Pharmacogenetics of psoriasis

Psoriasis is an inflammatory hyperproliferative skin disorder with a strong genetic predisposition. While many effective modalities are currently available for treating psoriasis, response to therapy is quite variable among patients. The genetic component underlying the response to pharmacotherapy in psoriasis is slowly beginning to emerge and represents a specialized field of genetics referred to as pharmacogenetics. The identification of genetic variants has the potential to improve the management of patient care by identifying which patients should avoid a specific drug and which patients should be administered a modified dose. A suitable approach in implementing such a strategy could potentially reduce medical costs and improve success of drug therapy. This article summarizes the clinical aspects of psoriasis, its genetic susceptibility and highlights the current landscape of genetic targets for psoriasis pharmacotherapy.     

Pharmacotherapy for post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a serious mental illness of considerable importance from a public health perspective. Management of PTSD may involve the use of various treatment modalities, involving both nondrug treatments and pharmacotherapy. Nondrug treatment is regarded as the first-line option for PTSD and should be routinely incorporated into management plans for patients with PTSD. However, some patients do not achieve a sufficient response to nondrug therapy or are left with disabling residual symptoms in one or more areas. Antidepressants are currently the preferred medication for PTSD, with the most substantial evidence available to support the use of the selective serotonin reuptake inhibitors. Many patients with PTSD have symptoms that are resistant to initial drug treatment, meaning that it is often necessary to explore additional pharmacotherapy options to achieve optimal symptom control: antipsychotics, anti-adrenergic drugs, anxiolytics and anticonvulsants have all been advocated as treatments for PTSD. In addition to the management of core PTSD symptoms, it is also necessary for clinicians to address important associated comorbidities, most notably, substance-use disorders and mood disturbances. Interpretation of research studies of the efficacy and safety of PTSD pharmacotherapy is often difficult owing to methodological limitations and factors such as inclusion bias. Further research in fundamental neurosciences and pharmacogenomics may help to elucidate optimal pharmacotherapy options for PTSD in the future.     

Treating inflammatory bowel disease during pregnancy: risks and safety of drug therapy.

The safety of drug therapy for inflammatory bowel disease during pregnancy is an important clinical concern. Current available information is largely derived from animal studies and clinical experience among patients with inflammatory bowel disease and autoimmune disorders and organ transplant recipients. However, these data are confounded by various factors including difficulty projecting the results of animal studies to humans, methodological deficiencies of some studies, insufficient experience with certain agents, difficulty distinguishing the fetal effects of underlying disease from drug therapy and a need to consider the impact of background rates of adverse fetal outcomes which apply to all pregnancies. In inflammatory bowel disease, the effects of active inflammation on the fetus are believed to be more harmful than those of drug treatment, and therapy is often justified to induce or maintain remission during pregnancy. The choice of appropriate treatment is determined by the severity of the disease and the potential for drug toxicity. No causal relationship has been established between exposure to sulfasalazine or other 5-aminosalicylic acid drugs and the development of congenital malformations. These drugs may be used with relative safety during pregnancy and lactation. Considerable experience with corticosteroids have shown them to pose very small risk to the developing fetus. Current evidence indicates that maternal use of azathioprine is not associated with an increased risk of congenital malformations, though impaired fetal immunity, growth retardation or prematurity is occasionally observed. Preliminary evidence derived from patients with inflammatory bowel disease show no significant fetal toxicity following first trimester exposure to mercaptopurine, though its elective use in pregnancy is controversial. Cyclosporin is not teratogenic, but may be associated with growth retardation and prematurity. Pregnancy should be avoided in women treated with methotrexate because of its known abortifacient effects and risk of causing typical malformations. Although treatment with metronidazole or ciprofloxacin for short durations appear to be devoid of adverse fetal reactions, the effect of prolonged exposure as required in Crohn's disease remains unknown.     

Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug–drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.     

Effects of antihypertensive drugs on the unborn child: what is known, and how should this influence prescribing?

