By T. Gorok. Chicago State University.

Even in Ghanaian hospital studies prednisolone 10 mg free shipping allergy grocer, where one would expect hemorrhage to be an uncommon cause of death purchase prednisolone 10 mg with mastercard allergy forecast dayton oh, it accounts for an estimated 17 to 22 percent of maternal deaths (Ganyaglo and Hill purchase prednisolone line allergy welts, 2012; Lee et al. Increasing access to emergency obstetric care is a key piece of any strategy to reduce maternal mortality (Campbell and Graham, 2006), one that lies on the assumption that lifesaving utero- tonic medicines are of reliable potency. The identifcation of falsifed and substandard medicines is more often incidental, found in newspaper accounts or uncovered in research that had a different primary aim. Medications for Chronic Diseases In 2009 a southwest China newspaper reported on a substandard version of the diabetes drug glibenclamide (also called glyburide) found to contain six times the pharmacopeial standard dose (Xiang, 2009). The medicine was tested only after killing two people and injuring nine (Cheng, 2009; Xiang, 2009). In a convenience sample of pharmacies in Lagos, Nigeria, researchers found that four of eight popular brands of metformin tablets failed one or more pharmacopeial tests of bioequivalence (Olusola et al. These are troubling fndings, given that an estimated 80 percent of the world’s 347 million diabetics live in low- and middle-income countries, where medi- cines quality is most variable, and diabetes case-fatality exorbitantly high (Unachukwu et al. Dora Akunyili, the former direc- tor of the Nigerian drug regulatory authority, worked against pharmaceu- tical fraud, a cause she committed to after her diabetic sister’s death from fake insulin (Cheng, 2009; Lemonick, 2005). Medication for other chronic diseases has been compromised in devel- oping countries. A Rwandan study on drug stability found that 20 percent of medicines in a sample of Kigali and Butare pharmacies were substandard at the time of purchase (Twagirumukiza et al. Two studies of the antihypertensive amlodipine’s quality in south Nigeria found problems: one study reported 30 percent of samples failed pharmacopeial tests for content uniformity (Eichie et al. The management of diseases such as type 2 diabetes and hypertension depend on maintenance medication and monitoring. The sheer amount of products used to treat these conditions raises the patients’ lifetime risk of encountering a bad product, even in countries with strin- gent regulatory authorities (see Box 2-1). The need for reliable medicines in low- and middle-income countries will become more pronounced as the burden of chronic disease increases in these countries. Already cardiovascu- lar disease is the main killer of adults in low- and middle-income countries, Copyright © National Academy of Sciences. OneTouch Ultra brand blood glucose moni- tors after LifeScan notifed the agency that it had received a number of customer complaints. The strips produced inaccurate blood glucose level readings, the results of which are used by diabetics to monitor their condi- tion and determine medication dosing (Bloomberg News, 2007). Diabetics rely on their blood glucose monitors to manage their self-treatment, and incorrect readings can lead patients to administer the wrong dosage of in- sulin or induce unnecessary panic. The manufacturer sold approximately one million substandard test strips to importers, and from there the strips went through the sup- ply chain to reach U. Over the course of the next year, the test strips made their way to 8 countries and 35 U. The Chinese authorities eventually arrested and imprisoned Henry Fu, owner of Halson Pharmaceuticals (Bloomberg News, 2007). The LifeScan recall is a reminder that substandard medical products can fnd their way into countries with strong regulatory systems. The United States and Canada have systems in place for prompt recalls, al- lowing them to mitigate the threat the product poses to public health. Within 2 years the fake test strips were fully recalled in the United States, but between 2009 and 2011 customers and investigators still found them in other countries, including Egypt, India, and Pakistan (Loftus, 2011). As the prevalence of diabetes increases rapidly in the developing world, new, loosely regulated markets attract potential counterfeiters. India is home to more than 50 million diabetics, more than any other country, and the number is expected to increase dramatically over the coming years (World Diabetes Foundation, 2013). In 2007, not long after the frst bad test strips appeared in the United States, there were ap- proximately 40. As the chronic disease burden in- creases in developing countries, falsifed and substandard versions of the expensive products used to treat them pose new risks. Maintenance medication for cardiovascular disease is a vulnerable target for fraud, but the need for these drugs is still unmet in much of the world (Gaziano, 2007). In developing countries, there has been a greater emphasis on controlling infectious disease, especially the infectious diseases of childhood. Considerable research indicates that the anti-infective drugs used to do this are often compromised in poor countries. A more recent survey in Egypt, Jordan, Lebanon, and