By G. Josh. Saint Olaf College.
PharmaCheck buy suhagra 100mg otc, which will weigh less than 10 pounds and ft in a shoebox cheap suhagra 100mg amex, promises to greatly reduce the need for confrmatory laboratory testing (Barlow generic suhagra 100mg amex, 2012; Gaffney, 2012). Coulter Foundation, Muhammad Zaman of Boston University has been developing a PharmaCheck, a portable drug analysis device (Barlow, 2012). The current prototype is the size of a shoebox, uses solar energy or battery power, and is designed as an “easy-to-use, robust system” for drug compa- nies, nongovernmental organizations, and government agencies, among others (Barlow, 2012; Seifert, 2012). Although originally developed for testing often copied malaria drugs, PharmaCheck will also be able to test other kinds of medications (Barlow, 2012). Zaman has said that the device should be undergoing testing in developing countries by early 2013 (Seifert, 2012). The organization recognized PharmaCheck’s potential with a $250,000 grant given to Zaman and his partners over the next 2 years to further develop the device, one of only 15 projects chosen out of the more than 500 applications (Saving Lives at Birth, 2012c; Seifert, 2012). Staub and colleagues developed a capil- lary electrophoresis system paired with time-of-fight mass spectrometry for analyzing protein-based drugs, such as insulin, without sample preparation (Staub et al. Radio wave technologies similar to those used in bomb detection are also being tailored for pharma- ceutical analysis (Sprey, 2010). The information a technique provides, as well as its reliability, cost, required expertise, speed, and portability make it more or less appropriate in any given situation. In order to conclude that a drug is of good quality, an inspector must test a sample for all of the main defciencies of substandard and falsifed drugs: fake packaging, incorrect color, shape, or markings, absent or incor- rect active ingredients, incorrect quantities of ingredients, impurities, and reduced dissolution or disintegration. Table 6-2 outlines which classes of analytical techniques can test for these problems and how well they can be used in the feld. In general, feld use describes a relatively straightforward assay or technique that depends on portable or sturdy equipment. Most feld methods can be used by professionals such as regulators, pharmacists, or health workers, but some, like mobile verifcation, are accessible to a layperson. Figure 6-9 shows how investigators in the network test samples in national drug quality surveys (Fernandez et al. The steps shown in green can be done in the feld, but samples are generally sent to a central laboratory for the steps show in brown (Fernandez et al. Fernandez and colleagues have used this system Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 275 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 276 Copyright © National Academy of Sciences. Poorly trained chemists and dilapidated infrastructure are common obstacles in performing accurate drug quality testing. Combining Techniques Although any one test may suffce to label a drug substandard or falsi- fed, no single analytical technique provides enough information to con- frm that a drug is genuine. Spectroscopic techniques are useful for identifying active ingredients but cannot rule out the presence of countless possible impurities. Chromatographic techniques may suggest that the drug contains suffcient active ingredient, but they do not provide any information about how much of that active ingredient will reach the patient. Time and budget allowing, the best understanding of drug quality comes from the several complementary experiments. Even combinations of techniques from within a class, such as spec- troscopy, can be helpful. One study illustrated how, due to differences in the ranges of their spectral regions, infrared spectroscopy may at times be better at identifying organic substances in tablet coatings, whereas Raman spectroscopy may better identify the inorganic components (Witkowski, 2005). Experiments that looked at the coating on Cialis tablets found that Copyright © National Academy of Sciences. Raman spectroscopy did not distinguish between the real coating and falsi- fed coating, but infrared spectroscopy did (Lim, 2012). For example, liquid chromatography-mass spec- trometry is a highly reliable separation technique, but does not directly provide quantitative data about the amount of active ingredient present; analysts must compare results to standards to determine content (Kaur et al. Mulligan and colleagues found that automated equilibrium headspace sampling with capillary gas chromatography provides information about volatile impuri- ties, but adding mass spec analysis provides extra qualitative information about the identity of any impurities present (Mulligan et al. When Captagon, a stimulant drug popular in the Middle East, was out- lawed, illegal manufacturers began selling the drug (Alabdalla, 2005). The copies were generally falsifed drugs containing amphetamines and caffeine meant to mimic Captagon’s therapeutic effects. The combined analysis also indicated, with reasonable certainty, which drugs were from the same batches (Alabdalla, 2005). Courts prefer them to other analytical techniques as forensic evidence (Rivier, 2003). Combining analytical techniques is a challenge both in the feld and in the laboratory. It is diffcult to determine which tests can be combined to allow inspectors to use the minimum number of different techniques. It is usually best to work through tests beginning with the easiest or least ex- pensive ones and to only move on to the more expensive or diffcult tests if the sample passes the earlier ones. For example, a drug that fails an identity test does not need to be tested for the amount of incorrect active ingredient. Using Technology in Developing Countries The question remains as to how to use analytical methods in parts of the world with limited laboratory capacity and trained chemists. Reliable reference materials to test samples against are often scarce in poor countries (Fernandez et al.