This review discusses the use of antihypertensive drugs in acute and long term treatment of hypertensive disorders of pregnancy, including their placental transfer and adverse effects on the fetus. All antihypertensive agents cross the placental barrier and are present in varying concentrations in the fetal circulation, with varying resultant effects on fetal metabolism. Antihypertensive drugs that are lipid soluble will pass through the placental barrier with ease whereas the most polar will not. Placental transfer diminishes under conditions that decrease the surface area or increase the thickness of the placenta. Highly protein-bound drugs form complexes which impair placental transfer while unbound drugs cross the placenta easily. The ionised drug form is highly charged and cannot cross lipid membranes while the un-ionised form can easily cross the placenta. A decrease in placental blood flow can slow down the transfer of lipid soluble drugs to the fetus. Close monitoring of the fetal and maternal condition is necessary for the rest of the pregnancy after antihypertensive therapy is commenced. Methyldopa is the initial drug of choice for long term oral antihypertensive therapy in pregnancy. Neither short term nor long term use of methyldopa is associated with adverse effects. In the short term (<6 weeks) beta-receptor antagonists are effective and well tolerated provided there are no signs of intrauterine growth impairment. ACE (angiotensin converting enzyme) inhibitors are contraindicated in the second and third trimesters of pregnancy because they are teratogenic. Intravenous dihydralazine is widely used for rapid reductions of severely elevated blood pressure. The use of nifedipine concurrently with MgSO4 must be approached with caution because the combination is associated with severe hypotension, neuromuscular blockade and cardiac depression. In the last decade, knowledge of antihypertensive drugs used in pregnancy has improved and new drugs, e.g. calcium antagonists, which have been shown to have great potential for use in pregnancy, have been introduced. Safety for the fetus with newer drugs has not yet been adequately evaluated. Currently, well established and cost effective drugs such as methyldopa (long term use) and intravenous dihydralazine (rapid reduction) are the agents of choice to treat hypertensive disorders of pregnancy.     

Lamotrigine use in pregnancy

Lamotrigine is a sodium-channel-modulating, antiepileptic drug (AED), which was approved in the USA in 1994 for use in partial-onset seizures. It was ultimately approved for monotherapy in 1998. Lamotrigine has gained widespread use in the USA as both an immediate and an extended-release agent. Lamotrigine is effective against a broad spectrum of seizure types and has a favorable metabolic profile, with few but significant drug interactions. Pregnancy registries in several countries have demonstrated that AED use in women with epilepsy is associated with an increased risk of fetal malformations, if the infant is exposed during the period of organogenesis. In addition, new evidence demonstrates that AEDs may affect the intellectual development of a child, as measured up until the age of 3 years. This information has made the choice of an anticonvulsant for a woman who might become pregnant significantly more important. Pregnancy registries have consistently demonstrated lamotrigine to be among the safest medications for a developing fetus, both in terms of fetal malformations and postpartum cognitive development. These findings make lamotrigine probably the first choice of AED for women wishing to become pregnant and for whom the medication is appropriate.     

Lamotrigine use in pregnancy

Lamotrigine is a sodium-channel-modulating, antiepileptic drug (AED), which was approved in the USA in 1994 for use in partial-onset seizures. It was ultimately approved for monotherapy in 1998. Lamotrigine has gained widespread use in the USA as both an immediate and an extended-release agent. Lamotrigine is effective against a broad spectrum of seizure types and has a favorable metabolic profile, with few but significant drug interactions. Pregnancy registries in several countries have demonstrated that AED use in women with epilepsy is associated with an increased risk of fetal malformations, if the infant is exposed during the period of organogenesis. In addition, new evidence demonstrates that AEDs may affect the intellectual development of a child, as measured up until the age of 3 years. This information has made the choice of an anticonvulsant for a woman who might become pregnant significantly more important. Pregnancy registries have consistently demonstrated lamotrigine to be among the safest medications for a developing fetus, both in terms of fetal malformations and postpartum cognitive development. These findings make lamotrigine probably the first choice of AED for women wishing to become pregnant and for whom the medication is appropriate.     

