sildenafil-citrate and Drug-Related-Side-Effects-and-Adverse-Reactions

To perform a comprehensive and systematic review regarding ophthalmic adverse drug reactions (ADRs) to systemic drugs to: (i) systematically summarize existing evidence, (ii) identify areas, ophthalmic ADRs or drugs that lacked systematization or assessment (namely drugs with original studies characterizing specific ophthalmic ADRs but without causality assessment nor without meta-analysis).. Systematic review of several electronic databases (last search 1/7/2012): Medline, SCOPUS, ISI web of knowledge, ISI Conference Proceedings, International Pharmaceutical Abstracts and Google scholar. Search query included: eye, ocular, ophthalmic, ophthalmology, adverse and reaction. Inclusion criteria were: (i) Primary purpose was to assess an ophthalmic ADR to a systemic medication; (ii) Patient evaluation performed by an ophthalmologist; (iii) Studies that specified diagnostic criteria for an ocular ADR. Different types of studies were included and analyzed separately. Two independent reviewers assessed eligibility criteria, extracted data and evaluated risk of bias.. From 562 studies found, 32 were included (1 systematic review to sildenafil, 11 narrative reviews, 1 trial, 1 prospective study, 6 transversal studies, 6 spontaneous reports and 6 case series). Drugs frequently involved included amiodarone, sildenafil, hydroxychloroquine and biphosphonates. Frequent ophthalmic ADRs included: keratopathy, dry eye and retinopathy.. To increase evidence about ophthalmic ADRs, there is a need for performing specific systematic reviews, applying strictly the World Health Organization's (WHO) definition of ADR and WHO causality assessment of ADRs. Some ophthalmic ADRs may be frequent, but require ophthalmological examination; therefore, ophthalmologists' education and protocols of collaboration between other specialties whenever they prescribe high-risk drugs are suggestions for the future.

Topics: Animals; Carbamazepine; Diphosphonates; Drug-Related Side Effects and Adverse Reactions; Eye Diseases; Humans; Piperazines; Purines; Sildenafil Citrate; Sulfones

Erectile dysfunction (ED) is an important worldwide health issue that has a significant negative impact on the quality of life and life satisfaction of both the affected individual and his partner. Here we review the prevalence of ED in Asia, associated factors that may influence sexual attitudes and sexual behaviours, and randomized clinical trials (RCTs) of phosphodiesterase-5 (PDE-5) inhibitors to evaluate the clinical efficacy and safety of PDE-5 inhibitors in Asian men. We searched for English-language articles in MEDLINE and PubMed from January 2000 to September 2010. Our results showed that the overall reported prevalence rate of ED in Asia ranged widely, from 2% to 88%. This finding indicates that ED is a common and major health problem in this region. However, sociocultural and economic factors in Asia prevent people from seeking and obtaining appropriate medical care. We found reports on five kinds of PDE-5 inhibitors for the management of ED: sildenafil, vardenafil, tadalafil, udenafil and mirodenafil. The results of RCTs showed that these five PDE-5 inhibitors are more effective than placebo in improving erectile function in Asian men with ED and that these drugs have similar efficacy and safety profiles.

Topics: Adult; Aged; Asia; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug-Related Side Effects and Adverse Reactions; Erectile Dysfunction; Humans; Imidazoles; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prevalence; Purines; Pyrimidines; Pyrimidinones; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

The aim of the present meta-analysis was to evaluate the efficacy and safety of treating pulmonary arterial hypertension (PAH) with inhaled iloprost, oral bosentan and sildenafil.. The randomized controlled trials on the 3 drugs and placebo were retrieved from the databases MEDLINE, EMBASE, BIOSIS Previews and CNKI up to August 2009. In total 11 studies and 1,391 patients were selected. Compared with placebo, iloprost, bosentan and sildenafil reduced clinical worsening significantly (odds ratio [OR] =0.33, 95% confidence interval [CI] =0.22-0.49, P<0.00001), improved New York Heart Association/World Health Organization functional class (OR =2.81, 95%CI =1.95-4.03, P<0.00001), increased the 6-min walk test by 33.19 m, reduced systolic pulmonary arterial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, increased the cardiac index by 0.40 L x min(-1) x m(-2) and increased the cardiac output by 0.53 L/min. The incidence of serious adverse events was similar in the medication groups and the placebo group (OR =1.09, 95%CI =0.69-1.71, P=0.72). In terms of the clinical worsening and functional class amelioration, insignificant differences were found among iloprost, bosentan and sildenafil, but iloprost had the highest incidence of serious adverse events among the 3 drugs.. Inhaled iloprost and oral bosentan and sildenafil are effective and safe in treating PAH.

