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By J. Tufail. Bluffton University. 2019.

The identification of future therapeutic targets will be driven by cross-fertilization between these two disciplines through bioinformatics discount 30gm acticin mastercard acne scar removal cream. A perfect prodrug is a molecule which has no intrinsic pharmacological activity until it is converted enzymatically to a new molecular form which displays pharmacological activity buy acticin 30gm line skin care clinic. In principle buy 30gm acticin visa skin care advice, prodrug activation simply mirrors activation processes which are used widely in biological systems to regulate important enzymatic cascades buy discount acticin 30 gm acne clothing. A particularly widespread example in biology is pro- protease activation, in which a small “extension” peptide can be used to restrain or “mask” inherent proteolytic activities which, if they occurred in inappropriate tissue locations, would pose a major problem. The digestive proteases enterokinase, trypsin and chymotrypsin are well-known examples of this phenomenon, although there are now a wide range of examples in which proteolytic activation cascades are known to regulate processes as diverse as virus assembly and 7-transmembrane receptor activation. It has 373 been estimated that over 2% of the expressed human genome is accounted for by proteases of one specificity or another, although only 300 of the expected 2,000 that this would indicate have so far been characterized. Elucidating the biological roles and locations of these novel proteases will provide opportunities for both new therapeutic target identification and protease-activated cell targeting of both macromolecules and small molecule drugs. In the context of drug delivery, certain cell surface receptor and ion-channel families are particularly appealing as drug delivery targets. Well-characterized examples include the lectin-like receptor gene family as receptors for glycosylated molecules, as well as vitamin- and trace element-uptake systems such as the transferrin-receptor. In the past, various serendipitous discoveries have capitalized on the differential expression of enzymes by host and viral infected cells. These compounds are selectively phosphorylated intracellularly to the 5′-triphosphate derivatives which inhibit the viral reverse transcriptase. Drug delivery and targeting is a key area which will benefit from cell and tissue-based information. It seems reasonable to expect similarly sophisticated drug delivery end-points to be achievable through design or screening approaches, given an understanding of the tissue-specific expression of particular activating enzymes, possibly mirroring those already exploited by naturally occurring viruses. The storage of genomic and protein sequences in easily searchable databases to allow comparison of protein and genomic sequences is essential if companies are to maximize the value of their biological data. There are now a number of high quality protein and genetic databases documenting the protein and gene expression of specific cell types under different conditions. Such databases have proved invaluable to companies investigating specific disease states. With the increasing automation of drug discovery with respect to combinatorial chemistry, high- throughput screening, proteomics and genomics, informatics has developed an increasingly important role. The integration of robotics and informatics with databases correlating molecular properties with biological properties is becoming increasingly important for the management of compound libraries. Such informatic systems allow companies to readily search compound libraries and identify agents with potential activity against other therapeutic targets. Robotic automation provides a means of extracting these libraries or further screening from storage as necessary. The combination of biological and chemical data in relational databases provides useful data for the computer-based database searching and advanced quantitative structure-activity-relationship studies. The power of these databases in identifying potential lead compounds against new disease states will increase with the integration of proteomic data. For example, knowing that a specific compound class interacts strongly with a particular peptide motif at various receptors/catalytic sites will facilitate the identification of lead compounds for receptors/enzymes with similar motifs. Generic approaches towards the identification of new targets for human drug discovery are now routinely practised within pharmaceutical companies. Simply trawling these databases for potential targets expressed in diseased tissue has already yielded novel homologs of key enzymes and receptors, many of which have been patented as drug discovery targets. We are still at an early stage of understanding the full complexity of the mammalian and human genetic vocabulary. A more pharmaceutically oriented approach is to search for novel members of certain key receptor families which are already known from pharmacological studies to be present in a target tissue. This combination of pharmacology and molecular