Antiretroviral therapy in pregnancy: a focus on safety.

Antiretroviral compounds differ from most other new pharmaceutical agents in that they have become widely prescribed in pregnancy in the absence of proof of safety. They are prescribed for the treatment of the mother and to reduce the risk of transmission of HIV to the fetus. In the animal models tested to date, no increased risk of malformations has been demonstrated for some compounds whereas others have been associated with malformations or developmental abnormalities in rats, mice or rabbits and, in the case of efavirenz, monkeys. Zidovudine monotherapy is still prescribed to reduce the risk of mother-to-child transmission of HIV. Combinations of 3 or more compounds are recommended when treatment of the mother is deemed necessary because of advanced HIV infection. Until recently, in vitro toxicity studies relevant to pregnancy were restricted to single agents; no animal teratogenicity or carcinogenesis studies of combination therapy have been published. Despite many thousands of women having taken antiretroviral therapy to reduce the risk of transmission, documented experience in human pregnancy remains sadly lacking, with the possible exception of zidovudine which has been prescribed in clinical trials to several hundred mother-infant pairs. For other compounds and for the numerous permutations of combination therapy, data are available only from small phase I/II studies, from retrospective investigations and from the prospective arm of the Antiretroviral Pregnancy Register (i.e. pregnancies in women taking antiretrovirals who were registered before delivery and then followed up). Antiretroviral monotherapy and combination therapy is widely prescribed in pregnancy because: (i) with appropriate management, which includes antiretroviral therapy, the risk of mother-to-child transmission can be reduced from 15 to 25% to less than 1%; (ii) pregnant women with advanced HIV infection require therapy; (iii) combination therapy with at least 3 compounds significantly reduces morbidity and mortality compared with dual or monotherapy; and (iv) the benefits of therapy for both the mother and the infant outweigh the risk. The choice of antiretroviral therapy in pregnancy may be influenced by the indication (prevention of transmission or maternal treatment), past antiretroviral therapy exposure/drug resistance, effects of pregnancy on the pharmacokinetics of the drug and factors influencing tolerability and adherence. In pregnancy, tolerability may be even more important than usual, especially if therapy exacerbates common complications of pregnancy, such as vomiting and glucose intolerance.     

The safety of antiretroviral drugs in pregnancy

Advances in HIV therapy and mother-to-child transmission (MTCT) prophylaxis have led to increasing use of antiretroviral drugs in pregnancy. Highly active antiretroviral therapy in pregnancy has been associated with prematurity, pre-eclampsia and gestational diabetes. Women may be at increased risk of nevirapine-associated hepatotoxicity but whether or not pregnancy is an additional risk is uncertain. Although animal studies suggest a possibility of congenital abnormalities with specific antiretrovirals, such as efavirenz, results from registries and cohort studies do not support an excess of congenital malformations associated with in utero antiretroviral exposure. Concerns regarding the health of uninfected, antiretroviral-exposed children include the potential for cancers, mitochondrial disease and haematological abnormalities. However, the absence of any excess mortality in large observational cohort studies of uninfected, antiretroviral therapy-exposed children born to HIV-infected women is reassuring. Based on current knowledge, the immense benefits of antiretroviral prophylaxis in reducing the risk of MTCT, far outweigh the potential for adverse effects.     

The safety of antiretroviral drugs in pregnancy

Advances in HIV therapy and mother-to-child transmission (MTCT) prophylaxis have led to increasing use of antiretroviral drugs in pregnancy. Highly active antiretroviral therapy in pregnancy has been associated with prematurity, pre-eclampsia and gestational diabetes. Women may be at increased risk of nevirapine-associated hepatotoxicity but whether or not pregnancy is an additional risk is uncertain. Although animal studies suggest a possibility of congenital abnormalities with specific antiretrovirals, such as efavirenz, results from registries and cohort studies do not support an excess of congenital malformations associated with in utero antiretroviral exposure. Concerns regarding the health of uninfected, antiretroviral-exposed children include the potential for cancers, mitochondrial disease and haematological abnormalities. However, the absence of any excess mortality in large observational cohort studies of uninfected, antiretroviral therapy-exposed children born to HIV-infected women is reassuring. Based on current knowledge, the immense benefits of antiretroviral prophylaxis in reducing the risk of MTCT, far outweigh the potential for adverse effects.     

