By Y. Ayitos. Southern Arkansas University. 2019.
Many coun- tries also have problems with unregistered medicines effective 5mg proscar man healthxnet, those not granted market authorization in a country order proscar 5mg without prescription prostate cancer yoga. Unregistered drugs may be of good quality buy generic proscar 5 mg on-line prostate 42, though some research indicates they often are not. Unregistered medicines usually circulate outside the controlled distribution chain and are therefore suspect. The drug failures of public health concern can be divided into two main categories: falsifed and substandard. Falsifed drugs are usually also sub- standard; national specifcations referenced in the defnition of a substan- dard drug can vary. International endorsement of these two categories could advance public discourse on the topic. Recommendation 1-1: The World Health Assembly should adopt def- nitions consistent with the following principles. The spirit of these defnitions and the exclusion of the term counterfeit are central to this recommendation. By far the more common problem, however, is medicine that simply does 3 Some regulatory authorities may accept standards below those in international phar- macopeias. In such cases, a drug that would be generally regarded as substandard might be technically acceptable in a given country. The supporting text describes the committee’s understanding of a substandard drug. Poor-quality medicines cause treatment failure, but doctors do not generally suspect medicines as a cause of disease progression. Lifesaving medicines can be of poor quality, which may be an uncounted root cause of high mortality in low- and middle-income countries. Medications for chronic and infectious diseases alike have been found falsifed and sub- standard. A considerable body of research indicates that inexpensive anti- microbial drugs in low- and middle-income countries are frequently of poor quality. Such drugs not only put patients at risk but also encourage drug resistance, thereby threatening population health for future generations. Substandard antimicrobials often contain low and erratic drug doses, while falsifed ones can be diluted. In either case, exposing pathogens to subtherapeutic doses of medicines selectively allows the growth of resistant organisms. Drug-resistant staphylococcus infections are an emerging problem, especially in India, Latin America, and sub-Saharan Africa. An- timalarial resistance threatens to undo the good that artemisinin therapies have done, threatening global malarial control programs. Medicines are expensive; patients and governments waste money on ineffective ones. Lingering illnesses decrease productivity, causing work- ers to forgo pay and spend more on treatment. Through encouraging antimicrobial resistance, illegitimate medicines reduce the effective life of a drug. Society must bear the cost of drug development, an expense that increases as drugs become more complex. Substandard and falsifed medicines undermine confdence in the health system and in all public institutions. Their sale fnances other crimes, buys weapons and ammu- nition, and conveys power to corrupt offcials. Victims of falsifed and sub- standard drugs usually do not even know they are victims and are therefore deprived of their right to redress. In many ways, the trade in illegitimate pharmaceuticals further erodes the already weak political infrastructure that allows them to circulate, part of a vicious cycle of poverty and crime. Governments and industry monitor problems with drug qual- ity, but this information is not usually public. The Pharmaceutical Security Institute, a network of the security divisions of 25 major pharmaceutical companies, has data that indicate that the illegal trade and manufacture of medicines is a global problem. It affected at least 124 countries in 2011, and the burden is disproportionately felt in the developing world. Interpol, an international organization that facilitates police cooperation, has conducted 11 opera- tions against illicit medicines since 2008. Police working in Interpol raids have confscated tons of suspect products, leading to hundreds of investiga- tions and arrests. Much of the scientifc literature about drug quality is in case studies: reports from clinicians who uncover substandard or falsifed drugs in their routine work. This kind of report provides context on how and when dif- ferent kinds of drugs are compromised; it can also trigger epidemiological investigation. Nonprobability or convenience samples are by far the most commonly used method to study drug quality. Such studies indicate serious problems with antibiotics in poor countries and antimalarial drugs in sub- Saharan Africa and Southeast Asia. The best estimate of the burden of illegitimate drugs comes from sys- tematic random samples, collected by patient actors from a representative cross section of drug sellers. More research in accordance with the recent guidelines on medicine quality assessment reporting would advance understanding and monitoring of the problem. Lack of clarity regarding the magnitude of the falsifed and substandard medicines market holds back coordinated international action. Consistent use of this system, eventually linking it to national pharmacovigilance systems, would advance international action and give a more nuanced understanding of the type of falsifed, substandard, and unregistered medicines in circula- tion and the extent of the trade. Recommendation 3-1: Governments should establish or strengthen systems to detect substandard, falsifed, and unregistered medicines. This surveillance should be integrated with established public health Copyright © National Academy of Sciences. Analysis and reporting should precisely describe the product’s quality, packing, and registration. Failure to adhere to good manu- facturing practices is the root cause of substandard drugs. Quality-control processes and verifcation add expense to manufacture, as does maintaining sterile water fltration and air handling systems. Proper quality control in- cludes dealing only with quality-assured suppliers, but small- and medium- sized manufacturers often neglect supplier quality because of logistical obstacles and cost. Multinational companies, both innovator and generic, operate on a scale that allows them to recoup the costs of running high-quality factories. Initial capital investments and infrastructure problems stand between qual- ity medicines and many small- and medium-sized medicine manufacturers.
