some of the active compounds had submicromolar affinities. With the ligand-based approaches, prior ligand knowledge is required, from which new ligands are derived. Examples of the first class are xanthine derivatives such as caffeine (compound 2 in Figure 1) and theophylline. These compounds share some structural resemblance: by aligning them using the furan substituent as an anchor, two rings of their ring system and the amine groups overlap. The (often unsubstituted) furan moiety is a common structural feature found in many A2A 23,24 antagonists. It is typically linked to a triazole ring that is part of a ring-fused system of two or three heterocycles, with a single amine group attached. Describing molecules in terms of molecular parts, or fragments, such as rings and ring systems, substituents and functional groups, provides an abstraction for chemists to reason about molecules. This helps, for instance, for identification of a common core in a set of molecules, or for finding the substituents that contribute to bioactivity. Although these approaches may be relatively assured of success, truly new chemistry is only seldom being discovered this way; structural derivatives often resemble their parent structures. The similarity between known ligands that are analysed and the proposed candidates that result may be reduced by analyzing the structures in closer detail; instead of only focusing on predefined fragments, one might consider all possible structural patterns that are present in the molecules. This may result in the discovery of more unusual structural patterns that potentially offer greater diversity when applied to the discovery of new ligands. This method was designed to be complementary to the recent structure-based virtual screening studies, although it was exclusively based on ligand information only. This so-called frequent substructure 150 Substructure-based Virtual Screening mining, i.
The oral doses of aciclovir for adults range from 200 mg every 4 h (while awake) to 800 mg three times a day for 5–10 days generic super levitra 80 mg otc. The oral dose for treatment of chickenpox and herpes zoster is 800 mg aciclovir every 4 h for 5–10 days cheap 80mg super levitra free shipping. Topical treatment of the affected skin or mucous membrane (not conjunctival) with 5% ointment or cream is given up to every 3 h generic super levitra 80 mg with visa. For ocular herpes simplex keratitis, a 3% ointment may be applied five times daily up to every 4 h until 3 days after healing (Gennaro, 1995; American Hospital Formulary Service, 1999; Royal Pharmaceutical Society of Great Britain, 1999). In young children, aciclovir is given intravenously at 250–500 mg/m2 of body- surface area every 8 h. In older children and adults, intravenous injections are given at 5–10 mg/kg bw every 8 h (Thomas, 1998; Royal Pharmaceutical Society of Great Britain, 1999). Doses of aciclovir should be reduced in patients with renal impairment (American Hospital Formulary Service, 1999; Royal Pharmaceutical Society of Great Britain, 1999). The patients were treated with aci- clovir at various doses, continously and/or for five-day periods for treatment of epi- sodes of infection. In 389 patients who were still under treatment and active surveillance five years after the beginning of the first study, one cancer each of the thyroid, pancreas (resulting in death) and ovary and one malignant melanoma were observed (Goldberg et al. Thus, the numbers of cancers that were expected were not given, and the relative risk could not be calculated. Furthermore, the low age of the patients, indicating a small expected number of cancers, resulted in poor statistical power to identify an effect. Tissues from control animals and those at the high dose were evaluated histologically. The mean body weights of females at the intermediate and high doses were 2 g higher than those of the control group (p < 0. Treatment did not affect survival in males, and females at the two higher doses had significantly (p < 0. Tissues from control animals and those at the high dose were evaluated by microscopy. Treatment did not affect survival rates, except that of females at the inter- mediate dose, which was significantly shorter than that of control females (p < 0. No increase in the incidence of benign or malignant tumours was observed (Tucker et al. This series of events occurs readily in herpesvirus-infected tissues but poorly in normal tissues, since the initial phosphorylation is accomplished mainly by a herpesvirus-specific deoxynucleoside (thymidine) kinase (Elion, 1983; Laskin, 1984; King, 1988). The aci- clovir triphosphate is formed readily and is more persistent than the parent compound, remaining for several hours