Mechanisms Of Adverse Drug Reactions Research Articles

Teaching pharmacovigilance: the WHO-ISoP core elements of a comprehensive modular curriculum.

The importance of pharmacovigilance (PV) for safe medicines and their safe use has increasingly been recognised during the last few years [1]. PV has been subject of intense research and regulation. In particular, it has earned more and more importance and attention in low-resource countries. This is largely due to the globalisation of trade and the availability of new, highly effective but potentially harmful chemical medicinal products in those parts of the world where traditional treatments, in particular herbal or other complementary remedies, used to prevail. A plethora of publications, guidelines and information about newly observed or further investigated adverse drug reactions (ADRs) from all over the world creates a growing burden for people working with medicines or patients to keep abreast of this development. Largely due to the global availability of information through the Internet, patients are nowadays more and more critical and often concerned about, or even frightened of, potential ADRs of their medicines. This poses an additional demand on the up-todate capacities of their doctors and other healthcare professionals (HCPs). A particular challenge is the multidisciplinary character of PV which requires know-how in topics as different as molecular mechanisms of ADRs, clinical medicine, pharmacoepidemiology, information technology, pharmaceutical manufacturing, legal aspects, public health situations on various levels, and traditions in The views expressed in this article reflect a consensus reached between the personal views of all authors. They do not necessarily reflect the views of the authors’ employers or any institutions the authors are otherwise affiliated to.

Expert consensus for postmarketing Chinese medicine intensive hospital safety monitoring.

It is of vital significance to conduct active postmarketing surveillance of Chinese medicine, as an active response to laws, rules and guidelines issued by the China Food and Drug Administration. These will provide technological support in evaluating adverse drug reactions (ADRs) or adverse drug events (ADEs). The expert consensus for postmarketing surveillance focuses on two surveillance designs; one is a large sample registry study to explore general population ADR/ADE characteristics, the other is a nested case-control study to explore the characteristic and mechanisms of ADRs.

Predicting putative adverse drug reaction related proteins based on network topological properties

Adverse drug reactions (ADRs) are one of the main issues restraining the development and clinical applications of new drugs. Owing to complicated molecular mechanisms of ADRs, various experimental and computational methods have been employed to detect them. It has been reported that a number of ADRs are induced by a series of actions triggered by drugs or their reactive metabolites that bind to therapeutic targets or other proteins involved in drug metabolism. The identification of these ADR-related proteins (ADRRPs) is an available avenue to explore adverse reactions of drugs. In this study, the human protein–protein interaction (PPI) network was constructed as a powerful tool for studying the molecular mechanisms of ADRs. Based on such a network, five network topological properties were calculated to characterize proteins quantitatively. Then a random forest model for ADRRP prediction was built which was dependent on these properties. The prediction model yielded a satisfactory result with a sensitivity of 87.3%, a specificity of 86.1% and an overall accuracy of 86.8%. Finally, text mining was applied to verify the predictions. Some of the predicted ADRRPs have been proved to be involved in regulating ADRs by experimental studies. The results suggested that the genome-wide human interaction network provides us with an effective channel for discovering ADRRPs.

Concentration-Dependent Mechanisms of Adverse Drug Reactions in Epilepsy

Antiepileptic drugs can cause some adverse effects ranging from mild to acute and serious ones. The inducing properties of some of them may result in vitamin D, vitamin K and estrogens catabolism and thus risk of fractures or efflux transport overexpression at the blood brain barrier and consequently lack of effect at the action site. Some are responsible for the formation of reactive metabolites, such as arene oxides or atropaldehyde intermediates, in skin, liver and other organs, causing hypersensitivity reactions or can enhance a commonly minor metabolic pathway increasing the formation of toxic metabolites. Drug-induced myopia and other visual problems have also been described with the use of antiepileptic agents. A pharmacological insight of the possible concentration-dependent mechanism involved in these reactions is given in this review and in some cases some preventive measures to revert them.

