By Y. Hauke. Rochester College. 2018.

Individuals with cocaine and/or opioid dependence and who are in close contact with a non-drug-using partner benefit from behavioural couples therapy generic hydrochlorothiazide 25 mg with mastercard, both during treatment and at follow-up generic 25 mg hydrochlorothiazide with visa. The earlier members of this population are able to access treatment services cheap hydrochlorothiazide 25 mg with amex, the better the outcome will be for their general physical health, the pregnancy and the neonate. A sensitive, non-judgemental approach is essential in engaging this population and optimising treatment effectiveness. Medical professionals have a role to play not only in portraying this through their own clinical care and manner, but in leading their clinical teams to be approachable, non-judgemental and patient centred in this situation. This will include attention not only to physical healthcare and management of drug use, but sensitive attention to the coexistent psychological difficulties and social concerns that the patient may be experiencing. The medical professional and the full multidisciplinary team will need to address the woman’s fears about the involvement of children’s services; anxiety and guilt about the potential impact of their drug use on their baby;62 and concerns the patient may have about finances, support networks, and coping strategies during pregnancy and their forthcoming parenthood. They also recommend that a variety of methods (eg text messaging) should be used to maintain contact and engagement, and to remind women of upcoming and missed appointments. Multiagency team work is also essential, working with social care professionals and ensuring seamless communication between general practice and the specialist services involved in the patient’s antenatal care, including obstetrics, specialist drug services and any other specialist healthcare services. Multiagency case conferences, with prospective parents invited as participating attendees, will facilitate good inter-team communication and optimise clinical care. Her family were very strict and she was not allowed to have friends outside the community. Between the ages of 10 and 13 she was subjected to regular sexual abuse by an uncle who lived with the family. She once told her mother about the abuse but was told to keep it quiet and not tell anyone, as it would bring shame on the family. She did well at school and started work in a local estate agent’s office when she left school. Mr Y was a heroin user and eventually she started smoking cigarettes that he gave her. After a few months, she noticed that she felt very unwell if she did not smoke and Mr Y told her that the cigarettes had heroin in them. She had very little antenatal care and avoided the appointments with the social worker, who she only met once. For a few weeks she went back, with her baby, to live with her parents (with the support of social services) and stopped using heroin but the rows with her mother were so bad she eventually left the baby with her mother and went to live with Mr Y in a big city. She came into treatment when Mr Y was arrested for aggravated burglary and went to prison. She was prescribed buprenorphine and managed in an antenatal liaison clinic, where she received antenatal care and drug treatment. Social services were involved from the beginning and found her a place in a local women’s hostel. Ms B was able to stop using heroin and begin to think about some of the problems she had with her abusive relationship and her history of sexual abuse. Her second baby, a little girl, was born at full term and was immediately subject to child protection proceedings and taken into foster care but Ms B had regular contact with the baby. She subsequently went, with the baby, to a mother and baby rehabilitation centre where her parenting could be assessed and she could reduce her buprenorphine. Ms B was clear she wanted to stop using all drugs, keep her daughter and re-establish a relationship with her son and her family. Case study details provided by Dr Emily Finch, a consultant addiction psychiatrist. It is safest to prescribe opiate substitution (see Chapter 8) ‘at a dose that stops or minimises illicit use’. In all pregnant women using or prescribed opioid drugs, particular consideration will also need to be given to their birthing plan, including pain management and the risk of fetal distress at birth. In view of the potential harms to the fetus and to the mother’s health, the pregnant woman should be given support to stop using cocaine during pregnancy. A non-judgemental, sensitive approach, with clear and effective multidisciplinary communication and team working are again essential, addressing the full spectrum of psychosocial and physical health needs. The maximum penalty is life imprisonment for supply of Class A drugs, with seven years for possession, but sentences between two and 14 years are used for possession or supply of Class B or C drugs (see Chapter 1). This has implications for the medical professional, as many illicit drug users first come into contact with the medical profession via the criminal justice system. This can create particular challenges for medical professionals working within the criminal justice setting, which are highlighted throughout this chapter. It offers a valuable opportunity for effective medical treatment of drug use disorder and ultimately the best chance for many dependent drug users to be rehabilitated. A report from the Probation Service explained that she had been picked up by police after having collapsed in the stairwell of a housing estate in east London. It also explained that she was homeless; she had been living in a local authority hostel but had been thrown out of it for taking men back into the hostel for the purpose of prostitution in order to raise funds to feed her drug habit.