In the course of γ-glutamyl carboxylation discount 100mg suhagra with amex, vitamin K quinol is transformed into vitamin K epoxide cheap suhagra 100 mg on line, 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 suhagra 100 mg sale. 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. A later study showed that menadione reacts with both the haem groups and the β-93 thiol groups of haemoglobin and that it oxidizes the haem groups of oxyhaemoglobin, resulting in the formation of methaemoglobin (Winterbourn et al. With elucidation of the toxic properties of menadione in newborn infants and, in the 1960s, the industrial synthesis of natural K vitamins, use of menadione for vitamin K prophylaxis in the newborn was discontinued in most countries (Vest, 1966). This suggestion stemmed from their studies with menadione, which was shown to inhibit the conversion of benzo[a]pyrene to its more polar metabolites in rat liver microsomes in vitro. The inhi- bition showed a plateau (25% of control) at a concentration of 100 μmol/L [17 μg/mL]. With phylloquinone, no inhibition to polar metabolites was evident at concentrations up to 50 μmol/L [8. The weaker effect of phylloquinone at lower concentrations is perhaps due to its much greater lipophilicity and reduced penetration and solubility in microsomal membranes as compared with menadione; this explanation would also be consistent with the absence of a difference in solubility at higher concentrations of phylloquinone. In parallel studies, tumorigenesis was inhibited in mice treated with the vitamin K antagonist warfarin and in mice made vitamin K-deficient by dietary deprivation. In these experiments, the compounds were given either before or both before and after benzo[a]pyrene (Israels et al. This dose resulted in significant increases in splenic weight and decreased blood packed cell volume and haemoglobin concentration. There was no evidence that menadione caused haemaglobinaemia, suggesting that the haemo- lysis is not intravascular but is due to the destruction of damaged erythrocytes by cells of the reticuloendothelial system. This dose regime was generally well tolerated with no relevant haematological changes, although there was a signifi- cant increase in spleen weight. Many studies have been reported of the cytotoxicity of menadione in isolated and cultured cells of several types, including isolated rat hepatocytes (Mirabelli et al. The cytotoxicity of menadione has also been studied in iso- lated rat platelets (Chung et al.