biology is proving particularly interesting, identifying far greater heterogeneity amongst targets than had previously been thought, with both receptor subtypes and the differential splicing of individual genes contributing to this complexity. The effective management of chemical and biological data underpins the effectiveness of any drug discovery group. All these aspects of drug discovery will impinge on drug delivery and targeting in the future. Furthermore, combinatorial chemistry and high-throughput screening will provide targeting molecules for disease-associated surface-expressed receptors and ligands. These may be linked to therapeutic drug molecules to increase epithelial transport by active transport processes and drug targeting selectivity. Describe the potential roles of proteomics and genomics in drug delivery and targeting. Identify two ways in which combinatorial chemistry may impinge on drug delivery and targeting. The preceding chapters in the last part of this book have highlighted the recent developments in gene therapy, drug discovery, genomics and proteomics as a consequence of the recent developments in molecular biology and chemistry. This chapter concludes this text by examining how the advances in chemistry and biology are providing opportunities for more effective site-specific drug targeting and bioresponsive pulsatile drug delivery. The chapter considers the development of prodrug-based technologies for cell-specific drug delivery, provides an overview of the use of smart polymeric systems, microchips and genetically engineered cell-based implants in addressing the challenges of chronopharmacology, and offers a perspective of the future of drug delivery and targeting in this new millennium. In the discovery process opportunities exist, as illustrated in Chapter 15, to identify cell-specific enzymes and ligands which may be used to target drugs to these cells. The integration of the considerations for drug delivery and targeting into the drug design process may ultimately allow the development of drugs which are not just potent and non-toxic but offer the advantage that their chemical structure dictates the targeting of the drug to its particular site of action through enzyme-based chemical delivery systems using prodrugs. A prodrug is a pharmacacologically inactive compound which undergoes chemical or enzymatic metabolism to the active. Some of the early pharmaceuticals were found to be prodrugs and this finding has led to the subsequent introduction of the metabolite itself into therapy, particularly in cases where the active metabolite is less toxic or has fewer side-effects than the parent prodrug. The administration of the active metabolite may also reduce variability in clinical response between individuals due to differences in pharmacogenetics. Most chemically designed prodrugs consist of two components; the active drug chemically linked to a pharmacologically inert moiety. The prodrug must be sufficiently stable to withstand the pharmaceutical formulation while permitting chemical or enzymatic cleavage at the appropriate time or site. After administration or absorption of the prodrug, the active drug is usually released by either chemical or enzymatic, hydrolytic or reductive processes. Prodrugs are most commonly used to overcome the biological and pharmaceutical barriers which separate the site of administration of the drug from the site of action (Figure 16. Prodrug design has been used to address a wide range of pharmaceutical problems including: • unpalatability • gastric irritation • pain on injection • insolubility • instability. Prodrug design has also been used widely to address pharmacological problems such as poor drug adsorption and drug distribution. As discussed in Chapter 1, prodrugs may be used to enhance the absorption of poorly adsorbed drugs by increasing the lipophilicity of the drug molecule. The modification of a drug to a prodrug may also lead to enhanced efficacy by differential distribution of the prodrug to particular body tissues before the release of the active drug. For example, the administration of the methoxymethyl ester of hetacillin (a 6-side-chain derivative of ampicillin) leads to a more extensive distribution of ampicillin in the body tissues than occurs on administration of ampicillin itself. Conversely, the restriction of tissue distribution which decreases toxic side-effects by restricting the action of a drug to a specific target site in the body may also be achieved through the use of certain prodrug systems as described below. An alternative strategy is to utilize phenotypic differences between cell types to target prodrugs to particular sites within the body through site- specific enzyme-based delivery systems. Improved selective localization of anticancer agents to neoplastic tissue may be achieved using non-toxic prodrugs which release the active drug within the tumor as a result of enhanced enzyme activity in the cell. For example, the prodrug cyclophosphamide is initially activated by hepatic cell enzymes to generate 4- hydroxycyclophosphamide which is then specifically converted to the alkylating cytotoxic phosphoramide mustard in the target cells.