Technical specifications for intensive hospital safety monitoring of post-marketing Chinese medicine(draft version for comments)

It is of vital significance to conduct active post-marketing surveillance of Chinese medicine, as an active response to laws, rules and guidelines issued by the China food and drug administration. The standards for technological specifications based on expert consensus have been drafted. These will provide technological support in evaluating adverse drug reactions (ADRs) or adverse drug events (ADEs). The technological specifications for post-marketing surveillance focus on two surveillance designs; one is a large sample registry study to explore general population ADR/ADE characteristics, the other is a nested case-control study to explore the characteristic and mechanisms of ADRs.

The cutaneous adverse drug reactions: risk factors, prognosis and economic impacts

The aim of this study was to explore the factors associated with the occurrence, subsequent prognoses and need for additional medications following cutaneous adverse drug reactions (ADRs) among inpatients. This is a case-control study, nested in a large cohort study of 473,446 inpatients hospitalised from 2005 to 2008, examined cutaneous ADRs. A 1 : 5 strategy of individually matching age and principal diagnosis was applied to the data of cases (n = 700) and corresponding controls (n = 3365).The severity of ADRs was evaluated using Naranjo algorithms by senior pharmacists in the medical centre. Medical chart reviews and claim data analyses were analysed to explore risk factors associated with the occurrence and impact of cutaneous ADRs. Economic impacts in terms of length of stay and medical expenses were also analysed. The number of drug prescriptions and secondary diagnoses, and the department to which the patient was admitted, significantly contributed to the risk of cutaneous ADRs and subsequent prognosis. In addition to physician's seniority, the Naranjo score was also positively associated with patients' prognosis. Medical expenses associated with cutaneous ADRs patients ($US 916) were more than 2.5-fold higher than those patients who were not afflicted ($US 318). The study identified risk factors for cutaneous ADRs in terms of both patient characteristics and drug complexity. The present analyses indicate characteristics and mechanisms of cutaneous ADRs among inpatients, which provide clues for future intervention strategies and management issues in healthcare settings.

Strengthening the Pharmacovigilance Programme in Nepal

The aims of pharmacovigilance are early recognition of previously unknown adverse drug reactions (ADRs), recognition of changes in frequency of known ADRs, identification of risk factors and mechanism of ADRs, quantitative analysis of benefit/risk ratio and dissemination of safety information for rational drug prescribing and regulation. The pharmacovigilance programme in Nepal is a recent development. The Department of Drug Administration (DDA) took the initiative to set up a pharmacovigilance program in 2002; however, it was initiated systematically only after two years. DDA acts as the National Pharmacovigilance Centre (NPC). It collects ADR case reports from the Regional Pharmacovigilance Centre (RPC). Currently there are six RPCs operating in the country. The current reporting trends suggest high under-reporting of suspected ADRs. This paper is a review of those studies which are focused on pharmacovigilance and healthcare professionals’ perspectives on ADR reporting in Nepal. It also recommends the possible ways to improve the ADR reporting based on the context of Nepal.DOI: http://dx.doi.org/10.3126/nje.v3i1.8286 Nepal Journal of Epidemiology 2013;3 (1): 230-235