Traditionally new chemical entities have been identified by the screening of natural products and chemical libraries to identify potential lead compounds generic 12.5 mg hydrochlorothiazide mastercard. These lead compounds have then been optimized through an iterative lead-optimization process involving the synthesis of analogs order hydrochlorothiazide 12.5 mg on line, the development of quantitative-structure-activity relationships and the use of molecular modeling to obtain new chemical entities with high specificity and affinity for the therapeutic target for pharmaceutical development discount hydrochlorothiazide 12.5 mg on-line. The development of combinatorial chemistry has led to the ability to produce vast libraries of compounds for initial screening. The evaluation of combinatorial libraries using high-throughput screening technologies allows the rapid screening of potential lead compounds with a wider molecular diversity against a broad range of therapeutic targets. Until recently, therapeutic targets were identified through the application of basic pharmacology and biochemistry with both receptor and enzyme targets being identified and isolated from specific tissues. The identification of potential therapeutic targets has been further enhanced through the recent development of genomics and proteomics. These techniques provide mechanisms to identify upregulated gene and protein expression in diseased tissue providing pointers towards potential means of therapeutic intervention. The advances in molecular biology have also led to the ability to clone receptors into various cell types to facilitate screening of potential ligands against such targets. The parallel development of cell biology has led to the ability to utilize cell-based assays rather than tissue-based assays for drug screening and the advances in robotics have led to the development of high-throughput screening technologies. The development of genomics, proteomics, high-throughput screening and combinatorial chemistry has led to an information explosion within pharmaceutical companies requiring better mechanisms for the storage and manipulation of biological and chemical data. This has driven the development of the field of bioinformatics which serves to provide searchable databases allowing comparison of molecular and biological information to potentially identify other therapeutic targets and lead compounds. This chapter aims to provide a brief overview of these different technologies to provide a basis for the reader to develop their understanding of this field in order to appreciate how these technologies will underpin the future of drug delivery and targeting. The majority of combinatorial approaches utilize polymeric solid supports as a base onto which the compounds are synthesized. However, there are also approaches which utilize solution- based chemistries to generate combinatorial libraries. Such supports are traditionally composed of polymeric resin beads on to which the synthesis of a peptide is undertaken in a stepwise fashion with each amino acid being added sequentially to the peptide chain (Figure 15. After coupling the amino acid to the peptide chain, the protecting group is removed from the terminal amino acid exposing a reactive site to which another amino acid may subsequently be coupled. This technique relies on the clean coupling of amino acids in peptide synthesis, the ability to easily remove reactants and solvents and wash the products between each stage of the synthesis and the ability to protect and deprotect reactive groups on the solid support as necessary. An example of a 3×3×3 combinatorial split and mix combinatorial synthesis is shown in Figure 15. The technique involves three initial batches of resin beads to which are initially coupled, for example, a different amino acid. These batches are then combined, mixed and split again into three batches; each batch now containing a mixture of beads containing different amino acids. A different amino acid is then coupled to each of these batches of beads, the beads mixed, split and the process repeated a third time. This simple 360 3×3×3 combinatorial split and mix approach generates a library of beads containing 27 different compounds in only 6 coupling reactions. A10×10×10×10×10 split and mix reaction scheme will produce 10,000 compounds in only 50 reactions. It is therefore clear that these strategies can produce large libraries of compounds of wide molecular diversity. As each resin bead contains only a single molecule the beads can be screened individually for bioactivity by either screening for activity of bound peptide in the biological assay or by cleaving the resultant peptide from the bead before undertaking the bioanalysis. The identity of any active compounds can then be determined by using mass spectrometry to sequence the active peptide. These involve the synthesis of a large number of combinatorial libraries making it possible to identify the sequence of the active agent from the identification of the libraries containing the active agent. For example, if we were interested in a 5 amino acid peptide we could use an indexed library approach. This approach involves the initial synthesis of 20 combinatorial libraries using 20 different amino acids as the first amino acid. By screening these libraries we would be able to identify a library containing the most active peptide against a therapeutic target—this library would indicate which amino acid is required in the first position of the peptide. If we then, keeping the first amino acid constant, synthesize a further 20 libraries using 20 different amino acids in the second position we will be able to identify the second amino acid required for optimal activity. Such a process allows the most active agent to be identified from a potential pool of 3. Parallel array libraries use a similar strategy but the libraries are all synthesized in parallel. For example, if we were looking for a small molecule drug which could be synthesized from three basic building blocks A, B and C each of which had 12 different possible variants (e. The first set of libraries would each contain a known variant of A, the second set of libraries a known variant of B and the third set of libraries a known variant of C. By screening all the libraries and identifying the most active library from each set it is immediately possible to identify the structure of the most active compound, as only one compound will be common to the libraries (e.