It is of diagnostic help with psychiatric cases by itself (24 generic proscar 5mg on-line prostate examination, 49 purchase 5 mg proscar with amex mens health yahoo answers, 90 order 5mg proscar overnight delivery prostate cancer in men, 95, 121), or following an intravenous barbiturate (37, 39, 70, 113). It is widely marketed and used in combination with a barbiturate as a mild stimulant drug for patients having neuroses and neurotic character problems. These authors claim, perhaps extravagantly, that such a psychopath is powerless under the influence of methamphetamine. Once the drug takes effect, they hold, the tempo of productivity and the insurmountable urge to pour out -119- speech gives the liar no time to think. They also claim that functional aphasics can be expected to recover their speech under the influence of intravenous methamphetamine. It should be noted again that amphetamine and its derivatives are among the main drugs that have been employed in well-designed and controlled studies, showing that the effects of drugs are variable and influenced by personality differences (83, 84, 126). In reaction to the "inner push" of ideas, emotions, and speech, some normal subjects report mild euphoria, but others report tension and displeasure. The occurrence of the predominant pharmacologic effects of this drug depends to some extent on the typical personality of the subject (57). Like amphetamine, pipradrol in single, small doses improves the performance of normal subjects in tracking tests (107). It has an advantage over amphetamine in having fewer undesirable side effects, particularly on the cardiovascular system. This drug has been used in the treatment of patients with "simple depressions" (3, 44, 120). Pharmacologic effects are noticeable in mentally ill patients, but more than a transient therapeutic effect has not been established. No studies are reported on the use of this pharmacologic agent for psychotherapeutic or interview purposes. In psychiatric practice this drug has been reported to exert beneficial effects on psychotic patients receiving reserpine (a rauwolfia tranquilizer), which sometimes induces manifest depressive reactions in patients as a side effect (45). But a double-blind, placebo-controlled study has not found ritalin to be of any benefit in chronic schizophrenia (29). The utility for interrogation purposes of the analeptic properties of this drug, as compared to those of other stimulants, such as amphetamine, cannot be evaluated from existing information. Its analeptic features were first noted in chronic debilitated tuberculous patients who were -120- receiving the drug as part of an experimental chemotherapeutic regimen (35). It has been said to improve the performance of normal individuals, enabling them to work more energetically and more effectively, and to need less sleep. Iproniazid has been used in the treatment of mental depression (97) with encouraging results. Definitive well-controlled studies, however, have been reported for neither normal subjects nor mentally ill patients. Several instances of fatal toxic hepatitis have occurred when doses over 150 mg a day were given. Nevertheless, the advent of drugs of such a presumably powerful therapeutic effect in depression, owing either to psychologic conflicts or secondary to chronic somatic illness, opens up further areas of exploration of relevance to the present topic. Hallucinogenic or Psychotomimetic Drugs It has been common knowledge for centuries that many drugs may modify the behavior of man to the extent of producing psychotic behavior. The interests of psychiatrists in these phenomena have stemmed largely from the supposed resemblance of these psychoses to schizophrenia, because of the time-honored, though as yet unproven, hypotheses (11) that schizophrenia is due to a "toxin. Two psychotomimetic drugs are discussed briefly here as examples, from the viewpoint of their psychopharmacologic effects and their possible pertinence to interrogation procedures. Mescaline has also been studied as a potential diagnostic and therapeutic adjunct with psychiatric patients. Cattell (27) found mescaline to be a useful drug in investigating personality structure, -121- but of no value in the therapy of psychiatric patients. New psychodynamic material was gained from the first two groups, but relatively little from the last group. Cattell reasoned that the new material obtained in the mescaline state had been condensed and repressed in the drug-free state. Mescaline in general (63, 65, 66, 110) has been found to produce perceptual distortions and hallucinations, accentuation of affective experiences, and increased psychotic manifestations. In some patients contact and communication were increased and in others decreased. Hoch (63) noted that mescaline in "normals" produced more of an "organic reaction" with some schizophrenic features, as compared to its effect in schizophrenics and latent schizophrenics where mescaline produced more complete schizophrenic disorganization. Hoch also emphasized that mescaline produced a falling off in intellectual functioning. These articles are typical of the reports on the psychopharmacologic effects of mescaline. When interrogators extrapolate clinical psychiatric observations of this kind to the problems of interrogation, mescaline might serve their purposes in attempting to create an atmosphere of fear or terror in the informant and the illusion of magical overpowering omnipotence about