Precautons Suspected cardiovascular disease (such patents should be assessed by a cardiologist before initatng therapy) 100 mg suhagra with amex, hypertension discount 100mg suhagra with mastercard, mild to moderate pre-eclampsia buy suhagra 100mg otc, hyperthyroidism, and hypokalaemia (partcular risk with potassium-depletng diuretcs). It is important to monitor pulse rate (should not exceed 140 beats per min) and the patent’s fuid and electrolyte status (avoid over- hydraton-discontnue drug immediately and initate diuretc therapy if pulmonary oedema occurs). It should also be used with cauton in diabetes-monitor blood glucose (risk of hyperglycaemia and ketoacidosis, especially with intravenous β2 agonist); pregnancy (Appendix 7c). Adverse Efects Nausea, vomitng; pulmonary oedema; palpitaton; tachycardia, arrhythmias, peripheral vasodilaton; headache, tremor, hyperglycaemia, hypokalaemia, muscle cramps and tension and hypersensitvity reactons (including angioedema, urtcaria, rash, bronchospasm, hypotension, and collapse). They also exert a cardiostmulatory efect which may be the result of a direct acton on the heart. Thyroid hormones are used in hypothyroidism (myxoedema) and also in difuse non-toxic goitre, Hashimoto thyroidits (lymphadenoid goitre) and thyroid carcinoma. Levothyroxine Sodium (thyroxine Sodium) is the treatment of choice for maintenance therapy. It is almost completely absorbed from the gastrointestnal tract but the full efects are not seen for up to 1 to 3 weeks afer beginning therapy; there is a slow response to dose change and efects may persist for several weeks afer withdrawal. Dosage of levothy- roxine in infants and children for congenital hypothyroidism and juvenile myxoedema should be ttrated according to clinical response, growth assessment and measurement of plasma thyroxine and thyroid-stmulatng hormone. Antthyroid Drugs: Antthyroid drugs such as propylthiouracil and carbimazole are used in the management of thyrotoxicosis. They are usually well- tolerated, with mild leukopenia or rashes developing in a few percent of cases, usually during the frst 6-8 weeks of therapy. During this tme the blood count should be checked every 2 weeks or if a sore throat or other signs of infecton develop. The drugs are generally given in a high dose in the frst instance untl the patent becomes euthyroid, the dose may then be gradually reduced to a maintenance dose which is contnued for 12-18 months, followed by monitoring to identfy relapse. There is a lag tme of some 2 weeks between the achievement of biochemical euthyroidism and clinical euthyroidism. Beta- adrenoceptor antagonists (beta-blockers) (usually propranolol) may be used as a short-term adjunct to antthyroid drugs to control symptoms but their use in heart failure associated with thyrotoxicosis is controversial. Treatment can be given, if neces- sary, in pregnancy but antthyroid drugs cross the placenta and in high doses may cause fetal goitre and hypothyroidism. The lowest dose that will control the hyperthyroid state should be used (requirements in Graves disease tend to fall during preg- nancy). If surgery (partal thyroidectomy) is contemplated, it may be necessary to give iodine for 10 to 14 days in additon to antthyroid drugs to assist control and reduce vascularity of the thyroid. Iodine should not be used for long-term treat- ment since its antthyroid acton tends to diminish. In patents in whom drug therapy fails to achieve long-term remissions defnitve treatment with surgery or (increasingly) radioactve iodine is preferable. Carbimazole* Pregnancy Category-D Schedule H Indicatons Thyrotoxicosis; Grave’s disease. Contraindicatons Nodular goitre; subacute thyroidits, postpartum painless thyroidits. Adverse Efects Nausea, mild gastro-intestnal disturbances; headache; rashes and pruritus, arthralgia; rarely, myopathy, alopecia, bone marrow suppression (including pancytopenia and agranulocytosis); vasculits; cholestatc jaundice, hepatc necrosis. Storage Store protected from light and moisture at a temperature not exceeding 30⁰C. Contraindicatons Lactaton (Appendix 7b), tuberculosis, bron- chits, asthma, hyperkalaemia, acne vulgaris. Adverse Efects Hypersensitvity reactons including coryza- like symptoms; headache; lacrimaton; conjunctvits, pain in salivary glands; laryngits, bronchits, rashes; on prolonged treatment depression, insomnia, impotence; goitre in infants of mothers taking