Placental drug transporters

Any treatment of a pregnant woman with medication (drugs) de facto results in the treatment of her unborn child, even when her unborn child is not the target of drug therapy. This is because, in most instances, the placenta is not a complete barrier to the passage of drugs from the maternal to the fetal compartment. This barrier is in part due to the presence of various efflux transporters in the placenta. The placenta is also richly endowed with influx transporters. In this article, we will review the physiological characteristics of the placenta and how it functions as a barrier to passage of drugs into the fetal compartment. In addition, we will review placental transporters that are important in modulating the exposure of the fetus to drugs and, therefore, the efficacy and toxicity of such drugs towards the fetus.     

Pregnancy exposure registries.

Scientifically valid data on the safety of drug use during pregnancy are a significant public health need. Data are rarely available on the fetal effects of in utero exposure in human pregnancies, particularly when a drug is first marketed. Data from animal reproductive toxicology studies, which function as a screen for potential human teratogenicity, are usually all that is available in a product's labelling. For practising clinicians, translating known animal risks into an accurate assessment of teratogenic risks in their patients is very difficult, if not impossible. Without human data on the effects of in utero drug exposure, it is difficult for physicians and other healthcare providers (e.g. genetic counsellors) to adequately counsel patients about fetal risks. Therefore, a pregnant woman may decide to unnecessarily terminate a wanted pregnancy or forego needed drug therapy. In spite of the lack of data on the safety of drug use during human pregnancies, pregnant women are exposed to drugs either as prescribed therapy or inadvertently before pregnancy is known (over one-half of pregnancies are unplanned). Because little is known about the teratogenic potential of a drug in humans before marketing, post-marketing surveillance of drug use in pregnancy is critical to the detection of drug-induced fetal effects. The existing passive mechanism of spontaneous reporting of adverse drug effects is inadequate to routinely detect drug-induced fetal risks or lack of such risks. Therefore, post-marketing pregnancy exposure registries are being increasingly used to proactively monitor for major fetal effects and to describe margins of safety associated with drug exposure during pregnancy. However, differing methodological rigour has been applied to the development of pregnancy exposure registries. It is important that all pregnancy registries develop epidemiologically sound written study protocols a priori. It is only through the use of rigorous methodology and procedures that data from pregnancy exposure registries will withstand scientific scrutiny. Successful recruitment of an adequate number of exposed pregnancies, aggressive follow-up, and complete and accurate ascertainment of pregnancy outcome are critical attributes of a well-designed registry.     

Drug use in pregnancy: how to avoid problems

The Obstetric Drug Information Service at the Queen Victoria Medical Center in Melbourne, Australia aims to provide relevant information relating to drug use in pregnancy. A preliminary study conducted by the Center revealed that 62.5% of pregnant women consumed drugs during their pregnancies (excluding iron and vitamins), with an average of 3 drugs per woman. Certain drugs are relatively safer than others, and the selection of the appropriate drug for a pregnant patient is very important to the future health and well-being of the child. At least 5% of all birth defects are drug induced. The drugs that produce fetal abnormalities are called "dysmorphogens" or "teratogens". General principles of drug use in pregnancy are outlined. These include the following: 1) no drug should be considered 100% safe to the developing fetus, including topical preparations; 2) a true indication must be present for the administration of any drug; 3) the potential benefits should always be weighed against the possible hazards of that drug to the mother and the fetus; and 4) the effect of a drug on the fetus may not necessarily be the same as the intended pharmacological effect on the mother. The following specific drug induced embryopathies are reviewed: fetal alcohol syndrome; Warfarin syndrome; fetal hydantoin syndrome; stilbestrol (diethylstilbestrol, DES) syndrome, VACTERL syndrome, and thalidomide embryopathy. Drugs which are safe for use in pregnancy are analgesics, hypnosedatives, antibiotics, antiemetics and antihistamines, psychotherapeutic drugs, antihypertensive drugs, antituberculous drugs, antimalarial drugs, antithyroid drugs, and antidiabetic drugs.     

The Placental Barrier: the Gate and the Fate in Drug Distribution

Optimal development of the embryo and the fetus depends on placental passage of gases, nutrients, hormones, and waste products. These molecules are transferred across the placenta via passive diffusion, carrier-mediated cellular uptake and efflux, and transcytosis pathways. The same mechanisms additionally control the rate and extent of transplacental transfer of drugs taken by the pregnant mother. Essentially all drugs cross the placenta to a certain extent, and some accumulate in the placenta itself at levels that can even exceed those in maternal plasma. Hence, even drugs that are not efficiently transferred across the placenta may indirectly affect fetal development by interfering with placental function. In this article, we describe key properties of the placental barrier and their modulation by medications. We highlight implications for pharmacotherapy and novel approaches for drug delivery in pregnant women and their fetuses.