Saudi Arabia found more than half of antibiotics sampled to be substandard (Kyriacos et al. A similar survey in Burma uncovered substandard drugs in 16 per- cent of amoxicillin and 13 percent of ampicillin samples (Wondemagegnehu, 1999). More recently, a survey of amoxicillin in the capital of Papua New Guinea found all samples outside of pharmacopeial specifcations; 14 per- cent had undetectable levels of active ingredient (Nair et al. In most low- and middle-income countries β-lactam antibiotics, an inexpensive and widely available class of drugs that includes penicillin and amoxicillin, are the frst-line treatment for dozens of bacterial infections, including scarlet fever, pneumonia, and respiratory and urinary tract infec- tions (Byarugaba, 2004). Alone it ac- counts for as much as 12 percent of all child deaths worldwide (O’Brien et al. This will remain the best strategy un- til the pneumococcal conjugate vaccine becomes more widely available. The treatment of pneumonia and other devastating bacterial infections depends on effective antibiotic supply. No research to date has attempted to quan- tify the proportion of child deaths attributable to falsifed and substandard medicines, but Table 2-1 presents the most common causes of child death and links them to verifed reports of substandard medicines. Chapter 5 describes the medicines supply chain in developing countries; in Copyright © National Academy of Sciences. If antibiotics are some of the oldest and most widely used medicines in the world, antiretrovirals are their opposites: new medicines, prescribed in complicated regimes, to a relatively small segment of the population. In 1995, during a meningitis epidemic, about 60,000 Nigeriens were injected with water disguised as meningitis vac- cine (Cockburn, 2005). More recently, in China, substandard hepatitis B and rabies vaccines killed or sickened about 100 babies (Jia and Carey, 2011). Precise infor- mation regarding the event is scarce due to the Chinese government’s denial of a connection between the vaccines and the incidents as well as its control over the Chinese media. According to the Associated Press, the original article in the China Economic Times that exposed the scan- dal stated that four children who died never had a precise diagnosis, but sufered from fevers and convulsions before their deaths; others who became ill were later diagnosed with encephalitis, among other conditions, and some sufered permanent damage (Associated Press, 2010a). About 200,000 doses of substandard rabies vaccine circulated in Jiangsu province in 2010 before a manufacturer recall (Associated Press, 2010b). These vaccines, like the falsifed meningitis vaccine used in Niger, convey no immunity to the patient. When herd immunity is an important result of vaccination, there is no such beneft to society. Assuming the patients survive injection with nonsterile, unidentifed liquids, they are still at risk for death from the disease they were not inoculated against. In September 2011, falsifed and substandard versions of the triple combination therapy Zidolam-N surfaced in Kenya, many samples molding and crumbling in the packages (Taylor, 2011). A year later, in Tanzania, the regulatory authority uncovered falsifed anti- retrovirals at a district hospital (Athumani, 2012).

Verapamil has a half-life in infants of 4 to 7 hours prednisolone 40 mg without prescription allergy forecast toronto, and prednisolone 40mg line allergy treatment dog dander, in adults purchase prednisolone australia allergy medicine blood thinner, of 4 to 12 hours. Use verapamil with caution in patients with severe left ventricle dysfunction, sick sinus syndrome, hepatic or renal impairment, and hyper- trophic cardiomyopathy. Verapamil administration may worsen myasthenia gravis and may decrease neuromuscular transmission in patients with Duch- enne’s muscular dystrophy. Verapamil may increase serum concentrations of digoxin, quinidine cyclosporine, and carbamazepine. Confusion, stu- por, nausea, vomiting, metabolic acidosis, and hyperglycemia may also be observed. Continu- ous infusion, initiate infusion of 10mg/h and increase by 5mg/h to 15 mg/h. When increasing the infusion dose, administer for less than 24 hours at a rate of less than 15 mg/h Conversion from I. Contraindications Severe hypotension, second- or third-degree heart block or sinus node dys- function, and acute myocardial infarction with pulmonary congestion are con- traindications for diltiazem use. Dubin Precautions/Warnings Use of diltiazem with β-blockers or digoxin can result in conduction abnor- malities. Drug-Drug Interactions Cimetidine use may increase diltiazem serum concentrations. The risk of bradycardia or heart block is increased with β-blocker or digoxin use. Diltiazem may decrease metabolism of cyclosporine, carbamazepine, digoxin, lovastatin, midazolam, and quinidine. Noncardiac symptoms include confusion, stupor, nausea, vomiting, metabolic acidosis, and hyperglycemia. Compatible Diluents/Administration The final concentration for infusion of diltiazem should be 1 mg/mL. Antiarrhythmic Medications 183 Mechanism of Action Adenosine is an endogenous purinergic agent. Contraindications Second- or third-degree heart block or sinus node dysfunction, unless a pace- maker is in place, are