Topics: Antihypertensive Agents; Bosentan; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil has been shown to preserve alveolar growth and lung angiogenesis in a rat model of bronchopulmonary dysplasia. We conducted a proof-of-concept randomised controlled pilot study to assess the feasibility of oral sildenafil treatment in extremely preterm infants with evolving bronchopulmonary dysplasia.. Preterm infants <28 weeks gestational age were eligible if they were mechanically ventilated on day 7 of life. Infants were randomised to a 4-weeks course of either oral sildenafil (3 mg/kg/day) or placebo solution. Pre-discharge cardiorespiratory outcomes and medication side effects were collected.. Twenty infants were randomised, 10 received sildenafil (mean gestational age 24 + 5 weeks (SD 4.9 days), mean weight 692 g (SD 98)) and 10 received placebo (mean gestational age 24 + 5 weeks (SD 6.5 days), mean weight 668 g (SD 147)). One infant in the sildenafil group did not receive treatment because of an early pneumoperitoneum. Two infants did not complete the study (transferred out). Of the remaining seven treated infants, three died (two from respiratory-related causes). One infant in the control group died from a non-respiratory cause. Sildenafil did not reduce length of invasive (median 688 versus 227 h) or non-invasive ventilation (median 1609 versus 1416 h). More infants in the sildenafil group required postnatal steroid treatment. One infant developed hypotension following sildenafil administration and was excluded after three doses.. In this pilot study, oral sildenafil treatment did not improve any short-term respiratory outcomes in extremely preterm infants.

Topics: Bronchopulmonary Dysplasia; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Feasibility Studies; Female; Gestational Age; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Male; Pilot Projects; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

To evaluate the efficacy and safety of intravenous sildenafil for immediate postoperative pulmonary hypertension (PH) in pediatric patients undergoing congenital heart surgery.. A double-blind, multicenter, placebo-controlled, dose-ranging, parallel-group trial was conducted. Patients were randomized to one of three doses of intravenous sildenafil, or placebo, for a minimum of 24 h.. The study was heavily underpowered. Whereas enrollment of 228 patients (57 per treatment arm) was required to achieve the sample size estimate to detect difference between arms, the sponsor terminated the study after 15 months owing to slow patient accrual. Seventeen patients (median age 5 months) experiencing postoperative PH were randomized and treated, five with placebo and four each with low-, medium-, and high-dose sildenafil. In the first 24 h, 40% of placebo and 17% of sildenafil patients required additional therapy (p = 0.330). Median time to extubation (3 versus 8 days, p = 0.023) and intensive care unit stay (6 versus 15 days, p = 0.008) were shorter for sildenafil patients. Mean ± standard deviation systolic pulmonary artery pressure was reduced with sildenafil (46 ± 11 to 35 ± 6 mmHg, p = 0.027 versus placebo). No adverse events or systemic hypotension were attributed to sildenafil.. Intravenous sildenafil reduced pulmonary artery pressure and shortened time to extubation and intensive care unit stay in children with postoperative PH.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infusions, Intravenous; Male; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Although contraindicated, there are situations when a patient who has recently taken a phosphodiesterase 5 inhibitor (e.g., sildenafil) might need intravenous nitroglycerin (NTG) treatment. This study determined if, and at what dose, intravenous NTG could be administered safely to men with coronary artery disease who had recently ingested sildenafil.. Double-blind, placebo-controlled, randomized, crossover trial.. Four clinical practice sites in Canada, Scotland, and the United States.. A total of 34 men (>or=35 yrs) with a history of angina pectoris and coronary artery disease (>50% stenosis of at least one coronary artery), most of whom were taking antihypertensives.. Sildenafil (100 mg) or placebo (single dose; crossover after 3-7 days) followed 45 mins later by escalating doses of intravenous NTG (160 microg/min maximum).. After sildenafil, there were slightly greater maximum (supine) blood pressure decreases and heart rate increases (e.g., 4 to 6 mm Hg [systolic] and