Peptide binding specificities of HLA-B*5701 and B*5801

Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idiosyncratic, adverse drug reactions (ADRs) and human leukocyte antigen-B*5701 (HLA-B*5701). Studies also found that abacavir-induced ADRs were seldom observed in patients carrying the HLA-B*5801 subtype. HLA-B*5801 of the same serotype (B17) as B*5701 differs by only 4 amino acids from B*5701. It is believed that because of these sequence differences, HLA-B*5801 cannot bind the specific peptides which are required for HLA-B*5701 to stimulate the T cell immune response. Thus, the difference in peptide binding profiles between HLA-B*5701 and B*5801 is an important clue for exploring the mechanisms of abacavir-induced ADRs. VHSE (principal component score vector of hydrophobic, steric, and electronic properties), a set of amino acid structural descriptors, was employed to establish QSAR models of peptide-binding affinities of HLA-B*5701 and B*5801. Optimal linear SVM (support vector machine) models with high predictive capabilities were obtained for both B*5701 and B*5801. The R(2) (coefficient of determination), Q(2) (cross-validated R(2)), and R(PRE)(2) (R(2) of test set) of two optimal models were 0.7530, 0.7037, 0.6153 (B*5701) and 0.6074, 0.5966, 0.5762 (B*5801), respectively. For B*5701 and B*5801, the mutations in positions 45 (MET-THR) and 46 (ALA-GLU) have little influence on the selection specificity of the P2 position of the bound peptide. However, the mutation in position 97 (VAL-ARG) greatly influences the selection specificity of the P7 position. HLA-B*5701 prefers the bulky and positively charged amino acids at the P7 position. In contrast, HLA-B*5801 prefers the non-polar hydrophobic amino acids at the P7 position while positively charged amino acids are unfavored.

Adverse Drug Reactions in Women's Health Care

Adverse drug reactions (ADRs) are drug-related adverse events that occur in individuals using usual or therapeutic doses of medication. Women have a nearly 2-fold greater risk for developing ADRs than men, and they are more likely to be hospitalized secondary to an ADR. This article reviews the physiologic mechanisms of ADRs, common clinical manifestations of ADRs to medications often prescribed in women's health care, documentation and reporting of ADRs, and ADR prevention strategies.

Clinical Implications of Pharmacogenetic Variation on the Effects of Statins

The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80 million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5, and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1), which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its application in medicine to individualize drug therapy has been previously shown to be clinically and economically beneficial through quality-adjusted life-year assessment. Therefore, polymorphisms affecting the pharmacokinetic and pharmacodynamic profiles of statins, which are widely used in therapy, with their potential application in the personalized prescribing of statin therapy, need further research. In this review, we update the recent literature with respect to genetic polymorphisms that may influence the pharmacokinetics and pharmacodynamics of statin therapy, and consider the relevance of these findings to the efficacy of treatment, prevention of ADRs and what this may mean for patient tolerance and compliance.

Modelling the Time to Onset of Adverse Reactions with Parametric Survival Distributions

It has been postulated that the time to onset of adverse drug reactions is connected to the underlying pharmacological (or toxic) mechanism of adverse drug reactions whether the reaction is time dependent or not. We have conducted a preliminary study using the parametric modelling of the time to onset of adverse reactions as an approach to signal detection on spontaneous reporting system databases. We performed a parametric modelling of the reported time to onset of adverse drug reactions for which the underlying toxic mechanism is characterized. For the purpose of our study, we have used the reported liver injuries associated with bosentan, and the infections associated with the use of the tumour necrosis factor (TNF) inhibitors, adalimumab, etanercept and infliximab, which are used in Crohn's disease and rheumatoid arthritis, reported to EudraVigilance between December 2001 and September 2006. The main results reflect the fact that the reported time to onset is a surrogate of the true time to onset of the reaction and combines three hazards (occurrence, diagnosis and reporting) that cannot be disentangled. Consequently, the modelling of the time to onset of reactions reported with TNF inhibitors showed differences that could reflect different pharmacological activities, indications, monitoring of the patients or different reporting patterns. These variations could also limit the interpretation of the parametric modelling. Some consistency that was found between the occurrences of the infections with the TNF inhibitors suggests a causal association. There are statistical issues that are important to keep in mind when interpreting the results (the impact of the data quality on the fit of the distributions and the absence of a test of hypothesis linked to the absence of a relevant comparator). The study suggests that the modelling of the reported time to onset of adverse reactions could be a useful adjunct to other signal detection methods.