in cultured cells. When taken orally, the drug is poorly absorbed from the gastrointestinal tract, with a reported bioavailability of 15–30%, owing to its limited solubility in an aqueous environment; therefore, intravenous dosing is considered more effective (O’Brien & Campoli-Richards, 1989). The drug is widely distributed throughout the body and has been found in plasma, kidney, lung, liver, heart, vagina, brain, cerebrospinal fluid, aqueous humor, saliva and skin (Laskin, 1983; de Miranda & Blum, 1983; Rogers & Fowle, 1983; Brigden & Whiteman, 1985; O’Brien & Campoli-Richards, 1989; Vergin et al. After oral doses of 200 mg taken four to five times daily or 400 mg taken two to three times daily, the peak plasma concentration is about 2 μmol/L (0. After oral administration, the amount of aciclovir in the kidney and lung was actually higher than that in plasma, while the concentration in cerebrospinal fluid was half of that in plasma (Blum et al. After topical administration, the epidermal concentration of aciclovir was enhanced 48-fold over that observed after oral dosing, but the delivery of the drug to viruses replicating in the basal epidermis was considerably less efficient (Parry et al. The pharmacokinetics of intravenously administered aciclovir has been described best by a two-compartment open model (Laskin, 1983; Rogers & Fowle, 1983; O’Brien & Campoli-Richards, 1989). The binding of aciclovir to plasma protein has been reported to be 9–33%; the peak concentrations in plasma are typically achieved within 1. After intravenous dosing with aciclovir, 45–75% of the drug is excreted in the urine as unchanged compound, but after oral dosing this percentage is reduced to 14–22%, with a large fraction appearing in the faeces (Laskin, 1983; de Miranda & Blum, 1983; Vergin et al. Two minor urinary metabolites, 9-carboxymethoxy- methylguanine and 8-hydroxy-9-(2-hydroxyethyl)guanine, have been reported to constitute 8–14% and about 0. Active renal clearance occurs by glomerular filtration and renal tubular secretion, with a half-time of 2–3 h (Laskin, 1983; O’Brien & Campoli-Richards, 1989) and a clearance rate of 3. In patients with renal impairment, the mean elimi- nation half-time can be extended to 20 h, and the total body clearance rate can be decreased 10-fold; it is therefore necessary to reduce the dose accordingly (de Miranda & Blum, 1983; Rogers & Fowle, 1983; Brigden & Whiteman, 1985; O’Brien & Campoli-Richards, 1989). Transplacental pharmacokinetics A 39-year-old pregnant woman, presumed to be at 30 weeks of gestation, was treated with aciclovir (350 mg, or 15 mg/kg bw) intravenously every 8 h throughout the remainder of gestation. Beginning at week 38 of gestation and continuing until delivery, seven women were treated orally with 200 mg aciclovir every 8 h and eight with 400 mg aciclovir every 8 h. The drug appears to be taken up efficiently by many tissues, including the brain and skin (de Miranda et al. Like humans, dogs, rats and rhesus monkeys show a biphasic decline in the plasma concentration of aciclovir, indicating a two-compartment open model, with a half-time of 1–3 h (de Miranda et al. Gastrointestinal absorption was poor in the 8-week-old rats, with a bioavailability of 7. Absorption of aciclovir in the gastrointestinal tracts of the young rats was shown to occur by an efficient passive diffusion process, which apparently becomes inefficient at the time of weaning (Fujioka et al. Beagle dogs given 20 mg/kg bw aciclovir had a mean peak plasma concentration of 42 μmol/L (10 mg/L) by 1. The body clearance was similar to the glomerular filtration rate, indicating the absence of active tubular secretion (de Miranda et al. Skin absorption occurred by a first-order process which resulted in excretion of about 0. When aciclovir is given orally, the doses are typically low and serious adverse events are extremely rare (Goldberg et al. Oral dosing is less frequently neurotoxic but was reported to induce acute disorientation in four patients, three of whom had renal insufficiency (MacDiarmaid-Gordon et al. Renal dysfunction is not an absolute requirement for aciclovir-induced neurotoxicity; but, apart from age and neurotoxic medications (Rashiq et al. The neurotoxicity induced by aciclovir manifests primarily as tremor (28–30%), myclonus (30%), confusion (30–43%), lethargy (17–30%), agitation (27–33%) and hallucination (20–26%) (Rashiq et al. Less frequent manifestations (3–17%) include dysarthia, asterixis, ataxia, hemipares- thaesia and seizures (Ernst & Franey, 1998). Neurotoxicity typically occurs during the first 24–72 h of drug administration, and discontinuation of the drug results in a complete return to normal by about 15 days (Rashiq et al. Haemodialysis has been shown to attenuate aciclovir-induced neurotoxicity effectively in symptomatic patients (Krieble et al. In patients receiving high doses of aciclovir, reversible increases in serum creatinine concentrations can occur (Kumor et al. The existence of compromised renal function, use of other nephrotoxic drugs, rapid infusion of large doses, advanced age and dehydration can all contribute to aciclovir-induced nephrotoxicity (Rosenberry et al. Like aciclovir-induced neurotoxicity, the nephrotoxic effects are typically transient and rapidly ameliorated by haemodialysis (Whitley et al. Topical adminis- tration may be associated with pain, burning or rash (Rosenberry et al.