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This relative omission can be explained by the problem being one unique to human beings: the use of language symbols to communicate and interact with other human beings buy discount acticin 30gm line skin care line reviews. A review of the literature illustrates a variety of effects produced by pharmacologically inert substances which simulate medication -129- (placebos) 30 gm acticin for sale skin care bandung. Depending on the personality of the subject and the circumstances under which the placebo is administered discount acticin 30 gm amex acne zapping machine, 30 to 50 per cent of individuals show or experience a reaction generic acticin 30 gm on line skin care gift sets. Well-designed studies can distinguish the pharmacologic effect of a drug from the placebo effect. The possibility is raised that an interrogator might exploit the "placebo phenomenon" with a susceptible subject, instead of employing a pharmacologically active drug. An examination of the literature demonstrates that the effects of drugs vary with the attitude and motivation of the person administering the medication and the person interviewing the informant. The sex and intelligence of the subject, the presence of mental or physical illness, the occurrence of biologic rhythms (e. The method of sampling the verbal behavior of an individual under the influence of a drug, directive, nondirective, free-associative, etc. For these reasons, it is recommended that a variety of sampling methods be used in experimental studies. The Efficacy of Drugs in Uncovering Information When one examines the literature for experimental and clinical studies that bear directly on the use of drugs in interrogation procedures, one finds relatively few studies. Reports dealing with the validity of material extracted from reluctant informants, whether criminal suspects or experimental subjects, indicate that there is no "truth serum" which can force every informant to report all the information he has. Experimental and clinical evidence indicate that not only the inveterate criminal psychopath may lie or distort under the influence of a drug, but the relatively normal individual may, with many drugs, successfully disguise factual data. Less well-adjusted individuals, plagued by guilt and depression, or suggestible individuals, who are compliant and easily swayed, are more likely to make slips revealing withheld information. Even they may, at times, unconsciously distort information and present fantasies as facts. The anesthetic action of the drug, as in narcosis with barbiturates, can interfere with cerebral functioning and promote the presentation of fantasy material as fact, or otherwise alter the form of verbalizations to render them relatively unintelligible. It would be very difficult under these circumstances for an interrogator to tell when the verbal -130- content was turning from fact to fantasy, when the informant was simulating deep narcosis but actually falsifying, which of contrary stories told under narcosis was true, and when a lack of crucial information coining from a subject under a drug meant the informant had none to offer. To derive useful information from an interrogation in which drugs are employed, an interrogator would have to consider and weigh many important factors: the personality of the subject, the milieu, other sources of evidence, the rapport obtained, and the skill of the questioning. These and other factors affect the validity of information obtained from an informant under sedation. Specific Effects of Drugs in Interrogation Situations Advantages and limitations of a number of different types of pharmacologic agents as adjuncts to interrogation can be examined by reviewing clinical and experimental data from the works of psychiatrists, neurologists, psychologists, physiologists, and pharmacologists. Barbiturates tend to increase contact and communication, decrease attention, decrease anxiety, decrease psychotic manifestations, and make the mood more appropriate and warmer. When combined with interview techniques that aim at arousing emotions, strong emotional reactions may be catalyzed for psychotherapeutic purposes. Barbiturates have been found helpful in detecting whether an individual is feigning knowledge of the English language and in getting mute catatonic schizophrenics and hysterical aphasics to talk. They are of no avail, however, in remedying the speech defects of true aphasics, even transiently. The use of barbiturates has helped to get more reliable estimates of intelligence and personality through psychological tests, particularly in emotionally upset individuals. The use of various stimulant and antidepressive drugs has been explored, for diagnostic and therapeutic purposes in psychiatric practice, but not to any extent for interrogation. Amphetamine, pipradrol, methylphenidylacetate have in common the capacity to produce an outpouring of ideas, emotions, and memories. An injection of amphetamine following an intravenous barbiturate is said to provoke a striking onrush of talking and activity from psychiatric patients. Without adequately controlling his study, one author claims that methamphetamine produces such a strong urge to talk that the criminal who feigns amnesia or withholds vital information cannot control himself and thus gives himself away. Iproniazid, an antidepressive drug which is relatively slow and sometimes dramatic in its thera- -131- peutic effect, should be considered for experimentation. This drug, and