Anti-epileptic drugs in pregnancy: current safety and other issues

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.     

Anti-epileptic drugs in pregnancy: current safety and other issues

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.     

Famciclovir: a focus on efficacy and safety

Importance of the field: Famciclovir is the prodrug of penciclovir, a guanosine analogue that inhibits viruses of the α sub-family of the Herpesviridae, as well as hepatitis B virus. It is indicated for management of mucocutaneous herpes simplex virus disease and acute herpes zoster, and has been investigated for management of hepatitis B virus infection.

Areas covered in this review: Data for this review were identified by searches of papers published in English on Medline and Scopus, spanning the years 1975 through 1 February 2010 with the key words: ‘famciclovir’, ‘famvir’, ‘penciclovir’, ‘herpes’, ‘oral’, ‘genital’, ‘varicella’, ‘zoster’ and ‘virus’ in association with ‘safety’, ‘toxicity’, ‘tolerability’, ‘efficacy’ and ‘indications’. Relevant references were also obtained from articles acquired through the search strategy.

What the reader will gain: Readers are also provided with up-to-date information on the use of famciclovir for infections due to herpes simplex, varicella zoster and hepatitis B viruses. Clinical data pertaining to the safety and tolerability of famciclovir are also reviewed.

Take home message: Famciclovir is a safe, convenient, and well-tolerated drug when used for its approved indications. The most common side effects indicated in the majority of studies were headache and nausea. Data for its use in childhood and pregnancy are limited.     

Use of herbal drugs in pregnancy: a survey among 400 Norwegian women

PURPOSE: To investigate the use of herbal drugs by pregnant women. METHODS: We interviewed 400 postpartum women at Ullev?l University Hospital in Oslo, Norway about the use of herbal drugs, within 3 days after giving birth by using a structured questionnaire in the period from February to June 2001. RESULTS: We found that 36% of the pregnant women had used herbal drugs during pregnancy with an average of 1.7 products per woman. The proportion of women using herbal drugs increased throughout the first, second and third pregnancy trimester. The most commonly used herbs were echinacea, iron-rich herbs, ginger, chamomile and cranberry. Among the women having used herbal drugs in pregnancy, 39% had used herbal drugs that were considered possibly harmful or herbs where information about safety in pregnancy was missing. Herbal galactagogues had been used by 43% of the women who had breastfed a prior child during their breast-feeding period. Use of herbal drugs in pregnancy had most commonly been recommended by family or friends. CONCLUSION: The widespread use of herbal drugs during pregnancy indicates an increased need for documentation about the safety of herbal drugs in pregnancy. To meet the needs of pregnant women, it is necessary for health care personnel to have knowledge about herbal drugs during pregnancy.     

The safety of antidepressant drugs during pregnancy

This article discusses known or suspected effects of maternal use of antidepressants during pregnancy on pregnancy outcome. It is unlikely that any marked teratogenic effect occurs with the possible exception of an increased risk for cardiovascular defects after maternal use of clomipramine or paroxetine. An increased risk for preterm birth is seen. Transient neonatal symptoms are common after the use of antidepressants in late pregnancy. Few firm data are available on the possible impact on the long-term neuropsychological development of the infants. The magnitude of the actual contribution from drug therapy is unclear; it is likely that the underlying pathology of the mother explains part of the anomalies. Selective serotonin re-uptake inhibitor drugs seem to represent a smaller hazard than tricyclic antidepressants. Further research to separate the effects of the drug and underlying pathology is urgently needed as are large-scale studies on long-term development. When a pregnant woman has a major depressive disease and non-pharmacological treatments are not enough, the relatively small risk with drug therapy has to be weighed against the considerable risk for a relapse of the disease if therapy is interrupted.     