Paradoxically buy 80mg super levitra fast delivery, the ‘therapeutic reformers’ within the agency – aiming for more accountable purchase super levitra 80 mg overnight delivery, independent and transparent regulatory practices – would carry the blame for this apparent loss of face in the international arena purchase super levitra mastercard. However victorious in the Dutch public arena, managing cultural mediation and imagination processes in the public sphere of a number 9 (1983): 129-131. They argued that this property was a distinct disadvantage of Halcion-like drugs that could be associated with a rebound phenomenon involving anxiety, stress and fear. The company motivated this step by referring to the ‘novel’ drug development concept of the ‘lowest effective dose’, which was also greeted with enthusiasm by the regulators in their efforts to improve their checks and balances. Once again consumer-led actions succeeded in placing product liability of Halcion on the public agenda. Ten years after the ‘Dutch hysteria’ the Halcion syndrome hit the headlines in Britain, swiftly followed by the United States. A series of media reports on serious safety problems that ranged from suicide to even murder fuelled the public controversy surrounding the most widely prescribed sleeping pill in the world. Although hardly any case would ultimately go to trial (settled outside court by Upjohn to prevent the public dissemination of company test data) the by-product was an enhanced public recognition of the danger of Halcion. Of key importance in this fnal backlash, as the sociological analyses of Jonathan Gabe and Michael Bury have shown, 36 E. But Halcion, that did not turn out to be the elixir its name implies, did not totally disappear from the international medical market. It still generates a world wide turn over of round about 100 million dollars on a yearly basis. On the contrary, as we have shown, the dynamics of a Seige cycle may differ signifcantly from country to country. The cycles become especially pronounced when the therapeutic drug becomes the subject of a public controversy. The Dutch cycle refects the important role of the mass media in establishing and amplifying associations between Halcion, consumers and drug safety and credibility issues. Given the media’s impressive capacity to amplify the message of peril and fear, we would like to stress that the media coverage was for the greater part a mirror of the expectations, legitimations and opinions circulating within the public realm. The questioning of medical, regulatory and industrial authority and credibility regarding Halcion as an effective and safe drug was connected with broader concerns over medical care and treatments. The role of Halcion as symbolic focus of social issues became more articulated with the forging of new alliances between patients, doctors and scientists. However local in terms of national identity, the ‘Dutch disease’ is exemplary for the growing interference of patients and consumer activist groups with the dynamics of the Seige cycle. In addition, the Halcion case shows us the important role the double bind dilemma plays in the trajectory of drug development, regulation and use of drugs. This dilemma means that actors in the feld, producers, regulators, prescribers and users, wish that the introduction of useful drugs is not delayed while at the same time being concerned about the licensing of drugs which later will shown detrimental side effects. The double bind in this context as the Halcion case shows is an essential ingredient of a regulatory system of checks and balances to account for a cultural 41 J. Bury, ‚Tranquillisers as a Social Problem‘, The Sociological Review 36 (1988): 320-352; J. Bury, ‘Halcion Nights: A Sociological Account of a Medical Controversy’ Sociology 30 (1996): 447-469. Our study suggests that consumers by interfering with the process of drug evaluation through trial at the bar have learned to use the double bind to their own advantage. Hence, the double bind is an important factor in