similar, less toxic analogs which are being developed, might be considered for use in special instances. For example, informants suffering from chronic depression, whether due primarily to emotional factors, situational stress, or physical debilitation, might become very responsive after using a medication of this type. As a class, the stimulants probably present the most obvious exploitative potential for an interrogator. The use of such drugs by an interrogator would tend to produce a state of anxiety or terror in most subjects, and promote perceptual distortions and psychotic disorientation. Their use could constitute a definite threat to most medically unsophisticated subjects, i. When the subject is not under the influence of such drugs, vital information might be extracted as a price for ceasing further medication. An enlightened informant would not have to feel threatened, for the effect of these hallucinogenic agents is transient in normal individuals. The information given during the psychotic drug state would be difficult to assess, for it may be unrealistic and bizarre. The introduction of new drugs like tranquilizers that sedate but do not impair intellectual functioning in moderate dosage (e. There is a possibility that these tranquilizers might be of use with selected informants who are highly agitated and disturbed, and who might give information they prefer to withhold in return for the tranquility they experience with such a sedative. Under the influence of this drug, the less emotionally upset informant might find that he can better master his anxieties and keep his resolve to remain silent. The ability of the subject to give information is not notably affected by a mainte- -132- nance dosage. The motivational effects of obtaining drug supplies, while extreme, are not of a different order for most subjects than those which the interrogator could produce by other more rapid means. The exploitation of addiction probably constitutes a threat to persons previously addicted, or to those who become addicted in the captivity situation as a sequel to other aspects of their treatment, rather than through the deliberate creation of addiction for exploitative purposes. Another use to which interrogators might put drugs and placebos would involve their ability to absolve the subject of responsibility for his acts. The popular meaning of being "drugged" or "doped" implies that an individual in this state has lost control over his actions and that society will not hold him responsible for them. When the transmittal of information is likely to induce guilt in the source, the interviewer can forestall some of this reaction by the administration of a placebo or drug. In some cases, this will be all that is require4l to remove the barrier to information transmittal. What are the over-all conclusions that can be drawn from this review and critical analysis of the use of pharmacologic agents in obtaining information? Are pharmacologic agents of any value to the interrogator in eliciting vital information? The answer is that drugs can operate as positive catalysts to productive interrogation. Combined with the many other stresses in captivity that an individual may be obliged to undergo, drugs can add to the factors aimed at weakening the resistance of the potential informant. However, for many reasons, the use of drugs by an interrogator is not certain to produce valid results. The effects of drugs depend to a large extent on the personality make-up and physical status of the informant and the kind of rapport that the interrogator is able to establish with him. Even under the most favorable circumstances, the information obtained could be contaminated by fantasy, distortion, and untruth, especially when hallucinogenic or sedative drugs are employed. Are there ways in which the informant can resist revealing vital information under interrogation with drugs? The informant should know that a drug of itself cannot force him to tell the truth, although it may make him talkative, overemotional, mentally confused, or sleepy. He should also know that the effects of drugs are quite variable from individual to individual, and that those who may use drugs against him cannot predict with certainty what effects will occur in his particular case.

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Rosiglitazone maleate is approved in some Dose–response relationships were assessed countries for the treatment of type 2 diabetes in fve studies purchase acticin 30 gm line acne around chin, three of which were high-quality mellitus cheap acticin 30gm without prescription skin care urdu tips. It is available both as a single agent and population-based studies (which adjusted for in combination with other oral medications for smoking or chronic obstructive pulmonary diabetes purchase 30gm acticin amex acne 6dpo. Until 2007 buy acticin 30gm otc acne 911 zit blast, rosiglitazone was among disease in the absence of data on smoking) the most widely used oral drugs for treatment conducted within the large health insurance of type 2 diabetes. No consistent pattern of increased risk relationship helped to mitigate concerns about was reported for any other specifc cancer site, or potential confounding by most risk factors; for all cancers combined for either drug. Administration of pioglitazone in the of disease in the populations studied as poten- feed caused a signifcant increase in the inci- dence of large intestine adenoma in one study tial explanations for positive associations with in genetically