himself. After such a transient state has been created, the susceptible informant might be induced subsequently to reveal information. The perceptual and cognitive disturbances produced by the drug make it unsuitable for obtaining undistorted information while the source is under its influence. From the viewpoint of the informant, the creation of a transient psychotic state by the ingestion of mescaline or lysergic acid might offer him some temporary protection against being successfully interrogated. An interrogator is not likely to consider an individual in a psychotic state a suitable candidate for providing reliable and useful information, at least until the drug effect wears off. They noted that the drug transiently increased the mental activity of their patients 30 to 60 rain after ingestion. The effect was a transitory toxic state in which repressed material came forth "sometimes with vivid realism" and emotional expression. Alterations were observed in thinking, speech, emotions, mood, sensation, time perception, ideation, and neurologic signs. The reaction was typical of an exogenous toxic state, simulating a schizophrenic reaction. The reaction was not specific and the extent to which it was dependent on the basic personality was not determined. An interesting, unexplained phenomenon was that only two out of the sixteen cases had the expected bizarre hallucinatory experiences. The conclusions reached on mescaline hold equally for the possible applications of this drug to -123- interrogation. Major Tranquilizers Recently a large number of new compounds with sedative and anxiety-relieving properties have been introduced, sufficiently different from the classical sedatives, such as paraldehyde, chloral hydrate, barbiturates and bromides, to warrant using new terms to describe them. The use of these drugs has revolutionized psychiatric therapeutic procedures, especially within the mental hospitals. A thorough review of their effects and mechanism of action in mental illness would be out of place here. Unfortunately, the usefulness of these tranquilizers in exploring psychologic processes and in facilitating communication has not been very extensively tested. Yet, for the sake of completeness, and to indicate the directions further research might take, the psychologic actions of these drugs deserve mention.
This suggestion was origi- nally made on the basis of the large concentration gradient of physiological concen- trations of phylloquinone between maternal and cord blood plasma and the inefficient maternal–fetal transfer of pharmacological doses administered as an intravenous injec- tion to the mother just before delivery (Shearer et al purchase 5 mg proscar fast delivery man health yoga. The poor placental transport of phylloquinone has been confirmed by others (Mandelbrot et al buy 5mg proscar amex prostate urination. There is now general agreement that the cord plasma concentration of phyllo- quinone is < 50 pg/mL [110 pmol/L] and that the average maternal–fetal concentration gradient is within the range 20:1 to 40:1 (Shearer proven 5mg proscar androgen hormone optimization, 1992). Few longitudinal studies have been conducted of plasma concentrations in infants who were not given vitamin K prophylaxis. In one such study, cord plasma concen- trations were compared for breast-fed and formula-fed infants and in blood on days 3, 7 and 28 after birth (Pietersma-de Bruyn et al. In entirely breast-fed infants, the blood concentration rose from undetectable (< 20 pg/mL) at birth to mean values of 0. In infants fed a milk formula containing 68 ng/mL phylloquinone, the plasma concentration rose steadily, with mean values of 1. A more detailed longitudinal comparison of plasma concentrations in breast-fed and formula-fed infants at 6, 12 and 26 weeks was made by Greer et al. Such an assessment of the intake of phylloquinone depends on both the analytical accuracy of the measurements in breast milk and validation of the milk collection and sampling technique; both have proved problematical. The results, summarized in Table 8, illustrate the extreme differences in intakes between breast-fed and formula-fed infants, which are also reflected in the plasma concentrations. The plasma concentrations in the formula-fed infants agree with those found by Pietersma- de Bruyn et al. The concentrations in entirely breast-fed infants aged one month and beyond tend, as in this study, to be at the lower end of the normal range in adults (~0. In contrast, the plasma concentrations in formula-fed infants are about 10-fold higher than the average values in adults (Pietersma-de Bruyn et al. Rapid depletion of hepatic reserves of phylloquinone was also seen in surgical patients placed on a low-phylloquinone diet (Usui et al. These results suggest that the body stores of vitamin K are replenished constantly. The route of hepatic catabolism leading to urinary excretion of vitamin K proceeds by oxidative degradation of the phytyl side-chain, probably involving the same enzymes used for ω-methyl and β-oxidation of fatty acids, steroids and prostaglandins. Two major metabolites or aglycones have been identified, which are carboxylic acids with five- and seven-carbon atom side-chains and are excreted in the urine as glucuronide conjugates (McBurney et al. The biliary metabolites have not been clearly identified but are initially excreted as water-soluble conjugates and become lipid-soluble during their passage through the gut, probably