contraindications for adenosine use. The initial dose of adenosine should be decreased in patients receiving dipyridamole. Atropine has a half-life in children younger than 2 years of 7 hours; in children older than 2 years, of 2. Precautions/Warnings Psychosis can occur with atropine use in sensitive individuals. Drug-Drug Interactions Atropine has additive effects when administered with other anticholinergic drugs. Dubin Mechanism of Action Magnesium sulfate suppresses early after-depolarizations that can trigger tor- sade de pointes. Contraindications Heart block, serious renal impairment, and coma are contraindications for magnesium sulfate use. Precautions/Warnings Use magnesium sulfate with caution in patients with renal dysfunction and those receiving digoxin. Compatible Diluents/Administration Magnesium sulfate is incompatible when mixed with fat emulsions, calcium gluceptate, clindamycin, dobutamine, hydrocortisone, polymyxin B, procaine hydrochloride, nafcillin, tetracyclines, and thiopental. Effect of acetyla- tor phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. Mexiletine: an effective antiarrhythmic drug for treatment of ventricular arrhythmias in congenital heart disease. Control of late post- operative ventricular arrhythmias with phenytoin in young patients. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. Usefulness of propafenone for supraven- tricular arrhythmias in infants and children. Intravenous esmolol for the treatment of supraventricular tachyarrhythmia: results of a multicenter, baseline-controlled safety and efficacy study in 160 patients. Double-blind titrated-dose comparison of metoprolol and pro- pranolol in the treatment of angina pectoris. Efficacy and safety of intravenous and oral nadolol for supraventricular tachycardia in children. Intravenous amiodarone for life-threatening tachyarrhythmias in children and young adults. Amiodarone in the treatment of cardiac arrhythmias in children: one hundred thirty-five cases. Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol. Bretylium tosylate: a newly available antiarrhythmic drug for ventricular arrhythmias. Cardiac decompensation following verapamil ther- apy in infants with supraventricular tachycardia. Acute conversion of paroxysmal supraventricular tachycardia with intravenous diltiazem. The addition of these agents reduces early acute rejection events and may improve long-term graft and patient outcomes. The most controversial issue is whether corticos- teroids should be routinely added to form a “triple therapy. Finally, there is no agreement on whether intravenous anti- body induction therapy should be routinely used. A summary of the options for induction and maintenance therapy is shown in Table 8-1. It should be noted that there have been no large-scale randomized controlled tri- als of any immunosuppressive therapy in pediatric thoracic transplantation. Corticosteroids (Methylprednisolone and Prednisone) Indication Corticosteroids have broad immunosuppressive and anti-inflammatory effects. Many pediatric heart transplant centers are using steroid-avoidance regimens or early steroid withdrawal to avoid the many side effects and complications associated with long-term steroid use in children. High-dose steroids remain the standard therapy for treatment of acute rejection episodes. Mechanism of Action Corticosteroids decrease inflammation through the suppression of the migration of polymorphonuclear leukocytes and the reversal of increased 8. Corticosteroids prevent immune activation by inhibiting antigen presentation, cytokine production, and proliferation of lymphocytes. Some centers use moderate-dose oral steroids for less severe episodes of acute rejection (e.

Ocular drug delivery targeting the retina and reti- nal pigment epithelium using polylactide nanoparticles buy discount prednisolone online allergy treatment kolkata. Chitosan nanoparticles as a poten- tial drug delivery system for the ocular surface: Toxicity effective prednisolone 10mg allergy to cold, uptake mechanism and in vivo tolerance discount 5mg prednisolone mastercard allergy treatment alternative medicine. Superparamagnetic nanoparticles for biomed- ical applications: Possibilities and limitations of a new drug delivery system. Biodistribution of colloidal gold nanoparticles after intravenous administration: Effect of particle size. Nanosystems for Dermal and Transdermal Drug Delivery Venkata Vamsi Venuganti and Omathanu P. Perumal Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota, U. However, the unique bioarchitecture of skin lim- its the transport of molecules through it (1). The skin also has appendages such as hair follicles and sweat pores, which constitute 0. The hair follicles originate from the dermis and terminate at the surface of the skin. It is made up of stacks of keratin-filled corneocytes interdispersed by tightly arranged lipid bilayers (2). The intercellular lipids mainly consist of free fatty acids, ceramides, and choles- terol (2). Molecules can penetrate the skin by three main routes: (i) intracellular (across the corneocytes), (ii) intercellular lipids, and (iii) appendageal [Fig. The intercellular lipids are the major transport pathways for most drugs, in which the molecule has to pass through successive hydrophilic and hydrophobic domains in the lipid