engineered male mice sensitive to pioglitazone. In a study in male and medical databases, which allowed for adjustment female neonatal mice, pioglitazone in the feed for potential confounding by medical factors, promoted mainstream cigarette smoke-induced but did not permit direct control for cigarette kidney adenoma in females. It also caused a signifcant positive trend in the Te potential for confounding by smoking is also incidence of subcutaneous lipoma in females. Furthermore, an excess of cancer of the bladder among pioglitozone users, and not cancer of the lung, was observed in the trial that randomized 5. Administration of diets containing rosigli- tazone caused a signifcant increase in the inci- 5. In a 2-year study including the liver, kidney, colorectum, lung, in male and female mice treated by gavage, a prostate, and breast, among patients using 372 Pioglitazone and rosiglitazone signifcant increase in the incidence of liver 6. Evaluation haemangiosarcoma was observed in males, but this was not treatment-related. Tere is limited evidence in experimental data animals for the carcinogenicity of rosiglitazone. Certain pioglitazone metabolites Rosiglitazone is not classifable as to its and rosiglitazone have given positive results in carcinogenicity to humans (Group 3). Urine acidifcation has no efect on peroxisome proliferator-activated and peripheral blood lymphocytes from rats. Use of medications containing piogli- zone metabolites; cytotoxicity, urolithiasis, and tazone (Actos, Competact) suspended June 9th 2011. Likewise, receptor-medi- determination of rosiglitazone by square-wave adsorp- ated efects may play a role in the tumorigenic tive stripping voltammetry method. Te use of pioglitazone and the liver cancer and colorectal cancer in type 2 diabetes risk of bladder cancer in people with type 2 diabetes: mellitus. Single- Bosetti C, Rosato V, Buniato D, Zambon A, La Vecchia and multiple-dose pharmacokinetics of pioglitazone C, Corrao G (2013). J Clin Pharmacol, thiazolidinediones for type 2 diabetes: a meta-anal- 45(10):1137–44. Important safety information on the Pharmacokinetics of oral rosiglitazone in Taiwanese use of medicinal products containing pioglita- and post hoc comparisons with Caucasian, Japanese, zone. Absorption, disposition, vitro characterization of rosiglitazone metabolites and and metabolism of rosiglitazone, a potent thiazoli- determination of the kinetic parameters employing dinedione insulin sensitizer, in humans. Review and evaluation of pharmacology macroVascular Events): a randomised controlled and toxicology data: Rosiglitazone. Avandia the dorsal and ventral urinary bladder and kidney (Rosiglitazone Maleate) Tablets, Application No. Cohort study of Medicines Agency recommends suspension of pioglitazone and cancer incidence in patients with Avandia, Avandamet and Avaglim. Assessment report Pioglitazone bladder cancer: a meta-analysis of controlled studies. Association of diabetes duration and tract of mice exposed to cigarette smoke and treated with diabetes treatment with the risk of hepatocellular carci- chemopreventive agents. Lancet, Lefebvre A-M, Chen I, Desreumaux P, Najib J, Fruchart 378(9802):1543–4, author reply 1544–5. Report estimation of metformin hydrochloride, pioglitazone with Data from 1 January 1997 to 31 December 2010. Diabetologia, thiazolidinediones and fractures in type 2 diabetes: 51(11):2108–16. High-performance liquid chromatography synthetic hypoglycemic drugs added illegally to ‘natural’ quadrupole time-of-fight mass spectrometry method anti-diabetic herbal products. Chromatographia, for the analysis of antidiabetic drugs in aqueous envi- 70:1353–1359. Rosiglitazone and risk of cancer: a meta-anal- Piccinni C, Motola D, Marchesini G, Poluzzi E (2011). Hazardous Substances Data Bank: National Radhakrishna T, Sreenivas Rao D, Om Reddy G (2002a). Biochem Biophys Res method for the simultaneous analysis of diltiazem, Commun, 278(3):704–11. Co-solvent solubilization urine by liquid chromatography/tandem mass spec- of some poorly-soluble antidiabetic drugs. Selective and validated spectro- cancer: a population-based cohort study in Taiwan. Int J human studies: is it diabetes itself, diabetes drugs, Clin Pract Suppl, (121):13–8. Determination of piogli- a population-based cohort study using the National tazone in dog serum using solid-phase extraction and Health Insurance in Taiwan. Diabetes Res Clin Simultaneous estimation of six anti-diabetic drugs– Pract, 98(1):159–63. Multi-component plasma quantitation of anti-hyperglycemic pharmaceutical compounds using liquid chromatography-tandem mass spectrometry. Quantitative determination of pioglita- zone in human serum by direct-injection high-perfor- mance liquid chromatography mass spectrometry and its application to a bioequivalence study. High-performance liquid chromatographic determination of pioglitazone and its metabolites in human serum and urine. Exposure Data Te Working Group noted that most of what has been used under the term “digitalis” in North America and Europe has been digoxin; Digoxin is a cardiac glycoside isolated from however, there may be parts of the world where plants of the genus Digitalis. William Withering published his monograph “An account of the foxglove and some of its medical uses” (Withering, 1785; Albrecht & Geiss, 2000). Furthermore, 3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl- the term “digitalis use” found in many reports -(1→4)-O-2,6-dideoxy-β-D-ribo-hexo- probably refers not to the use of plant