     

Treatment of recurrent depression: a sequential psychotherapeutic and psychopharmacological approach

The chronic and recurrent nature of major depressive disorder is receiving increasing attention. Approximately eight of ten people experiencing a major depressive episode will have at least one more episode during their lifetime, i.e. recurrent major depressive disorder. In the 1990s, prolonged or lifelong pharmacotherapy emerged as the main therapeutic tool for preventing relapses of depression. This therapeutic approach is based on the effectiveness of antidepressant drugs compared with placebo in decreasing relapse risk and on the improved tolerability profile of the newer antidepressants compared with their older counterparts. However, outcome after discontinuation of antidepressant therapy does not seem to be affected by the duration of administration. Loss of clinical effects, despite adequate compliance, has also emerged as a vexing clinical problem. The use of intermittent pharmacotherapy with follow-up visits is an alternative therapeutic option. This leaves patients with periods free of drugs and adverse effects and takes into account that a high proportion of patients would discontinue the antidepressant anyway. However, the problems of resistance (that a drug treatment may be associated with a diminished chance of response in subsequent treatments in those patients whose symptoms successfully responded to it but who discontinued it) and of discontinuation syndromes are substantial disadvantages of this therapeutic approach. In recent years, several controlled trials have suggested that sequential use of pharmacotherapy in the treatment of the acute depressive episode and psychotherapy in its residual phase may improve long-term outcome. Patients, however, need to be motivated for psychotherapy, and skilled therapists have to be available. Despite an impressive amount of research into the treatment of depression, there is still a paucity of studies addressing the specific problems that prevention of recurrent depression entails. It is important to discuss with the patient the various therapeutic options and to adapt strategies to the specific needs of patients.     

药物滥用流行病学调查研究进展

本项“药物滥用流行病学调查”研究分为以下三个方面:(1)甘肃、贵州、湖南、辽宁、浙江五省药物滥用流行病学调查。目的是了解甘肃等五省药物滥用流行水平并探索在我国开展社区药物滥用流行病学调查的方法。2004年6月-2005年7月共在甘肃等五省调查了30个区县,34个城镇社区和85个行政/自然村,15-50 a有效调查人口161 888人。(2)药物滥用快速评估调查方法学研究。采用Delph i方法,在禁毒和药物滥用防治专家以及药物滥用人群中进行调查评估。这项工作目前在北京完成了预调查,进一步的调查正在实施之中。(3)阿片依赖复吸的流行病学调查。此研究包括纳曲酮预防复吸的回顾性调查和海洛因成瘾者复吸情况调查两个方面。纳曲酮预防复吸的回顾性调查表明,该药预防复吸效果明确,作为一个复吸预防维持用药,具有在社区、家庭中应用的明显优势。但纳曲酮也有局限性。     

他汀类药物的安全性风险评价

他汀类药物是最广泛的可用药物治疗降低胆固醇水平,并控制其发展的处方药。所有的他汀类药物,如阿托伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀和辛伐他汀可用于心血管疾病事件的预防。众所周知,在治疗过程中一些服用他汀类药物的患者出现不良反应,如肝损害、癌症的风险和骨骼肌损害。因此,认识他汀类药物的安全性风险是很重要的。根据发表的他汀类药物的临床研究文献数据,分析和认识这类药物的安全性、不良反应及毒性的风险,并简要介绍了由美国心脏协会和美国心脏病学院基于4年评述而制定的2013年他汀类降胆固醇药物新使用指南。     

Rare platelet GPCR variants: what can we learn?