bilayers. On the other hand, the skin appendages serve as a shunt pathway for drug molecules. Since the appendages occupy only a fraction of the skin surface, they contribute very little to the drug transport. However, the appendages consti- tute a significant pathway for the iontophoretic transport of charged molecules and the penetration of particulate systems (3,4). Drugs are delivered to and through the skin for the treatment of skin diseases and systemic diseases, respectively. These include various types of formulations/ delivery systems such as powders, solutions, sprays, suspensions, emulsions, oint- ments, creams, pastes, gels, and patches. For dermatological applications, formu- lations are targeted to different layers of the skin to protect (e. In contrast, the goal in transdermal systems is to maximize drug absorption in the systemic circulation. The rate and extent of drug penetration into different layers of skin and into systemic circulation are governed by the drug properties and formulation characteristics. The concentration gradient drives the passive permeation of drug molecules through the skin, whereas the rate and extent of drug permeation are influenced by the physicochemical properties of the drug such as drug solubility in the vehicle, relative solubility of the drug in both the vehicle and the skin (partition coefficient), and molecular size, among others. Both K and Cs mainly depend on the drug property, whereas D and h mainly depend on the membrane (skin) characteristics. Different theories have been proposed to predict the transport of hydrophilic and lipophilic permeants (6). For the transport of hydrophilic molecules, the pore transport theory has been proposed by Peck et al. The pore estimates vary depending on the size of the permeant used to characterize the pores and the geometry of the measured pore (8). Chemical and physical enhancement methods are believed to increase drug permeation by increasing the effective pore radius and/or the number of pores (7,9). On the other hand, for the transport of lipophilic permeants, both porous and lipoidal pathways have been proposed (10,11). The general physicochemical properties for passive skin permeation have been widely accepted, and all the transdermal products in the market fulfill these criteria (Table 2). At the same time, the stringent requirements imposed by the skin also explains why only a handful of transdermal drugs have reached the market, in spite of intensive research over the last two decades. This has led to a number of passive and active skin per- meation enhancement strategies (13). Passive enhancement strategies include the use of chemical enhancers and prodrug approaches to improve drug partitioning and/or increase drug diffusion through the skin (13). On the other hand, active enhancement strategies use physical methods such as electric current, ultrasound, laser, or mechanical methods (12,13). All these enhancement strategies alter the drug characteristics and/or the skin barrier properties to improve skin permeation. The recent emergence of nanotechnology has opened up new opportunities to develop nanosystems for topical and transdermal applications. If not all, some of these nanosystems have been specifically developed for skin applications. The nanosystems can be classified based on the properties of the carriers as shown in Figure 2. For drug delivery applications, the nanosystems generally range in size from 1 to 1000 nm. The goal of this chapter is to provide a comprehensive overview of the formulation characteristics, mechanism of skin penetration, applications, and future prospects of nanosystems for dermal and transdermal drug delivery systems. On mixing with an aqueous medium, the phosphate groups of the phospholipids orient themselves to the hydrophilic environment spontaneously forming unilamellar or multilamellar bilayer vesicles (Fig. Cholesterol is usu- ally included to improve the stability of the vesicles, impart fluidity to the bilayer membrane, and prevent the leakage of vesicle contents (14). In addition, steary- lamine or diacetyl phosphate can be included to impart a net positive or negative charge respectively (15). Hydrophilic drugs are incorporated in the aqueous core, whereas lipophilic drugs are entrapped within the bilayer. In general, hydrophilic drugs have higher encapsulation efficiency than lipophilic drugs (14). The use of liposomes as a topical delivery carrier was first demonstrated by Mezei and Gulasekharam (17). In comparison to topical application of a simple lotion, the liposomes delivered four to five fold higher steroid concentrations in the skin layers. Since then, there has been an exponential growth in the use of liposomes as topical delivery vehicles (15). On the other hand, the use of liposomes as trans- dermal drug delivery vehicles is debatable (18). Now it is clear that the conventional liposomes have little value for transdermal drug delivery and in fact may decrease the drug penetration (18). The organic solvent is removed under reduced pressure and lyophilized to remove any traces of solvent. The thin lipid film is redispersed in aqueous medium and sonicated to give a uniform dispersion. Reverse-phase evaporation A water-in-oil emulsion is prepared by dissolving phospholipids in the organic phase.