Topics: Aged; Aged, 80 and over; Blood Circulation; Coronary Disease; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Infusions, Intravenous; Male; Middle Aged; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), and has been shown to improve 6-minute walk distance (SMWD) and World Health Organization (WHO) functional class in patients with idiopathic pulmonary arterial hypertension (iPAH) and PAH associated with connective tissue disease or with repaired congenital systemic-to-pulmonary shunts. Despite the efficacy of sildenafil in patients on conventional therapy with diuretics and anti-coagulants, little is known of the safety and efficacy of transitioning patients already established on parenteral prostanoid therapy to sildenafil.. We studied 14 patients on long-term subcutaneous treprostinil for PAH (from a cohort of 51 patients [27%]), who wished to discontinue treatment because of injection-site pain. The etiology of their PAH included iPAH (7 of 14), PAH secondary to scleroderma (2 of 14), thromboembolic disease (3 of 14) and PAH post-surgical correction of ventricular septal defect (2 of 14). Treprostinil was gradually weaned and all patients were started open-label with 50 mg sildenafil four times per day for 3 months. New York Heart Association (NYHA) functional class, SMWD, echocardiogram and quality-of-life (QOL) measures were determined at baseline and after 3 months of therapy with sildenafil.. Of 14 patients, 4 discontinued the transition because of deterioration during treprostinil withdrawal, despite the introduction of sildenafil. Replacement of chronic subcutaneous treprostinil with sildenafil was possible in 10 of 14 patients (71%), who demonstrated stable NYHA class (mean +/- SD: 3.1 +/- 0.3 at baseline to 2.6 +/- 0.8 at 3 months, p = 0.138), stable SMWD (434 +/- 83 m at baseline, 451 +/- 72 at 3 months, p = 0.23) and significantly improved QOL measures at 3 months.. The transition from subcutaneous treprostinil to sildenafil was safely achieved in most (71%), but not all, patients with pulmonary arterial hypertension of varied etiology. These patients had an improvement in both NYHA functional class and QOL, and maintained stable walk distances over a 3-month period on sildenafil therapy.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Drug-Related Side Effects and Adverse Reactions; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Middle Aged; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adverse Drug Reaction Reporting Systems; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Phosphodiesterase 5 Inhibitors; Product Surveillance, Postmarketing; Pyrimidines; Retinal Artery Occlusion; Retinal Vein Occlusion; Sildenafil Citrate; Tadalafil; United States; United States Food and Drug Administration; Vardenafil Dihydrochloride

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.

Topics: Adolescent; Antihypertensive Agents; Bosentan; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Infant; Infant, Newborn; Male; Piperazines; Product Surveillance, Postmarketing; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; United States; United States Food and Drug Administration; Vasodilator Agents

In recent years, there has been increasing interest in the use of herbs and supplements as an alternative to drugs used for the treatment of erectile dysfunction, in order to enhance sexual performance. Over the years, adverse events associated with the consumption of natural health products for sexual enhancement and the treatment of erectile dysfunction have been reported.. The objective of this work was to assess the safety and quality of 175 sexual enhancement health products seized from makeshift stalls in red-light districts of Singapore.. Seven raids were conducted by the Health Sciences Authority, Singapore, in two red-light districts in February and March 2008. 175 sexual enhancement health products seized from makeshift stalls were extracted with methanol and screened for Western drug adulterants using high performance liquid chromatography and gas chromatography-mass spectrometry. The labels and claims of the products were also evaluated.. Of the 175 products evaluated, 134 (77%) were found to be adulterated with Western drugs or their analogues. Most of these 134 samples (123 [92%]) were found to be adulterated with sildenafil. The extent of adulteration of these illegal health products with Western drugs, including synthetic phosphodiesterase type 5 enzyme (PDE-5) inhibitors, and the risks of consuming such illegal sexual enhancement products are discussed in this study. Because of the scope of the raids, sildenafil was the most common adulterant found. In addition, some products were found to contain high contents of sildenafil (>100 mg) and high contents of the antidiabetic drug, glibenclamide (glyburide). The resultant severe hypoglycaemia has led to ten fatalities.. The presence of Western drug adulterants and their analogues in illegal sexual enhancement products seized from red-light districts in Singapore, and their often misleading labels and claims, put the health of consumers at risk. To safeguard public health, greater public awareness of the danger of consuming such illegal products and the lack of quality control of these illegal sexual enhancement health products is important.