Platelet-expressed GPCRs are critical regulators of platelet function. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis associated with coronary atherosclerosis and ischaemic stroke. However, anti-thrombotic drug therapy is associated with high inter-patient variability in therapeutic response and adverse bleeding side effects. In order to optimize the use of existing anti-platelet drugs and to develop new therapies, more detailed knowledge is required relating to the molecular mechanisms that regulate GPCR and therefore platelet function. One approach has been to identify rare, function-disrupting mutations within key platelet proteins in patients with bleeding disorders. In this review, we describe how an integrated functional genomics strategy has contributed important structure-function information about platelet GPCRs with specific emphasis upon purinergic and thromboxane A₂ receptors. We also discuss the potential implications these findings have for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders.     

Treatment issues for opioid-dependent women during the perinatal period.

Opioid dependence has been studied with regard to its effects on the woman, the fetus, and the child for the past three decades, and it continues to be a serious problem that must be recognized and addressed by the health care delivery system in order to provide optimal medical care. The use of pharmacotherapy, such as methadone maintenance treatment (MMT), is only one of a variety of treatment modalities to provide optimal services for opioid-dependent women. The complete schema for treating opioid dependence in the perinatal period is complex and intense, but MMT serves multiple purposes. Primarily, it removes the addicted woman from the drug-seeking environment, eliminates the necessary illicit behavior, and prevents the peaks and valleys in the maternal heroin level that may occur throughout the day. In addition, maternal nutrition is usually improved and MMT patients become amenable to prenatal care and psychosocial rehabilitation. It is evident from the findings of numerous studies that when the physical, psychological, and socioeconomic issues of pregnant opioid-dependent women and their children are coupled with MMT, the potential physical and behavioral effects of psychoactive drugs on the mother, the fetus, the newborn, and the child may be markedly reduced.     

Synthetic glucocorticoids: antenatal administration and long-term implications

A clear relationship between intrauterine development and later life predisposition to long-term disease is well established. Weight at birth provides a surrogate measure for fetal development and low birth weight predicts changes in most endocrine axes in adulthood. The exposure of the fetus to elevated levels of either endogenous or synthetic glucocorticoids, pre and periconceptional nutritional status and immediate postnatal development including catch-up growth all contribute substantially to the development of adult onset disease. Fetal exposure to high levels of glucocorticoids has direct clinical relevance. Synthetic glucocorticoids (betamethasone/ dexamethasone) are administered to women at risk of preterm delivery to advance fetal maturation and reduce neonatal morbidity and mortality. However, in human pregnancy, evidence suggests that fetal exposure to synthetic glucocorticoids has detrimental effects on birth outcome, childhood cognition and long-term behavior. Studies in animals have established a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development as well as changes in placental function. These developmental alterations appear to be permanent. Whether this is the case in humans awaits long-term follow-up of children enrolled in randomized controlled trials of prenatal glucocorticoid therapy. The research challenges in this field are now centered on uncovering the mechanisms by which glucocorticoids are involved in programming the fetus for its future life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced. The purpose of this mini-review is to provide a background into the use of antenatal synthetic corticosteroids and to highlight and summarize recently published clinical and animal-based studies.     

The safety of antithrombotic therapy during pregnancy

A number of clinical conditions can require the use of antithrombotic drugs during pregnancy. These mainly include prevention of venous thromboembolism (VTE) and fetal complications in high-risk patients, treatment of VTE and prevention of arterial emboli in patients with mechanical heart valve prostheses. However, there are several problems when using antithrombotic drugs during pregnancy. Warfarin, as well as the other coumarin compounds, crosses the placenta and has the potential to cause both bleeding in the fetus and teratogenicity, therefore its use is not recommended during the first trimester and during the perinatal period. Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) do not cross the placenta and are safe for the fetus, but long-term treatment with UFH is problematic because of its inconvenient administration, the need to monitor anticoagulant activity and because of its potential side effects, such as heparin-induced thrombocytopenia and osteoporosis. LMWH is the drug of choice in the prevention and treatment of VTE during pregnancy because of its practical advantages over UFH and because of a lower risk of side effects. Patients with mechanical heart valve prostheses represent a major clinical challenge. Warfarin, the drug of choice in non-pregnant women, can be administered between the 12th and 36th week. Full-dose UFH is recommended in the first trimester and after week 36. The use of LMWH as an alternative to UFH is still a matter of debate, because inadequate data are available.