Advice to patient • To minimize possible photosensitivity reaction generic 20mg prednisolone allergy medicine safe for high blood pressure, apply adequate sunscreen and use proper covering when exposed to strong sunlight buy cheap prednisolone on-line allergy forecast milwaukee. Adverse reactions • Common: drowsiness 40 mg prednisolone fast delivery allergy medicine dosage for babies, dizziness, ataxia, confusion, nausea, vom- iting, rash, blurred vision, nystagmus. Clinically important drug interactions • Drugs that increase effects/toxicity of carbamazepine: isoni- azid, cimetidine, diltiazem, verapamil, erythromycin, propoxy- phene, danazol. Editorial comments • Carbamazepine has not been shown to be efficacious for the treatment of myoclonic, akinetic, or absence seizures. Exacer- bation of mixed type seizures with this agent has been seen in pediatric patients. Susceptible organisms in vivo: Staphylococci, Streptococcus pneumoniae, beta-hemolytic streptococci, Escherichia coli, Proteus mirabilis, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Enterobacter sp, Pseudomonas aeruginosa. Adjustment of dosage • Kidney disease: creatinine clearance 10–20 mL/min: dosage adjustment may be necessary, exact guidelines are not avail- able; creatinine clearance <10 mL/min: therapeutic urine levels will not be achieved. Editorial comments: This was the first penicillin with activity against Pseudomonas aeruginosa. In general, carbenicillin is not used in patients with kidney disease because of the requirement for large doses, increased toxicity, and the availability of better alternatives. In combi- 2 nation with cyclophosphamide: 300 mg/m q4wk + 600 2 mg/m cyclophosphamide. Intermittent courses generally 3 repeated after neutrophil count ≥2000 mm , platelet count 3 ≥100,000 mm. Contraindications: History of hypersensitivity to mannitol, car- boplatin, or related compounds, severe bone marrow depression, acute bleeding. Warnings/precautions • Use with caution in patients with the following conditions: kidney disease, prior chemotherapy. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Adverse reactions • Common: nausea (10–18%), vomiting (65–80%), electrolyte abnormalities (see below), bone marrow depression (see below). Clinically important drug interactions: Nephrotoxic agents, eg, aminoglycosides, aluminum increase effects/toxicity of carbo- platin. Parameters to monitor • Serum electrolytes including calcium, magnesium, sodium, and potassium. Treat with peroxide, tea, topical anesthetics such as benzocaine, lidocaine, or antifungal drug. Editorial comments • It is recommended that this drug be administered only by physicians who are well versed in the use of alkylating agents of this type. Mechanism of action: Oxytocic: stimulates uterine contraction by altering calcium transport. Warnings/precautions • Use with caution in patients with the following conditions: asthma, hypotension, renal or hepatic disease, diabetes, epilepsy, cardiac or adrenal disease. Advice to patient: Use two forms of birth control including hor- monal and barrier methods. Clinically important drug interactions: Carboprost increases effects/toxicity of oxytocin and other oxytocic drugs. Mechanism of action: Blocks interneuronal activity in spinal cord, and reticular formation, causing muscle relaxation (animal data). Onset of Action Duration 30 min 4–6 h Food: Administer with food if gastric upset occurs. Contraindications: Hypersensitivity to carisoprodol, aspirin, or related compounds, eg, meprobamate; acute intermittant por- phyria, bleeding disorders. Warnings/precautions • Use with caution in patients with the following conditions: kidney or liver disease, history of drug abuse. This is characterized by weakness, quadriple- gia, visual disturbance, confusion, dysarthria. Advice to patient • This drug may cause dizziness and faintness especially at the beginning of use. Adjustment of dosage 3 3 • Leukocyte nadir 2000–3000 m , platelets 25,000–75,000 mm : reduce dose to 70% of standard; leukocytes <2000: reduce dose to 50% of standard. Contraindications: Hypersensitivity to carmustine, bone marrow depression from various causes including previous chemother- apy, previous resistance to the drug. Warnings/precautions • Use with caution in patients with the following conditions: his- tory of seizures, head trauma, potential epileptogenic drugs, renal or hepatic disease, bone marrow depression. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Adverse reactions • Common: nausea, vomiting, pain at infusion site, dizziness, ataxia, alopecia, flushing. Clinically important drug interactions: Cimetidine, etoposide increase effects/toxicity of carmustine. Editorial comments • It is essential to perform a complete hematologic evaluation every 2 weeks for patients on this drug. Clinicians should con- sult published protocols for current dosages of this and other chemotherapeutic agents as well as the method and sequence of drug administration. Mechanism of action: Competitive blocker of β-adrenergic receptors in heart and blood vessels. Adjustment of dosage • Kidney disease: creatinine clearance >60 mL/min: dose q24h; creatinine clearance >20–60 mL/min: dose q48h; creatinine clearance <20 mL/min: dose q72h. Mechanism of action: Binds to penicillin-binding proteins and disrupts or inhibits bacterial cell wall synthesis. Susceptible organisms in vivo: Comparable to cefuroxime axetil, but less active against Hemophilus influenzae and Moraxella catarrhalis. Extended-release tablets: all uses • Acute exacerbations (bacterial), chronic bronchitis, secondary bacterial infections of acute bronchitis Ð Adults: 500 mg q12h, 10 days. American Academy of Pedia- trics considers cephalosporins to be compatible with breastfee- ding. Contraindications: Hypersensitivity to other cephalosporins or related antibiotics, eg, penicillin. Warnings/precautions • Use with caution in patients with the following condition: kidney disease. For group A beta-hemolytic streptococcal infections, therapy should be continued for 10 days. Anegative response to peni- cillin does not preclude allergic reaction to a cephalosporin. Advice to patient: Allow at least 1 hour between taking this medication and a bacteriostatic antibiotic, eg, tetracycline or amphenicol. Clinically important drug interactions: Cefaclor increases effects/ toxicity of oral anticoagulants. Editorial comments: Cefuroxime is more effective than cefeclor for otitis media and pharyngitis due to improved coverage for Hemophilus influenzae and Moraxella catarrhalis. Mechanism of action: Binds to penicillin-binding proteins and disrupts or inhibits bacterial cell wall synthesis. Adjustment of dosage • Kidney disease: creatinine clearance <50 mL/min: no adjust- ment; creatinine clearance 25–50 mL/min: 12-hour intervals; creatinine clearance 10–25 mL/min: 24-hour intervals; creati- nine clearance 0–10 mL/min: 36-hour intervals.