Topics: Drug Contamination; Drug-Related Side Effects and Adverse Reactions; Erectile Dysfunction; Glyburide; Humans; Legislation, Drug; Male; Piperazines; Purines; Risk Assessment; Sildenafil Citrate; Singapore; Sulfones

Recent high-profile medicine withdrawals have highlighted the complex decision-making process that regulators, pharmaceutical companies, prescribers, and patients must undertake in determining whether a drug has an appropriate benefit-risk balance. Our objective was to analyze the utility of different drug safety data sources and methods, using the experience of sildenafil citrate (Viagra) and post-approval concerns about its potential association with cardiovascular (CV) events (i.e., myocardial infarction [MI] and death) as a case study.. We evaluated safety data from three sources: the standard passive surveillance system (i.e., spontaneous reports filed to Pfizer Inc), pooled clinical trial data, and a prospective observational cohort study, the International Men's Health Study (IMHS).. More than 28 000 spontaneous reports were received in the first 7 years after approval. Between 2001 and 2005, the proportion filed by persons other than healthcare professionals (61%) was approximately double the proportion averaged across five other drugs from the manufacturer's safety database. CV events and/or deaths represented 22.0% of reports, and 23% of reported deaths were medically unconfirmed reports made by persons other than healthcare professionals. In contrast, MI and all-cause mortality rates for sildenafil from both the pooled clinical trial data and the IMHS were similar to placebo, despite differences in methods and populations.. These results suggest that passive surveillance may generate apparent signals of risk, as was the case with sildenafil and CV events. However, to adequately assess the benefit-risk profile of a drug, these signals must be evaluated via other data sources such as clinical trial and epidemiologic studies, as the apparent signal was not supported by more rigorously collected data. Our post-marketing analysis was unable to examine all potential influences of spontaneous reports, and the study data sources (although large for erectile dysfunction studies) were not designed to exclude small CV risks.

Topics: Adverse Drug Reaction Reporting Systems; Clinical Trials as Topic; Cohort Studies; Data Interpretation, Statistical; Databases, Factual; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

Topics: Adult; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Diseases; Liver Transplantation; Male; Piperazines; Pulmonary Artery; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

To highlight the challenges of postmarketing surveillance for drug-related adverse events in the practice of ophthalmology.. A retrospective review of the medical literature and postmarketing surveillance databases.. MEDLINE literature review of sildenafil-associated or amiodarone-associated optic neuropathy and chloramphenicol-associated blood dyscrasias.. Sildenafil, amiodarone, and chloramphenicol may all cause adverse ocular events; however, the data are not conclusive.. Reports in peer-reviewed medical journals may be proven incorrect over time. For drug-induced adverse ocular events, there is little true science after the drug reaches the marketplace, so the percentage of incorrect conclusions may be high. Clinicians should be wary of reports of adverse ocular effects until data are confirmed by multiple authors over the long-term. Even so, spontaneous reports from postmarketing surveillance databases may be the first and only signal of an adverse ocular event.

Topics: Adverse Drug Reaction Reporting Systems; Amiodarone; Chloramphenicol; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Optic Nerve Diseases; Paraproteinemias; Piperazines; Product Surveillance, Postmarketing; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones

Topics: Coronary Disease; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Blindness; Carbolines; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Erectile Dysfunction; Humans; Imidazoles; Incidence; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Assessment; Risk Factors; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; United States; Vardenafil Dihydrochloride; Vasodilator Agents; Video Recording

Topics: Adult; Aged; Contraindications; Drug-Related Side Effects and Adverse Reactions; Erectile Dysfunction; Humans; Libido; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Acetates; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antitubercular Agents; Antiviral Agents; Capecitabine; Cyclopropanes; Deoxycytidine; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Etanercept; Fluorouracil; Humans; Immunoglobulin G; Isoxazoles; Leflunomide; Phosphodiesterase Inhibitors; Piperazines; Purines; Quinolines; Receptors, Tumor Necrosis Factor; Rifampin; Sildenafil Citrate; Sulfides; Sulfones; Thionucleotides