mate- pyranosyl-(1→4)-2,6-dideoxy-β-D-ribo- rial, which is not commercially available as a hexopyranosyl)oxy]-12,14-dihydroxy-, medicinal product, but to the use of the isolated (3β,5β,12β)- (SciFinder, 2013) compounds. Te Working Group 4,5-dihydroxy-6-methyloxan-2-yl] estimated that digoxin represents at least 90% of oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4- the world market for digitalis glycosides. Tus, studies reporting thren-17-yl]-2H-furan-5-one (PubChem, use of “digitalis” should be carefully scrutinized 2013) since the agent to which people were actually Synonyms: 12β-hydroxydigitoxin exposed could have been any one of the four digitalis glycosides. Te purity of digoxin is pressure, 760 Torr) (SciFinder, 2013) 382 Digoxin typically at least 95% (see Section 1. Name: 3β-[(O-2,6-dide- glucosidase enzymes at 30–37 °C until glucose oxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6- is completely removed. Extraction procedures, dideoxy-β-D-ribo-hexopyranosyl-(1→4)- usually followed by precipitation of tannic 2,6-dideoxy-β-D-ribo-hexopyranosyl) acid and related phenolic products with lead oxy]-14-hydroxy-4β,14β-card-20(22)-enolide. Compendial methods to determine digoxin and digitoxin in pharmaceutical preparations 1. For detection in (a) Indications human plasma or urine, liquid chromatography Digoxin and digitoxin are therapeutically the with mass spectrometric detection is required to most widely used digitalis glycosides. Te lists the most commonly reported clinical indica- analytical methods are summarized in Table 1. Digoxin is generally maintenance therapy because its long half-life less efective than other drugs in producing (5 – 9 days) provides a sustained therapeutic efect consistent reduction of heart rate, particularly even if a dose is missed. For congestive heart failure, use of digoxin (b) Dosage fails to improve survival (Digitalis Investigation Group, 1997) when compared with placebo, Administration is typically oral, although unlike other leading therapies. It does, however, preparations for intravenous administration provide symptomatic benefts in some cases exist.

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Manufacturers are aware purchase acticin 30 gm line skin care natural, however order 30 gm acticin free shipping skin care zarraz, that low- and middle-income countries are less likely to enforce these standards discount acticin 30gm without a prescription acne quiz. Some companies exploit this and produce drugs of lower quality for the loosely regulated markets (Caudron et al acticin 30 gm otc skin care qualifications. When a manufacturer produces medicines of inferior quality for less exacting markets, it is known as tiered or parallel production (Caudron et al. Tiered production is a complicated problem, in part because some kinds of tiered production are legal. International manufacturers may sup- ply to multiple markets which use different legal product quality standards. For example, the British Pharmacopoeia monograph for amoxicillin gives no dissolution standard (British Pharmacopoeia, 2012); the U. Assay limits may also be different, making a product illegal by one pharmacopeia but legal by another. A manufacturer may supply to one country that stipulates a uniformity of dosage at 90-120 percent of declared dosage and to another country that stipulates 85-115 percent, for example. Both these standards aim to correct for the fact that drugs such as antibiotics degrade quickly, making a high initial dose accept- able. However, manufacturers could technically aim to fll only the lower bound of the dosage requirements and be within the letter of the law. A study of amoxicillin samples in Arab countries found that most samples’ ac- tive ingredient concentrations were bordering the U. The authors admitted, however, that many of Copyright © National Academy of Sciences. Participants at the public meetings for this study mentioned concerns with parallel production, but evidence for it is largely anecdotal. There is reason to suspect tiered manufacturing when the dose of active ingredient is consistently lower, never higher, than the label claim (Bate et al. Drugs, especially tablets, of less than half the labeled potency before the ex- piry date are particularly dubious. A 2006 Lancet report described a shift in Russia from most bad medicines being falsifed drugs made “in basements and small backroom enterprises” to ones coming from legitimate companies running “a ‘night shift’ to produce extra quantities of a certifed drug that does not pass quality control, or sophisticated copies of well-known drugs. Jiben Roy reported on a similar case: A Bangladeshi company delib- erately kept the active ingredients in paracetemol, ampicillin, and cotri- moxazole below the labeled concentrations after repeated warnings from the regulatory authority (Roy, 1994). In the same paper he attributed the manufacturer’s quality failures in their cheaper product lines to negligence alone. Their B-vitamins, for example, contained the proper ingredients, but in erratic doses (Roy, 1994). This paper was able to make distinctions between the deliberate quality failures and negligence because the author had close knowledge of the manufacturer and its history. Usually only the national regulatory authority could have the information needed to make this distinction. In many countries, even the regulatory authority would not have that information or the political will to act on it (Christian et al. Pinpointing cases of deliberate tiered manufacturing is diffcult