through deconjugation by the gut flora. There is no evidence that the body stores of vitamin K are conserved by enterohepatic circulation. Vitamin K itself is too lipophilic to be excreted in the bile, and the side-chain-shortened carboxylic acid metabolites are not biologically active. Its function seems to be to serve as a salvage pathway to conserve tissue reserves of vitamin K. In the course of γ-glutamyl carboxylation, vitamin K quinol is transformed into vitamin K epoxide, and the epoxide product is recycled in two steps; firstly by vitamin K epoxide reductase activity to produce vitamin K quinone and secondly by quinone reductase activity to produce the co-enzyme vitamin K quinol. Both these activities are thiol-dependent and are probably effected by the same enzyme (Suttie, 1987). An important property of the dithiol-dependent epoxide and quinone reductase is their sensitivity to certain antagonists, especially those based on 4-hydroxycoumarin (e. It is now clear that their anticoagulant action is based on their ability to inhibit epoxide reductase activity and block the recycling of the vitamin. They deduced that all the absorbed menadione was transported exclusively via the portal vein to the liver, unlike phylloquinone which is transported by the lymphatic pathway. Also unlike phylloquinone, menadione participated in rapid entero-hepatic circulation after excretion in the bile. Direct evidence for some lymphatic transport was found by experiments in dogs, showing that about 10% of the absorbed menadione was recovered in thoracic duct lymph. In studies with bile exclusion, the absorption of menadione in rats was found not to be dependent on bile, as would be expected if menadione is absorbed predomi- nantly via the portal vein. Radiolabel was initially detectable in blood, but the concentrations later declined. Small amounts of activity were sometimes detected in liver, lung and kidney, but no significant amounts were found in skin, bone or muscle (Solvonuk et al. A comparison of the tissue distribution of [14C]menadione and [14C]phylloquinone in rats after intravenous administration of a pharmacological dose (5 mg/kg bw) showed a much higher (24-fold) concentration of radiolabel in the livers of animals given phylloquinone than in those given menadione, and a fivefold greater accumulation of phylloquinone was found in the spleen. The rapid, extensive excretion of [14C]menadione in the urine was confirmed by Losito et al. They also showed that the urinary excretion of menadione (again unlike phyllo- quinone) was not dependent on an intact liver, as hepatectomized rats excreted the same amount of the dose (70%) as normal rats. A similar pattern was seen in rats given an intraperitoneal injection of about 2 μg of the water-soluble salt menadiol diphosphate; 17 h later, some 43% of the radiolabel had been excreted in urine and about 4% in faeces. The compound was not concentrated in any tissue but was distributed throughout all body organs, and the distribution was the same in vitamin K-replete and -deficient animals. This water-soluble compound underwent rapid conversion to lipid- soluble forms, and the compound and its metabolites were found generally to be asso- ciated with the membranous fractions of cells (Thierry & Suttie, 1969). After oral administration of menadione to rabbits, Richert (1951) isolated the sulfated compound 2-methyl-4-hydroxy-1-naphthyl sulfate and noted increased excretion of glucuronic acid. The chromatographic pattern in hepatectomized rats was different, but the major peak was shown to be a glucuronide conjugate, showing that animals have the capacity for extrahepatic conjugation of menadione with glucuronic acid (Losito et al. The early evi- dence that both menadione and phylloquinone could be converted in birds and rats has been reviewed (Martius, 1967). The enzymic alkylation of menadione to menaquinone- 4 was subsequently confirmed by more sophisticated techniques both in vivo in rats (Taggart & Matschiner, 1969) and in vitro in chick liver homogenates (Dialameh et al. The greatest alkylating activity was found in the microsomal fraction and was six to seven times higher in chick liver microsomes than in rat liver microsomes (Dialameh et al. Rare cutaneous reactions to another vitamin K preparation, AquaMephyton, have been reported and are suspected to be immunologically mediated (Sanders & Winkelmann, 1988). This preparation contains a polyoxyethylated fatty acid derivative as the emulsifying agent (Rich & Drage, 1982). Severe complications resulting in cardiopulmonary arrest were reported after intravenous injection of AquaMephyton (Rich & Drage, 1982). The increased erythrocyte breakdown may lead to hyperbilirubinaemia and kernicterus. These effects are clearly dose-dependent, as premature infants given 30 mg of menadiol sodium phosphate had higher serum bilirubin concentrations, more Heinz bodies, lower haemoglobin concentrations and lower erythrocyte counts than those given 1 mg. The toxic reactions are more pro- nounced and may lead to severe haemolysis in premature infants and in infants with a congenital defect of glucose 6-phosphate dehydrogenase. An explanation for the haemolytic toxicity of menadione is provided by studies showing the high reactivity of the 3-position of menadione with sulfhydryl compounds. Canady and Roe (1956) showed that when menadione is added to blood, it combines directly with blood proteins, probably by forming a thio ether at the 3-position.