shaping and surviving the Seige cycle. Drugs can be understood as tools for the management of disease, industrial products, commercial goods, or research objects: in short, they experience multiple “modes of existence”. Given this observation, one might ask how specifc compounds cut through commercial, medical, legal, and experimental regimes in the course of their existence. This seemingly unproblematic question erroneously views drugs as well-defned substances that maintain their chemical identity during their trajectory through different drug-making and drug-using practices. Borrowing from Andrew Barry’s discussion of chemical substances as “informed material” , we believe that it is possible to go beyond this uneasy mix of (soft) social constructivism and realism, and to track the circulation and testing of therapeutic substances as a process of “progressive informational enrichment”. In Barry’s original formulation, informed molecules, rather than discrete objects, are “constituted in their relations to informational and material environments”: such entities, in other words, are constituted by a space defned, on the one hand, by the distance between the properties of a molecule and the properties of the models used in deriving those properties, and, on the other hand, by the distance between a molecule and its competitors in the legal and economic environment in which it operates and to whose defnition it contributes. Barry notes that the notion of a chemical space is a native category, routinely used by chemists and pharmacologists. And indeed, recent contributions to the novel area of analysis that lies at the interface of pharmacology and computational biology commonly resort to this notion, in both a metaphorical and literal sense. We would like to thank the participants in the Drug Trajectories V Workshop, and in particular Harry Marks, for their comments and suggestions, and to further extend our thanks to the clinicians who kindly accepted to be interviewed for this project. Cancer clinical trials: a device for the informational enrichment of anti-cancer drugs As noted by several authors, randomized clinical trials have become the obligatory passage point for the translation of a given substance into a legitimate prescription drug. Our claim refers both to the production of new nosological categories (as when a given kind of cancer is shown to consist, in fact, of two different kinds of neoplasms, i. For instance, one of the early chemotherapy protocols in the treatment of leukemia was Protocol No. Chapel Hill: University of North Carolina Press, 2004; Harry M Marks, The Progress of Experiments: Science and Therapeutic Reform in the United States, 1900-1990. The innovation consisted of treating different phases of the disease, which were the direct creation of the protocol itself, as separate kinds of disease. For instance, remission and relapse were treated as independent events occurring in the same person with ostensibly the same disease. By replacing the natural history of a disease with its treated history, protocols incorporate an evolving understanding of the biology of the disease. They thus reveal new targets for therapeutic substances, modifying, in the process, the socio-technical space of these substances. Of special interest, in this respect, is the fact that contemporary protocols often defne their target population (or target disease) on the basis of prior treatment with other substances as, for instance, in the case of “Tamoxifen-treated, node-negative breast cancer”11 or “Desatinib in Imatinib-resistant, Philadelphia Chromosome-positive leukemias”. For each substance we see, with the exception of the last few years, a constant growth in the number of papers over a period of approximately 40 years. This is obviously not due to an increase in the number of clinical trials devoted exclusively to that substance but, 11 S. The latter vary according not only to the quantities administered and the modes and schedules of administration, but also to the type and number of substances they mobilize. Two different regimens may deploy the same substance with different routes of admission (e. The protocol specifed that the two regimens would be tested on patients suffering from “metastatic breast carcinoma”. In other words, protocols further diversify the space of therapeutic experimentation by adding such qualifcations as the stage of a patient’s disease trajectory as well as a growing set of parameters 13 G. These strictures integrate the results of previous interventions, insofar as the comparison of two different regimens can be performed as part of a protocol that aims at developing a frst-line (standard) chemotherapy, or an adjuvant chemotherapy (i.