In the third German trial effective prednisolone 5mg allergy boston, patients who relapsed after initial therapy with cisplatin and etoposide received two cycles of standard-dose cisplatin discount prednisolone 10 mg online allergy symptoms green mucus, etoposide and ifosfamide followed by carboplatin order cheap prednisolone line allergy symptoms ginger, 300–400 mg/m2 etoposide and ifosfamide. All the patients in France were treated with high-dose etoposide-containing chemotherapy including cisplatin, carboplatin and cyclophosphamide or ifosfamide, either as first-line consoli- dation therapy (patients with poor prognostic criteria) or as treatment for relapsed germ-cell tumour. All patients received either autologous bone marrow or autologous peripheral blood stem-cell support, and most patients also received granulocyte- or granulocyte–macrophage colony-stimulating factor after high-dose chemotherapy. The median cumulative dose of etoposide was 5000 mg/m2 (range, 2400–14 000 mg/m2). Six patients developed a secondary haematological malignancy (four acute myeloid leukaemias and two myelodysplastic syndromes). The two cases of myelodysplastic syndrome occurred in patients with a primary mediastinal germ-cell tumour and were excluded from the analysis. For the total group of 302 patients, the cumulative incidence of acute myeloid leukaemia was 1. Two of the malignancies were acute monoblastic leukaemia and two were acute myelomonocytic leukaemia; three were found in patients with testicular cancer as the primary tumour. Patients who did not achieve complete remission or who died of germ-cell cancer were not excluded from the analysis. A total of 541 patients were followed-up for more than two years and 331 for more than five years. None of them had a primary mediastinal germ-cell tumour, and only one patient had received radio- therapy. The median interval between the onset of treatment and the development of leukaemia was 27 months. Four of six cases were acute myelomonocytic leukaemia, one was acute myeloid and the other acute myeloblastic leukaemia. The cumulative dose of etoposide in the cases of leukaemia ranged from 720 to 5000 mg/m2. Two of 25 patients who received total doses > 2000 mg/m2 developed acute myeloid leukaemia, whereas four of 636 who received < 2000 mg/m2 developed acute myeloid leukaemia (p = 0. Four patients developed solid tumours (excluding cancer of the contra- lateral testis). Six patients with acute myeloid leukaemia were identified; however, four of them had a mediastinal germ-cell tumour. One patient aged 31 with testicular cancer had received cisplatin, etoposide (cumulative dose, 2000 mg/m2), vinblastine, bleomycin, dactinomycin and cyclophosphamide as induction plus salvage therapy. The second patient with testicular cancer, a man aged 35, had received induction therapy consisting of cisplatin, carboplatin and etoposide (cumulative dose, 1300 mg/m2). Thus, one of the 310 patients (291 treated with bleomycin, carboplastin and cisplatin) who had received only one etoposide- containing induction chemotherapy regimen subsequently developed acute myeloid leukaemia, giving a definite incidence [an approximate actuarial risk] of less than 1. Three of the five developed acute leukaemia associated with a primary mediastinal germ-cell tumour and were excluded from the study. Twelve cases of leukaemia or myelodysplastic syndrome (10 cases of acute myeloid leukaemia, one case of acute lymphoblastic leukaemia and one of myelodysplastic syndrome, were observed among 1720 patients with germ-cell tumours. On the basis of 8699 patient–years of follow-up and an annual incidence rate of 3–4 cases of acute myeloid leukaemia per 100 000 population (Parkin et al. According to Bokemeyer and Schmoll (1995), the cumulative risk for acute myeloid leukaemia was only 0. Cohort studies of other types of cancer are summarized in Table 4 and are described below. The expected number of cases of acute myeloid leukaemia in the general population can be approximated from a world standardized incidence rate of 4–5 per 100 000 persons (see text). After having achieved complete remission, the patients received maintenance treatment with epipodophyllotoxins according to seven schedules (Table 5): 580 patients received teniposide (see monograph, this volume), and a substantial