Hepatic adverse drug reactions: a case/non-case study in Italy

Adverse drug reactions (ADRs) can involve all tissues and organs. Liver injuries are considered among the most serious and are a cause for concern among physicians and patients. To assess the extent of drug-induced liver injuries in Italy we compared the number of cases of hepatic ADRs with reports of all other drug-related reactions present in the same database. Spontaneous reports from six Italian Regions collected from January 1990 to May 2005 were analysed. Adverse reactions were classified according to WHO Adverse Reaction Terminology for causality assessment, and only those with "certain", "probable" or "possible" causality assessment were included. Association between drugs and hepatic ADRs was assessed using the case/non case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. On May 2005, the database contained 35,767 ADR reports, of which 11,829 were excluded because they were unclassifiable or unlikely in terms of causality assessment. Therefore, the analysis was carried out on 23,938 reports, of which 1,069 concerned hepatic ADRs (cases) and 22,869 concerned non-cases. The proportion of serious ADRs was about 40% in the overall database, and about 74% among cases. The drug classes with the highest number of cases were statins (ROR = 2.9, 95% CI 2.4-3.5), antiplatelet agents (ROR = 3.5; 95% CI 2.6-4.6), NSAIDs (ROR = 2.9; 95% CI 2.1-3.9) and macrolides (ROR = 1.7; 95% CI 1.2-2.3). Hepatic adverse drug reactions remain a serious concern for several drugs widely used in clinical practice. Monitoring hepatic enzymes on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications known to be hepatotoxic. A better knowledge of the epidemiology and mechanisms of hepatic ADRs may contribute to minimising their occurrence.

Increased Adverse Drug Reactions to Antimicrobials and Anticonvulsants in Patients with HIV Infection

To review the incidence, signs, symptoms, and mechanisms of adverse drug reactions (ADRs) to sulfonamides, anticonvulsants, and antimycobacterial medications among people with HIV. Searches of MEDLINE/PubMed (1980-November 2005) and National Library of Medicine Meeting Abstracts (1989-November 2005), as well as hand searches of journals and abstracts, were conducted to identify primary literature. Reference lists were reviewed to identify additional relevant reports. Relevant articles and abstracts, particularly of in vitro experiments and clinical studies, were compiled and reviewed. ADRs, especially in HIV-infected patients, are a cause for concern. Sulfonamides, anticonvulsants, and antimycobacterial drugs are commonly used to prevent and treat complications of HIV, including seizures and opportunistic infections. Patients with HIV have a much greater rate of ADRs to these drug classes, including severe and life-threatening hypersensitivity reactions. Several mechanisms of these ADRs have been postulated. Sulfamethoxazole and anticonvulsant hypersensitivity may involve the increased formation and decreased detoxification of reactive metabolites. The mechanisms for the marked increase in hypersensitivity ADRs to antimycobacterial drugs may be related to an altered immune profile in patients infected with both tuberculosis and HIV. ADRs to antimicrobial and anticonvulsant therapy cause markedly increased morbidity and mortality in HIV-positive patients. Further research involving the interaction between HIV and the increased ADRs to these drugs is required.

Adverse drug reactions of antidepressants and antipsychotics: Experience, knowledge and attitudes among Norwegian psychiatrists

Efficient prevention of adverse drug reactions (ADRs) requires knowledge about their severity and pharmacological mechanisms and is dependent on reliable data on their frequencies and possible risk factors. The study was conducted to investigate the prescribers’ experience and understanding of the ADRs of psychotropic drugs, and their attitude towards reporting these. In a questionnaire, physicians treating adult psychiatric patients were asked which ADRs that they regarded bothersome for some of the most widely used antidepressants and antipsychotics. Questions about the relationship between blockade of drug receptors and ADRs, and about the physicians’ personal experience of and attitudes towards reporting of ADRs were also included. In total, 70 of 91 questionnaires (78%) were returned. The mean number of ADRs regarded bothersome ranged from 2.4 to 9.3 for the various drugs/drug classes. Qualified psychiatrists stated a significantly higher number of bothersome ADRs than did the residents. The percentage of physicians associating blockade of a receptor with a specific ADR varied from 76% (histamine receptor blockade and sedation) to 37% (α1-adrenergic blockade and tachycardia). Thirty-nine per cent of the physicians had never reported an ADR to the Norwegian Medicines Agency. The number of ADRs considered bothersome was relatively high. The pattern of these ADRs generally mirrored the typical ADR profiles of the drugs. The knowledge of the underlying mechanisms of ADRs was more or less incomplete. The reporting rate of ADRs to the national regulatory authorities was low.