These rules are discussed in this chapter generic hydrochlorothiazide 25mg otc, but much more information is provided regarding solubility buy 25mg hydrochlorothiazide free shipping, membrane transport buy 25mg hydrochlorothiazide fast delivery, and metabolic stability. In conclusion, this book provides a primer for anyone in the feld of drug discovery and specifcally in the area of the use of peptides as molecules for both the discovery phase and, in favorable cases, the fnal phase of the creation of new molecular entities that can be moved into further studies to evaluate their potential as therapeutic drugs. I want to thank the authors of the chapters for their friendship, for many discussions, and for their excellent writing for this book. Craik, Institute for Molecular Bioscience, The University of Queens- land, Brisbane, Queensland, Australia Ayman El-Faham, Department of Chemistry, Alexandria University, Alexandria, Egypt; Department of Chemistry, King Saud University, Riyadh, Kingdom of Saudi Arabia Gregg B. During that period a number of great peptide drugs such as Sandostatin, Lupron, Copaxone, and Zoladex were developed with great therapeutic beneft. It was not until the last decade that we have seen a signifcant surge in the number of peptide therapeutics on the market (Figure 1. While 10 peptides were approved between 2001 and 2010, the current decade has thus far witnessed the approval of six new peptide therapeutics – a remarkable yearly increase [1, 2]. The number of peptides in development is also steadily growing roughly doubling every decade (Figures 1. This is due to the advances made in our understanding of peptide stability, peptide syn- thesis, and formulation over the last three decades. Although the market share of peptide drugs is still relatively small (about 2% of the global market for all drugs), the approval rate for peptide drugs is twice as fast as the rate for small molecules, and the market is growing similarly at a rate that is twice the global drug market [3, 4]. With the exception of a few peptides, the approved drugs so far tar- get the extracellular compartment, and thus have to compete with biologics. We have seen a great advance in extending the circulating half-life of the peptides through the use of unnatural amino acids and formulation technologies, but have not yet reached the half-life achieved by antibodies. To dramatically heighten their impact, peptides need to access the intracellular space to target protein–protein interactions. These interactions represent a vast source of potential targets with signifcant biological impact (there are estimated 300,000 such interactions in the cell), and will not in the majority of cases be modulated by small molecules. Peptides and biologics, given their relative size and ability to bind to extended surface areas, are the perfect candidates to inhibit protein–protein interac- tions. The duration of action of peptides needs to be extended, and while peptides are inherently selective against their targets, they need to more selectively distribute to the desired tissue. Finally, the route of administration needs to be expanded to include oral delivery. Many of the techno- logical advances are already proving that it is possible to make peptides permeable to cells, target tissues, have longer half-lives, and be orally bioavailable. The discovery that certain peptides can penetrate cells and can, therefore, be an effective therapeutic on their own or alternatively bring other drugs into cells allowed for the frst time to imagine targeting the intracellular compartment (Figures 1. It is hard to compete with the screening of the mil- lions of small molecule compounds in various pharmaceutical companies and more recently in many academic centers. Indeed, over the last decade, there has been an explosion of very elegant tech- nologies that now allow the generation of large to extremely large libraries of linear and macrocyclic peptides with unnatural amino acids and unnatural linkers. For the frst time, it is possible to engineer stability, cell permeability, and possibly oral bioavailability at once and screen for the desired properties very rapidly. These major advancements have resulted in the generation of a number of companies that are pushing the limits of these technologies to rapidly screen and identify novel peptide therapeutics against protein–protein interaction targets (Figure 1. Through medicinal chemistry optimization, they have now identifed picomolar inhibitors with good properties [15]. These peptides contain a com- bination of natural, unnatural, and N-methyl amino acids and exhibit good physico- chemical properties and membrane permeability [17]. They recently presented on their discovery of potent antagonists of mcl-1 and Ras with good cell permeability [18]. David Craik and colleagues at Cyclotide are systematically exchanging the various loops present on cyclotides with sequences that have important biological function [19]. Moreover, novel technologies developed for the rapid generation and screening of extremely large libraries of knottins and cyclotides will undoubtedly have a major impact on this class of peptide therapeutics. Of note is the Intein-based technology from Julio Camarero capable of introducing unnatural amino acids to facilitate screening [21]. Sutro and MitiBio also have very sophisticated and effcient biosynthetic methods to generate very large libraries. Finally, Verdine and Wollensky and colleagues [22, 23] as well as the investiga- tors at Aileron Therapeutics have developed a novel stapling technology that imparts stability and membrane permeability to alpha helical structure. This is due to the fact that once the peptide enters the cell, the major elimination pathway is through enzymatic catabolism. Not only can stability be tuned for circulating half-life, it can also be tuned to withstand cellular catabolism to lengthen the desired effcacy.