proportion of these (301) also received etoposide. In addition, most patients received methotrexate, mercaptopurine, prednisone, vincristine, asparaginase and cytarabine, and some patients received cyclophosphamide, doxorubicin and cranial irradiation. Acute myeloid leukaemia developed in 21 children (as a first adverse event in 17), with an overall cumulative risk of 3. The median interval between the diagnoses of acute lymphoblastic leukaemia and acute myeloid leukaemia was 40 months. Six of the cases were acute myelomonocytic leukaemia, eight were acute monoblastic leukaemia, three were acute myeloblastic leukaemia, one was acute mega- karyoblastic leukaemia, one was acute myeloid leukaemia and two were acute undiffer- entiated leukaemia. In four patients, acute myeloid leukaemia developed after relapse had occurred, and these were not included in the statistical analyses. In the analysis of leukaemia risk, the doses of teniposide and etoposide were weighted equally, since the potency of teniposide in vitro—10 times that of etoposide—is offset in vivo by exten- sive protein binding, resulting in 10 times less unbound (active) drug (see section 4). The schedule of epipodophyllotoxin treatment appeared to be a crucial factor in deter- mining the risk for acute myeloid leukaemia, as the strongest evidence was obtained by comparing two subgroups that differed only in their schedule of epipodophyllotoxin administration. The multivariate analysis indicated that the frequency of epipodophyllotoxin administration was a much more important determinant of risk for acute myeloid leukaemia than cumulative dose. The induction and maintenance treatment consisted of prednisone, vincristine, dauno- rubicin, asparaginase, methotrexate, mercaptopurine, leucovorin, intravenous etoposide (300 mg/m2) and cytarabine. The first 33 patients received teniposide instead of eto- poside at half the dose. Ten children developed secondary acute myeloid leukaemia, two of which were of the myelomonocytic type and two of the monoblastic type; one developed myelodysplastic syndrome (consistent with chronic myelomonocytic leukaemia), and one had refractory anaemia with excess blasts in transformation. The interval between the diagnosis of acute lymphoblastic and acute myeloid leukaemia ranged from 23 to 68 months. The median dose of etoposide administered was 7900 mg/m2 (range, 5100–9900 mg/m2). One child with acute myeloid leukaemia had received teniposide instead of etoposide. The Working Group also noted that it was not completely clear in these two studies whether the diagnosis of acute lympho- blastic leukaemia excluded primary mixed leukaemia and thus allowed differentiation of lymphoblastic from myeloid disease. A total of 465 children [ages not given] with primary rhabdomyosarcoma (diagnosis around 1984) took part in this trial. The analysis was restricted to 207 children who had survived more than 36 weeks from entry into the protocol. They had received etoposide daily in combination with two courses of dactinomycin (cumulative dose of etoposide, 600 mg/m2) or three courses of cisplatin (cumulative dose of etoposide, 900 mg/m2), after they had been treated with induction regimens that included cyclophosphamide and doxorubicin. Interim analyses of the risks for acute myeloid leukaemia and myelodysplastic syndrome were carried out when four cases had been observed. Two of the four cases had received etoposide (600 mg/m2) and dactino- mycin, and two had received etoposide (900 mg/m2) and cisplatin. The three cases of acute myeloid leukaemia were of the myelomonocytic and monoblastic types and myelodysplastic syndrome progressing to acute myeloid leukaemia; the other case was myelodysplastic syndrome. The calculated cumulative six- year rate of development of acute myeloid leukaemia or myelodysplastic syndrome was 3. Twelve trials were selected from a pool of approximately 100 in which etoposide or teniposide had been used. Selection was made without knowledge of the number of secondary leukaemias that had occurred to date in the trials. The 12 trials (11 for patients with solid tumours and one for patients with acute lymphoblastic leukaemia) were divided into three strata according to the cumulative dose of eto- poside: low (< 1500 mg/m2), moderate (1500–3000 mg/m2) and high (> 3000 mg/m2).