These results were attributed to a favorable interaction of the enzyme with this speciﬁc copolymer (74 buy 5mg proscar otc prostate cancer metastasis sites,75) trusted 5mg proscar prostate cancer 20. Transdermal drug delivery has been approved and has become widely accepted for the systemic administration of drugs proscar 5 mg on-line prostate cancer zoladex. This noninvasive approach avoids the hepatic “ﬁrst-pass” metabolism, maintains a steady drug concentration (extremely important both in the case of drugs with a short half-life and in the case of chronic therapy), allows the use of drugs with a low therapeutic index, and improves patient compliance. For charged and polar molecules or macro- molecules, skin delivery is difﬁcult and has advanced substantially within the last few years. To facilitate the delivery of such entities, a number of strategies were developed. In recent years, specially designed carriers have claimed the ability to cross the skin intact and deliver the loaded drugs into the systemic circulation, being at the same time responsible for the percutaneous absorption of the drug within the skin. Transfersomes are composed of highly ﬂexible membranes obtained by combining into single-structure phospho- lipids (which give structure and stability to the bilayers) and an edge-active compo- nent (to increase the bilayer ﬂexibility) that gives them the capacity to move spon- taneously against water concentration gradient in the skin. It has now been proven that intact Transfersomes, in contrast to liposomes, penetrate the skin without dis- ruption (77). These carriers comprise at least phosphatidylcholine and an edge- active molecule acting as membrane softener. In structural terms, Transfersomes are related to liposomes and many of the techniques for their preparation and characterization are com- mon. For Transfersomes, a properly deﬁned composition is responsible for mem- brane ﬂexibility and consequently for vesicle deformability necessary for through- the-skin passagework. Transfersomes are much more ﬂexible and deformable than liposomes, which are assessed by using membrane penetration assays (78). Among the many drugs that can be incorporated in Transfersomes (79,80), including polypeptides and proteins (81–85), enzymes were also reported to be transferred into the body through the skin after incorporation in these systems. In vitro pen- etrability of deformable vesicles was characterized and was not affected by the incorporation of the studied enzymes (78). Successful enzyme incorporation was obtained by using other membrane-softening agents such as Tween 80, without compromising the vesicles deformability (87). This study on transdermal transport of antioxidant enzymes contributed to an innovative approach in the ﬁeld of the protein transdermal delivery (6). Ethosomes are a special kind of unusually deformable vesicles in which the abundant ethanol makes lipid bilayers very ﬂuid, and thus by inference soft (89). This reportedly improves the delivery of various molecules into deep skin layers (90). No reports on transdermal or dermal region-speciﬁc delivery of enzymes mediated by ethosomes are available to date. Other so-called “elastic vesicles” were found to be responsible for major mor- phological changes in the intercellular lipid bilayer structure in comparison with rigid vesicles (91). No results on the transdermal delivery of enzymes by using these systems were reported. This study is one of the few reporting topical application of enzymes, while using nondeformable liposomes. Although proteins in general and enzymes in particular are relatively new as therapeutic agents, it is envisaged that they will play an important role in the bat- tery of nonconventional formulations of this millennium. 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