The safety of antidepressant drugs during pregnancy

This article discusses known or suspected effects of maternal use of antidepressants during pregnancy on pregnancy outcome. It is unlikely that any marked teratogenic effect occurs with the possible exception of an increased risk for cardiovascular defects after maternal use of clomipramine or paroxetine. An increased risk for preterm birth is seen. Transient neonatal symptoms are common after the use of antidepressants in late pregnancy. Few firm data are available on the possible impact on the long-term neuropsychological development of the infants. The magnitude of the actual contribution from drug therapy is unclear; it is likely that the underlying pathology of the mother explains part of the anomalies. Selective serotonin re-uptake inhibitor drugs seem to represent a smaller hazard than tricyclic antidepressants. Further research to separate the effects of the drug and underlying pathology is urgently needed as are large-scale studies on long-term development. When a pregnant woman has a major depressive disease and non-pharmacological treatments are not enough, the relatively small risk with drug therapy has to be weighed against the considerable risk for a relapse of the disease if therapy is interrupted.     

Assessing the safety of drugs in pregnancy: the role of prospective cohort studies.

Since, for obvious reasons, systematic testing of the teratogenic properties of drugs in humans is not possible in the premarketing phase, the epidemiological approaches to postmarketing risk evaluation are of major importance. Cohort studies, with their prospective exposure assessment, their ability to study even exposure to drugs not commonly used in pregnancy, and their ability to monitor both adverse and beneficial fetal outcomes, seem to be the most promising study type from a methodological viewpoint. Although there are numerous cohort studies on the harmful effects of drug use in pregnant women, only a few have been able to demonstrate a risk in terms of an increase in the prevalence of malformations. Most studies with significant findings were those investigating the risk potential of one group of drugs, the anticonvulsants. The lack of cohort studies showing a risk for drug use in pregnancy, however, is not necessarily indicative of some methodological deficiency. Rather, it may suggest that, for the majority of drugs, their use in pregnancy is not associated with an increased risk of congenital malformations.     

Echinocandin antifungal drugs in fungal infections: a comparison

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2?μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC??) values are typically <2?μg/mL but 100-fold higher MIC?? values are seen with Candida parapsilosis (1-2?μg/mL) and Candida guilliermondii (1-4?μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2?μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35?mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors. All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only micafungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutropenia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.     

Use of antiemetic drugs during pregnancy in Sweden

Background More than one-half of all pregnant women suffer from nausea and vomiting during pregnancy (NVP), primarily during the first trimester. Methods Prospectively ascertained information on drug use during pregnancy was obtained from the Swedish Medical Birth Register during the period July 1, 1995 to 2002. Antiemetics (antiemetic antihistamines, dopamine modulators, and ondansetron) primarily used for NVP were studied, and women reporting the use of these drugs were compared with all women who gave birth during the study period. Results Use of these antiemetics was reported in 4.5% of the pregnant women – 86% of whom reported their use before the first antenatal visit (usually weeks 10–12). Meclozine, followed by other antihistamines, accounted for 68% of the drugs reported. Young maternal age, multiparity, non-smoking, and a period of unwanted childlessness increased the probability of using any of the antiemetics during pregnancy. Women with a low education used these drugs more often than women with a relatively higher education. Neonates born to women who used any of the antiemetics had a reduced risk for low birthweight, prematurity, being small-for-gestational age, and having a malformation. No specific differences were observed with respect to the outcome following a comparison of different antiemetic drugs. Conclusions Women using antiemetics as a rule have a better delivery outcome than other women, probably due to an effect of a well-functioning placenta, which is associated with NVP. There were no signs of any significant teratogenicity of the drugs studied, but for some drugs the number of exposures was low.     

Evolution of schizophrenia drugs: a focus on dopaminergic systems

Many of the drugs currently marketed for the treatment of schizophrenia are dopamine D2 receptor antagonists or partial agonists with or without mixed receptor pharmacology, and primarily treat the positive symptoms of schizophrenia. These drugs, depending on their pharmacological profile, have been categorized as typical (with low or no serotonergic component) and atypical (with a high serotonergic, 5-HT2A and 5-HT1A component) antipsychotics. Atypical antipsychotics have increased tolerability compared with typical antipsychotics, particularly against extrapyramidal side effects which are caused by D2 receptor antagonism, and an increased efficacy for the treatment of the negative symptoms associated with schizophrenia. However, over the course of treatment, adverse effects such as weight gain, metabolic disorders, QT prolongation and sexual dysfunction have been observed, and thus current research efforts are being directed to the identification of new antipsychotics that have better tolerability and efficacy against the positive and negative symptoms of schizophrenia.     