iodides; eosinophilia, hypothyroidism, abdominal pain, arrhythmia. Storage Store in ground glass stoppered container or earthenware container with waxed bungs. Dose Oral Adult- Hypothyroidism: Initally 50 to 100 µg daily (25 to 50 µg for those over 50 years) before breakfast, increased by 25 to 50 µg every 3 to 4 weeks untl normal metabolism maintained (usual maintenance dose, 100 to 200 µg daily); where there is cardiac disease, initally 25 µg daily or 50 µg on alternate days, adjusted in steps of 25 µg every 4 weeks. Child- Congenital hypothyroidism and juvenile myxoedema; Up to 1 month: initally 5 to 10 µg/kg daily. Over 1 month: initally 5 µg/kg daily, adjusted in steps of 25 µg every 2 to 4 weeks, untl mild toxic symptoms appear, then reduce dose slightly. Immunologicals Actve Immunity: Actve immunity may be induced by the administraton of micro-organisms or their products which act as antgens to induce antbodies to confer a protectve immune response in the host. Vaccinaton may consist of (a) a live atenuated form of a virus or bacteria, (b) inactvated preparatons of the virus or bacteria, or (c) extracts of or detoxifed exotoxins. Live atenuated vaccines usually confer immunity with a single dose which is of long duraton. Inactvated vaccines may require a series of injectons in the frst instance to produce an adequate antbody response and in most cases, require reinforcing (booster) doses. Extracts of or detoxifed exotoxins require a primary series of injectons followed by reinforcing doses. Passive Immunity: Passive immunity is conferred by injectng preparatons made from the plasma of immune individuals with adequate levels of antbody to the disease for which protecton is sought. This immunity lasts only a few weeks but passive immunizaton can be repeated where necessary. Sera and Immunoglobulins Antbodies of human origin are usually termed immunoglob- ulins. Because of serum sickness and other allergic-type reactons that may follow injectons of antsera, this therapy has been replaced wherever possible by the use of immunoglobulins. Contraindicatons and Precautons Anaphylaxis, although rare, can occur and epinephrine (adrenaline) must always be immediately available during immunizaton. Immunoglobulins may interfere with the immune response to live virus vaccines which should normally be given either at least 3 weeks before or at least 3 months afer the administra- ton of the immunoglobulin. Intravenous injecton; Systemic reactons including fever, chills, facial fushing, headache and nausea may occur, partc- ularly following high rates of infusion.
Valacyclovir cheap suhagra 100 mg without a prescription, a prodrug of Acyclovir 100mg suhagra, can be given by mouth as an alternatve treatment for herpes simplex infectons of the skin and mucous membranes (including inital and recurrent genital herpes) suhagra 100 mg overnight delivery. Mainte- nance therapy with oral ganciclovir should be given to prevent relapse of retnits. Genital herpes simplex treatment; 200 mg 5 tmes daily for 5 days or 400 mg three tmes daily for three days. Herpes simplex preventon of recurrence; 200 mg 4 tmes daily or 400 mg twice daily reduced to 200 mg two or three tmes daily interrupted every 6 to 12 months. Intravenous infusion Severe inital genital herpes, Varicella zoster, Herpes simplex infecton; 5 mg/kg body weight every 8 h for fve days. Precautons Maintain adequate hydraton; renal impairment (Appendix 7d); lactaton (Appendix 7b); pregnancy (Appendix 7c); paediatrics. For infusion: Store protected from moisture in a sterile tamper evident container sealed so as to exclude micro-organisms at a temperature not exceeding 30⁰C. Antmigraine Drugs Chronic recurrent headache is associated with many disor- ders, both somatc and psychogenic. An accurate diagnosis must consequently be made before appropriate treatment can be initated for migraine. Untreated migraine atacks last for several hours and sometmes for as long as 3 days. Migraine headache is frequently accompanied by episodes of gastrointestnal disturbance including nausea and vomitng. The headache may be preceded or accompanied by aura (clas- sical migraine) which is characterised by visual disturbances such as fickering lines and fragmented vision or sensory disturbances such as tngling or numbness; rarely, hemiparesis or impaired consciousness may occur. Migraine without aura (common migraine) is the more common form occurring in about 75% of