The accuracy and precision of melting point is dependent on a number of factors such as—capillary size buy 12.5 mg hydrochlorothiazide with visa, sample size purchase hydrochlorothiazide 12.5 mg on-line, initial temperature of heating-block and the rate of rise of temperature per unit time (minutes) purchase hydrochlorothiazide 25mg with visa. Keeping in view the different manufacturing processes available for a particular drug the melting point has a definite range usually known as the melting range. Mestranol 146 154 Thus the melting range takes care of the variance in manufacture together with the storage variance over a stipulated period of time. Boiling Point It is also an important parameter that establishes the purity of a substance. Depending on the various routes of synthesis available for a substance a boiling point range is usually given in different official compendia. Refractive Index It is invariably used as a standard for liquids belonging to the category of fixed oils and synthetic chemicals. Weight Per Millilitre Weight per millilitre is prevalent in the Pharmacopoeia of India for the control of liquid substances, whereas Relative Density (20°/20°) or Specific Gravity is mostly employed in the European Pharmacopoeia. Specific Optical Rotation As pharmacological activity is intimately related to molecular configuration, hence determination of specific rotation of pharmaceutical substances offer a vital means of ensuring their optical purity. Morphine Hydrochloride – 112° – 115° Calculated with reference to the dried substance in a 2% w/v soln. Light Absorption The measurement of light absorption both in the visible and ultraviolet range is employed as an authentic means of identification of offcial pharmaceutical substances. Viscosity Viscosity measurements are employed as a method of identifing different grades of liquids. Specific Surface Area The surface area of powders is determined by subsieve-sizer which is designed for measurement of average particle sizes in the range of 0. Swelling Power The swelling power of some pharmaceutical products are well defined. Examples : (i) Isphagula Husk : When 1 g, agitated gently and occasionally for four hours in a 25 ml stoppered measuring cylinder filled upto the 20 ml mark with water and allowed to stand for 1 hour, it occupies a volume of not less than 20 ml and sets to a jelly. Infrared Absorption Measurement and subsequent comparison of the infrared spectrum (between 4000-667 cm–1) of compounds with that of an authentic sample has recently become a versatile method for the identification of drugs having widely varying characteristics. Examples : Infrared spectroscopy is employed to compare samples of chloramphenicol palmitate (biologically active form) recovered from chloramphenicol palmitate mixture vis-a-vis an artificially prepared mixture of authentic sample consisting 10 per cent of the ‘inactive polymorph’. Miscellaneous Characteristics A large number of miscellaneous characteristics are usually included in many official compendia to ascertain the purity, authenticity and identification of drugs—including : sulphated ash, loss on drying, clarity and colour of solution, presence of heavy metals and specific tests. Sulphated Ash Specifically for the synthetic organic compounds, the Pharmacopoeia prescribes values for sulphated ash. The sulphated ash is determined by a double ignition with concentrated sulphuric acid. The method is one of some precision, and provides results which are rather more reproducible than those obtained by simple ignition. Loss on Drying Loss on drying reflects the net weight of a pharmaceutical substance being dried at a specified tempera- ture either at an atmospheric or under reduced pressure for a stipulated duration with a specific quantity of the substance. Clarity and Colour of Solution When a pharmaceutical substance is made to dissolve at a known concentration in a specified solvent it gives rise to a clear solution that may be either clear or possess a definite colouration. Heavy Metals Various tests are prescribed in the offcial compendia to control heavy metal e. Hence, a stringent limit is recommended for the presence of heavy metals in medicinal compounds. Specific Tests In fact, certain known impurities are present in a number of pharmaceutical substances. The presence of such impurities may be carried out by performing prescribed specific tests in various official compendia in order to ascertain their presence within the stipulated limits. Obviously the amount of any single impurity present in an official substance is usually small, and therefore, the normal visible-reaction-response to any test for that impurity is also quite small. Hence, it is necessary and important to design the individual test in such a manner so as to avoid possible errors in the hands of various analysts. It may be achieved by taking into consideration the following three cardinal factors, namely : (a) Specificity of the Tests : A test employed as a limit test should imply some sort of selective reaction with the trace impurity. It has been observed that a less specific test which limits a number of possible impurities rather instantly has a positive edge over the highly specific tests. Exmaple : Contamination of Pb2+ and other heavy metal impurities in Alum is precipitated by thioacetamide as their respective sulphides at pH 3. The sensitivity is governed by a number of variable factors having a common objective to yield reproducible results, for instance : (i) Gravimetric Analysis : The precipitation is guided by the concentration of the solute and of the precipitating reagent, reaction time, reaction temperature and the nature and amount of other substance(s) present in solution. A number of such tests shall be discussed here briefly with specific examples wherever possible and necessary : 1. Limits of Insoluble Matter The limits of insoluble matter present in pharmaceutical substances and stated in various official com- pendia are given below : S.