to do, though it is easier to see practices that allow it happen. Companies provide contract manufacturers with the materials, includ- ing packaging, to make their products. As Dilip Shah, Secretary General of the Indian Pharmaceutical Alliance, explained to a committee delegation in India, “Very few companies, foreign or domestic, monitor the [contract manufacturer’s] process loss of raw materials, active ingredients, and pack- aging materials. I have known of cases of 15 to 20 percent packaging mate- rial losses and companies are not bothered. Because the contract manufacturers have the processes and materials needed to produce a proper drug, they will sometimes sell perfectly made drugs outside of the licit distribution system. Pharmaceutical exporting countries can also unintentionally facilitate tiered manufacturing by not requiring the same evaluations for exported drugs as for those sold domestically (Caudron et al. In general, regulatory agencies are responsible for protecting their country’s domestic medicine supply; ensuring quality for exported products is often beyond their mandate and budget. It is more diffcult for low- and middle-income countries to ensure checks on drug quality during manufacture, a problem discussed later in this chapter. Procurement and Substandard Medicines When regulatory checks on production are inconsistent, procurement practices can help ensure that quality medicines get the largest market share. The Global Fund explains the goal of good procurement as supplying medicine “meeting agreed quality standards at the lowest possible price and in accordance with national and international laws” (Global Fund, 2009, p. Government agencies procuring medicines have to reconcile a tension between quality and price (Torstensson and Pugatch, 2012). The frms that offer the cheapest prices may do so by buying impure ingredients or cutting corners in formulation. Good procurement dictates that the cheapest tenders are not accepted Copyright © National Academy of Sciences. Chinese provincial procurement, for example, is known for “pressuring manufacturers to produce the lowest cost possible while preserving their profts” (Burkitt, 2012). These agencies face pressure to supply medicines for entire populations on tight budgets; sometimes there is added demand to support local manufacturers (Dickens, 2011; Torstensson and Pugatch, 2012). Openness in procurement can bal- ance these pressures by exposing unnecessarily high costs or bad quality, but transparency, which also includes vetting procurement offcers for con- ficts of interest, auditing suppliers, documenting decisions, and scrutinizing procurement agents, adds costs to the process (Torstensson and Pugatch, 2012). In Argen- tina, for example, a health transparency program brought down the pro- curement costs of medicines (Lewis, 2006). Reducing costs of procurement would be especially helpful in the poorest countries, which tend to spend a higher proportion of their health budget on drugs and where medicines are often expensive (Torstensson and Pugatch, 2012). In a study of 36 low- and middle-income countries, Cameron and colleagues found that public procurement agencies in the western Pacifc, Africa, and the former Soviet bloc pay an average of 34 to 44 percent above the international reference prices (Cameron et al. Donors may attempt to cover unmet demand for drugs, though donor procurement also has problems. Many European donors ask their recipients to assure quality of medicines procured with donated funds (Moore et al. Proper precaution in the medicines procurement process can prevent poor-quality products from infltrating the market. Good procurement involves separating the various steps of procurement process identifed in Table 4-2. Good procurement also puts a strong emphasis on controlling corruption and promoting transparency. Recommendation 4-2: Procurement agencies should develop a plan, within the next 3 to 5 years, to comply with the World Health Orga- nization’s Model Quality Assurance System for procurement agencies and work to remove any barriers to compliance. The model draws on the accumulated experience of these agencies’ procure- ment experts and combines advice on the procurement of medicines, vac- cines, diagnostic kits, and devices. The model focuses on four key activities: prequalifcation of pharmaceutical products and manufacturers and drug purchase, storage, and distribution. At its launch in 2006, the model had an aspirational element; it de- scribed standards that few if any of the international procurement agencies were able to maintain at that time. In the past 6 years, large procurement agencies have made great progress toward meeting the standards laid out in the model (van Zyl et al. The committee sees the model quality assurance system as a useful independent standard to assess procurement agencies. The system is a practical tool that can be used by national and international procurement agencies. Pharmaceutical procurement almost always means working with foreign suppliers; a practice that exceeds capacity of national regulators, who cannot hope to inspect foreign manufacturers as they would domestic ones. Good procurement also means that only organi- zations that follow the model system should import medicines. Small-scale importation and procurement by small actors threaten the medicines supply chain. Countering the Problem of Falsified and Substandard Drugs 149 Copyright © National Academy of Sciences.

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