patents who experience migraine. Emotonal or physical stress, lack of or excess sleep, missed meals, menstruaton, alcohol and specifc foods including cheese and chocolate are ofen identfed as precipitatng factors; oral contraceptves may increase the frequency of atacks. Avoidance of such precipitatng factors can be of great beneft in preventng or reducing the frequency of atacks and should be addressed in detail. Women taking combined oral contraceptves who experience an onset or increase in frequency of headaches should be advised of other contra- ceptve measures. The two principal strategies of migraine management are treatment of acute atacks and prophylactc treatment. Prophylaxis can reduce the severity and frequency of atacks but does not eliminate them completely; additonal symptomatc treatment is stll needed. However, long-term prophylaxis is undesirable and treatment should be reviewed at 6-monthly intervals. Of the many drugs that have been advocated beta-adrenoceptor antagonists (beta- blockers) are most frequently used. Propranolol, a non-selec- tve beta-blocker and other related compounds with similar profle such as atenolol are generally preferred. The poten- tal for beta-blockers to interact with ergotamine should be borne in mind. Tricyclic antdepressants, such as amitriptyline or calcium-channel blocking drugs such as funarizine or verapamil may be of value. Adverse Efects Drowsiness; weight gain; depression; gastric pain, dry mouth; insomnia; extrapyramidal side efects. Precautons First-degree atrioventricular block; renal impairment; liver disease; pregnancy (Appendix 7c); lactaton (Appendix 7b); portal hypertension; diabetes mellitus; myasthenia gravis; history of hypersensitvity (increased reacton to allergens, also reduced response to epinephrine (adrenaline); interactons (Appendix 6a, 6b, 6d). Adverse Efects Bradycardia, heart failure, hypotension, conducton disorders, bronchospasm, peripheral vasoconstricton, exacerbaton of intermitent claudicaton and Raynaud phenomenon; gastrointestnal disturbances, fatgue, sleep disturbances including nightmares; rarely; rash, dry eyes (reversible); exacerbaton of psoriasis. Treatment is generally by mouth; some drugs are available as suppositories which may be administered if the oral route is not efectve (poor oral bioa- vailability, or absorpton from the gut impaired by vomitng) or not practcable (patent unable to take drugs orally). Peristalsis is ofen reduced during migraine atacks and, if available, a dispersible or efervescent preparaton of the drug is preferred because of enhanced absorpton compared with a conventonal tablet. The risk of Reye syndrome due to acetylsalicylic acid in chil- dren can be avoided by giving paracetamol instead. Frequent and prolonged use of analgesics by migraine suferers may lead to analgesic-induced headache. Ergotamine should be considered only when atacks are unresponsive to non-opioid analgesics. Rectal suppositories may ofer an advantage when other routes of administraton are unsatsfactory. To be fully efectve ergotamine must be taken in adequate amounts as early as possible during each atack. Adverse efects limit how much ergotamine can be used in a single atack and consequently the recommended dosage should never be exceeded and at least four days should elapse between successive treatments. Even normal dosage can lead to dependence, tolerance to adverse efects and to a with- drawal syndrome on discontnuing the drug. To avoid depend- ence the frequency of administraton should be limited to no more than twice a month. Adverse efects include nausea, vomitng, diarrhoea and vertgo; chronic ergotsm is charac- terized by severe peripheral vasoconstricton which can lead to gangrene in the extremites. The severity of adverse efects prevents the use of ergotamine for migraine prophylaxis. Products which contain barbiturates or codeine are undesir- able, partcularly in combinaton with ergotamine, since they may cause physical dependence and withdrawal headaches. Intravenous infusion Terminaton of an acute atack of cluster headache, migraine: Adult- 0. Contraindicatons Peripheral vascular disease, coronary heart disease, obliteratve vascular disease and Raynaud’s syndrome, temporal arterits; hepatc impairment, renal impairment, sepsis; severe or inadequately controlled hypertension, hyperthyroidism, pregnancy (Appendix 7c); lactaton; porphyria, ischaemic heart disease; angina pectoris.