Molecular mechanisms of adverse drug reactions

Background: Other than alkylating agents used in cancer chemotherapy, most drugs that cause adverse reactions require metabolism to structures that can react with constituents of our cellular environment to form products that initiate a chain of chemical and biochemical events leading to cellular damage. The mechanisms of formation of reactive metabolites that can cause cellular injury, the nature of the enzymes involved in their formation, and the structures of reactive intermediates have been characterized in some cases. Much less is known about the mechanisms of interaction of reactive metabolites with cellular molecules and how that interaction leads to tissue injury. Objective: This paper focuses on the general mechanisms involved in the formation of reactive metabolites and the drug structures commonly associated with these reactions. Methods: Both MEDLINE and TOXLINE databases were searched through the year 2000, and additional books and articles published through March 2001 were reviewed. Mechanisms for the formation of reactive metabolites from the following general substructures are described: arylacetic and arylpropionic acid nonsteroidal anti-inflammatory drugs, anilines and anilides, hydrazines and hydrazides, aromatic and heteroaromatic compounds, halogenated alkyl compounds, and fatty acid-like compounds. A few specific drugs (eg, acetaminophen, felbamate, troglitazone) and herbal products (eg, pennyroyal) are used as examples to illustrate the likely role of the metabolism of specific substructures in drug-mediated toxicities. Conclusions: Substantial toxicologic experience with some chemical substructures and research on reactive metabolite formation from these structures have provided a basis for semiempirical assessment of possible risk from these structures. The adult and pediatric populations are subject qualitatively to similar risks, but quantitatively the degree of risk may vary, depending on several factors.

In Lasting Tribute: Max Samter, MD

In Lasting Tribute: Max Samter, MD

The role of reactive drug metabolites in immune-mediated adverse drug reactions.

To highlight recent advances in the understanding of adverse drug reactions (ADRs), with a focus on models outlining interactions between drug metabolism, disease processes, and immunity. Specific mechanisms that identify the metabolic pathways responsible for drug bioactivation to reactive drug metabolites (RDMs) involved in the initiation and propagation of specific immune-mediated hypersensitivity reactions are discussed. Drug classes well known to be associated with immune-mediated ADRs are reviewed and the clinical implications of current research are discussed. Original experimental research and immunologic review articles relevant to ADR diagnosis and etiology. Results of relevant in vitro experiments and clinical reactions to drug therapy were compiled and reviewed. Critical discoveries concerning the identification of RDMs involved in ADRs were highlighted, with respect to RDM involvement in the production of an immune response to drug haptens. Drug adverse effects are classified according to clinical characteristics, immune interactions, and mechanistic similarities. Cytochrome P450 bioactivation of drug molecules to RDMs is a prerequisite to many ADRs. An electrophilic metabolite may react with cellular macromolecules (i.e., lipids, proteins, nucleic acids), resulting in direct cellular damage and organ toxicity. Covalent binding of an RDM to cellular macromolecules may also result in the formation of a hapten that is capable of eliciting a cellular or humoral immune response against drug or protein epitopes, culminating in the characteristic symptoms of hypersensitivity reactions. Mechanistic details concerning the identification of stable protein-metabolite conjugates and their interaction with the immune system remain unclear. Genetic imbalance between bioactivation and detoxification pathways, as well as reduced cellular defense against RDMs due to disease or concomitant drug therapy, act as risk factors to the onset and severity of ADRs. Adverse reactions to drug therapy cause significant morbidity and mortality. Identification of the pathways involved in drug bioactivation and detoxification may elucidate the potential of chemical agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to current xenobiotics is helpful in the prevention and management of ADRs, and may prove useful in the design of novel therapeutic agents with reduced incidence of severe adverse events.