An update on the safety and interactions of antifungal drugs in stem cell transplant recipients

Introduction: Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Improvement in the management of IFDs have been achieved with the availability of new effective and safe antifungal drugs, however, many of these newer treatments have some limitations in their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions.

Areas covered: This article is an update of a previous review published in this journal evaluating the safety profile of the antifungal drugs. Interesting new features include the availability of the new drug isavuconazole and the new tablet and intravenous formulations of posaconazole. Different dosages and new ways of administration of liposomal Amphotericin B (L-AmB) and echinocandins may be considered in the HSCT practice.

Expert opinion: Nephrotoxicity continues to be a clinically relevant and frequent side effect of L-AmB which may cause a reduced clearance of other renally eliminated drugs frequently used in HSCT patients. Echinocandins are favorable therapeutic options in view of their low toxicity and uncommon drug-drug interactions. Important limitations of triazoles are represented by hepatic toxicity and certain side effects particularly after prolonged treatments. The new triazole isavuconazole and the new tablet formulation of posaconazole will be probably increasingly used in the HSCT setting not only due to their efficacy but in particular for their interesting toxicity profile and pharmacokinetic characteristics. The knowledge of these pharmacological findings is crucial in the daily care of allogeneic HSCT patients.     

Use of anti-asthmatic drugs during pregnancy. 1. Maternal characteristics,pregnancy and delivery complications

Objective To study, in a large cohort, the association between the use of anti-asthmatic drugs during pregnancy and pregnancy complications. Methods Using the Swedish Medical Birth Register, we identified 24,369 women who reported the use of anti-asthmatic drugs in early pregnancy and 7778 women who were prescribed such drugs later during pregnancy by antenatal care system centres, during the period July 1, 1995 up to and including 2004. We studied maternal characteristics and pregnancy and delivery complications. Comparisons were made with all women having given birth to a child recorded in the register during this period. Results Women using anti-asthmatic drugs were characterized by a young maternal age, low parity, increased rate of smoking, low education, and high body mass index. An association with subfertility was also observed. Pre-existing diabetes did not occur in excess. A number of pregnancy and delivery complications occurred at an increased rate with the use of anti-asthmatic drugs, notably when three or more such drugs had been used: gestational diabetes [odds ratio (OR) = 1.59], preeclampsia (OR = 1.44), haemorrhage at delivery (OR = 1.32) and premature rupture of membranes (OR = 1.59); no excess of placenta abruption or previa was found. Primary weak contractions occurred more often than expected in women that used anti-asthmatic drugs (OR = 1.15), and this was tentatively linked to the use of β-2 adrenergic agonists. Most of the increased risk for caesarean section (OR = 1.79) could be explained by these pregnancy complications. An increased risk for delivery induction (OR = 1.74) was found among deliveries that did not start with a caesarean section. Conclusion An increase risk of pregnancy complications occurs with the use of anti-asthmatic drugs by pregnant women, which results in an increased rate of caesarean sections.     

Resistance to echinocandin-class antifungal drugs.

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandin drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking beta-1,3-d-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by 1000-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom.     

Mitochondrial dysfunction and targeted drugs: a focus on diabetes

Diabetes is a severe, heterogeneous, multifactorial, chronic disease. Diabetes and oxidative stress are related to continuous and acute overproduction of reactive oxygen species (ROS). These ROS are released principally from mitochondria, but also have other sources. Oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms responsible remain elusive. ROS are necessary for the proper functioning of the cell, but their excessive production can be harmful, making antioxidant defenses essential. Some substances with antioxidant properties, such as vitamins C and E, have been used to eradicate the oxidative stress associated with diabetes. The results of clinical trials employing anti-oxidative stress reagents in patients with diabetes are contradictory, perhaps due to inadequate study design or the specific targets selected. This review considers the process of diabetes from a mitochondrial perspective and evaluates strategies currently under development for the targeted delivery of antioxidants or other molecules to mitochondria. The evidence compiled herein endorses the selective targeting of specific molecules to mitochondria as an effective strategy for modulating mitochondrial respiration and ROS production and protecting mitochondria against oxidative stress.