Example structure (see also Figure 1) split into ring systems purchase prednisolone 20 mg otc allergy testing joplin mo, linkers order genuine prednisolone on-line allergy symptoms 12, and 27 side chains according to the algorithm of Lameijer et al buy generic prednisolone 10 mg line allergy forecast ynn. Again, boxed ‘B & atom type’ labels are used to indicate a connection point to a ring. This already yielded useful information, for instance which ring systems occur, and which do not, i. In total, 13,509 ring systems were found, 18,015 side chains, 9,675 linkers with two ring systems, 2,531 linkers with three ring systems, and 2,280 linkers with four or more ring systems (up till 18 ring systems). Branches with a higher number of attachment points seemed to have lower abundance. An exception to this rule was formed by linkers with six, or multiples of six, attachment points. These linkers occurred much 44 Computational Approaches more frequent than their neighbors did. The co-occurrence of fragments was also analyzed, to see whether the occurrence of one fragment in a molecule is related to the occurrence of another. This type of analysis can be compared to studying the contents of a shopping basket in a supermarket, a so-called Market Basket Analysis. Wine and olives may be frequently brought together as are beer and potato chips, where beer and olives might be rarely observed together. Market Basket Analysis is a data-mining tool for finding regularities in shopping behavior of customers of supermarkets, online shops, etc. A stochastic experiment was conducted first since for frequently occurring fragments the chance is higher that a relationship is found, even if there is none. Fragments were randomly divided over virtual molecules in the new database and each combination was counted. This process was repeated a thousand times, after which the expected occurrence of each fragment pair was calculated, together with the standard deviation of the occurrence. A significant difference between the simulated/expected and the real co- occurrence implies that the fragments are correlated. Some fragment pairs that occurred much more and much less often together than expected. This is 19 (2292/122) times more than expected, and very significantly different (z value of 206) from the simulated database. The explanation is that the combination is found in (substituted) nucleosides that have been tested for anti-tumor activity. The second row presents another example of frequently co-occurring fragments that present a single structure class, viz. A possible explanation for this effect might be that the ‘avoiding’ fragments belong to different compound classes with little overlap. Typical members from one class will be abundant in that class and scarce in others, adding to an overall reduction in co-occurrence frequency. Tetrahydrofuran-containing compounds generally differ in origin from phenyl-containing compounds. The tetrahydrofuran ring is often stemming from the ribose moiety of nucleosides, either natural or chemically modified, whereas the phenyl ring is often found in industrial chemicals. The authors suggest that the derived fragment and co-occurrence lists are useful in creating new chemistry. For instance, these listings provide insight into the most popular and therefore most commonly used side chains and ring systems for synthesis. Rarer fragments also come forward through these lists, indicating less explored parts of chemical space. Finally, by looking at the fragments that do not occur together, new chemical space can be explored. Examples of fragment pairs that are replacements of one another are chlorine and bromine, or naphthalene and 27 27 benzene. These fragment pairs rarely occur together, possibly because of their comparable physicochemical properties. A “scaffold” was defined as a molecular fragment without side chains, essentially identical to the definition of frameworks (Figure 6). A “side chain” was defined as any acyclic chain or functional group with a single connection point to the rest of the molecule. Only a minor overlap was observed: 2,945 scaffolds and 407 side chains occurred in both sets. The ratios between the number of unique scaffolds and database size, suggest that on average one scaffold is found in 2. The ten most frequent side chains accounted for almost 75% occurrences, whereas the majority occurred only once. Among the top-ten were classic substitutions as halogens, the nitro group, the hydroxy group, and organic functional groups such as the methoxy group. The rationale behind this approach was that medicinal chemists intuitively group compounds based on scaffolds and functional groups, and not so much on structural descriptors that most classification algorithms use. However, unsaturated bonds connected to a ring were considered part of the scaffold, since they change the chemical behavior of the ring system. Normally, scaffold analysis overlooks aliphatic compounds, since scaffolds are defined to consist of at least one ring. To overcome this, an extended definition of scaffold was adopted that also covered the aliphatic compounds. Double and triple bonds of acyclic compounds were treated as ring bonds, so part of the scaffold. For saturated acyclic compounds, the scaffold consisted of the heteroatoms and carbon atoms that connect them. Although the purpose of this extended definition is to extract scaffolds from all possible compound classes, some compounds from the same class may appear unrelated. For instance, amino acids that possess a cyclic side chain are separated from those with an aliphatic chain. The structural scaffold derived will be the ring system in the first case and the characteristic amino/carboxyl group core in the second case. The complexity was calculated from four structural descriptors, namely number of rings in the smallest set of smallest rings, number of heavy atoms, number of bonds, and the sum of heavy atomic numbers in the scaffold. How much a molecule resembled its class center was determined by the amount of side chains attached to the scaffold. The similarity of a drug with the class center was reflected in the membership value. The membership value was based on the sum of heavy atomic numbers, the number of rotating bonds, the number of one and two nodes, and the number of double and triple bonds in a molecule compared to its scaffold. Since the membership value indicated the contribution of rings in the class center for a certain molecule, this term was called 35 14 29 36 cyclicity.

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