Adverse Drug Reactions in Neonates

Adverse drug reactions (ADR) are uncommon causes of admission of neonates to the neonatal intensive care unit. The neonate, however, is potentially at significant risk for adverse drug reactions because of underdeveloped mechanisms and systems for handling drugs (the Gray Baby Syndrome with chloramphenicol as a classic example), the fact that infants in neonatal intensive care units are often critically ill with multiple organ system dysfunction, that they may be on multiple drugs, and that they may present with an adverse drug reaction as a result of exposure while still a fetus. There is also a history of misadventures in the neonatal intensive care unit and newborn nurseries due to exposure to antibacterial agents that produced systemic effects from percutaneous absorption. In this review, an overview of the mechanisms of adverse drug reactions will be presented, followed by a general review of the experience of adverse drug reactions in neonates and some specific examples of current adverse drug reactions and a suggested approach for the prevention and evaluation of adverse drug reactions in neonates.

Le dosage de l'histamine plasmatique lors de réactions anaphylactoïdes chez le sujet anesthésié: Influence des méthodes de prélèvement et de la préparation du plasma sur l'histaminémie mesurée

Plasma histamine assay in man is indicated for the diagnosis of histamine release, as well as the elucidation of the mechanisms of adverse drug reactions, and the identification of clinical situations in anaesthesia and surgery where a pathological plasma histamine level may occur. Normal and pathological plasma histamine levels vary considerably in the literature. Data from various studies, especially one involving 300 patients in Heidelberg (G.F.R.), allow us to define the normal range for human plasma histamine as 0–1.0 ng · ml −1. Values greater than 1 ng · ml −1 have to be considered as pathological. The problems related to blood collection and plasma preparation are considered here. Any judgement concerning the method described in the text must take into consideration our long experience of 15 years with it, its reliability in clinical conditions, its practicability, its relatively low cost, and finally, the absence of radioisotopes.

Textbook of Adverse Drug Reactions.

D.M. Davies: History of adverse drug reactions D.H. Lawson: Epidemiology of adverse drug reactions M.D. Rawlins & J.W. Thompson: Mechanisms of adverse drug reactions N.P. Bown & D.F. Roberts: Chromosome disorders R.E. Ferner & J.M. Smith: Disorders of the fetus and neonate J.C. Cowan, M.W. Baig & L-B. Tan: Disorders of the heart D.M. Davies: Disorders of the peripheral vascular system N.P. Keaney: Respiratory disorders J.G. Walton & R.A. Seymour: Dental disorders D.N. Bateman: Gastrointestinal disorders M. Davis & R. Williams: Hepatic disorders D.N.S. Kerr & M.J.D. Cassidy: Renal disorders V.T.F. Yeung & C.S. Cockram: Endocrine disorders I, J.C.N. Chan & C.S. Cockram: Disorders of metabolism R. Swaminathan: Disorders of metabolism H.G.M. Shetty, P.A. Routledge & D.M. Davies: Disorders of muscle, bone, and connective tissue R.H. Felix & A.G. Smith: Skin disorders P.G. Blain & R.J.M. Lane: Neurological disorders S.I. Davidson & M. Hickey-Dwyer: Eye disorders C. Diamond: Ear, nose, and throat disorders K. Davison & F. Hassanyeh: Psychiatric disorders Disorders of blood cells and haemostasis: G.H. Jackson & S.J. Proctor: Part I - Blood cells P.J. Carey & S.J. Proctor: Part II - Haemostasis D.M. Davies: Effect of drugs on infection J.S. Malpas: Neoplastic disorders Drug allergy and tests for its detection: E-S.K. Assem: Part I - Drug allergy E-S.K. Assem: Part II - Tests for detecting drug allergy J.F. Dunne: Systemic toxicity of antiseptics G. Ansell: Toxicity of opaque media used in X-ray diagnosis K.W. Woodhouse: Disorders of temperature regulation Linda Beeley: Drug-induced sexual dysfunction and infertility M.C.L'E. Orme: Drug interactions of clinical importance.