Pedro F. Escobar, MD

• Assistant Professor of Surgery, Section of Gynecologic Oncology, Department
• of Obstetrics and Gynecology, Obstetrics, Gynecology, and Women? Health
• Institute, Cleveland Clinic, Cleveland, Ohio

The drug may also cause mucocutaneous side effects requiring dose reductions muscle relaxant in anesthesia 50 mg imuran overnight delivery, with the most commonly seen effects being a result of dryness of the skin and mucosae spasms colon symptoms discount 50 mg imuran amex. Patients should be informed about the most common mucocutaneous side effects before the start of treatment and monitored at each clinical visit muscle relaxer kidney pain discount imuran 50mg on-line. Cases of idiopathic intracranial hypertension have been reported with the use of acitretin (38) muscle relaxant renal failure imuran 50mg otc, and a fundoscopic examination of the eye should be performed in the presence of such complaints as severe headache muscle relaxant drugs side effects buy 50 mg imuran with mastercard, nausea spasms under eye discount imuran 50 mg online, vomiting, and problems with vision (34). Visual impairments may include decreased color image, blurred vision, and decreased night vision (26,33,35), although dry eyes and irritation are among the most common ophthalmological side effects in this regard. Drivers and pilots should be warned about these side effects, and use of contact lenses may also be limited (39). An increase in liver enzymes may occur due to hepatotoxicity (26,33,35), with transient and reversible increases in liver Acitretin Acitretin has significant metabolic, skeletal, and teratogenic side effects (26). Accordingly, patients should be questioned in Laboratory and Clinical Follow-Up enzymes having been reported in more than 15% of patients using acitretin in studies (34,40), although severe hepatotoxic reactions such as cholestatic hepatitis and cirrhosis are rare (41). In cases where treatment is stopped, transaminase levels should be checked at 1- to 2-week intervals until they decline to normal levels. One case has been reported with pancreatitis due to high serum triglyceride levels (41), while those with diabetes, obesity, and excessive alcohol use and those with a family history of hypertriglyceridemia are in the high-risk group for development of pancreatitis. If the therapeutic response is good but the serum lipid levels are continuously elevated, dietary precautions should be taken prior to the start of a lipid-lowering drug. Incidences of vulvovaginitis caused by Candida albicans have also been reported during acitretin treatment (45). Acitretin use with antidiabetic drugs may cause hypoglycemia due to increased insulin sensitivity (46). Such patients are advised to check their glucose levels regularly and even more often than normal during the early phases of the treatment. In a study evaluating the effects of acitretin on wound healing, 44 complex wounds in transplant recipients were followed up, and no significant effect of the drug during the treatment period was observed in wound infection, dehiscence, hypertrophic scarring, or hypergranulation, meaning that there was no need to cease treatment during routine operative procedures (47). Accordingly, it is recommended that the administered dosages be adjusted in order to optimize the effect and compliance and to reduce side effects. Clinical evaluation for the response to treatment should be made after the 12th week of treatment (33). There are some drugs that should be used with caution during acitretin treatment due to the potential for drug interactions and common side effects, as summarized in Table 32. Laboratory tests should be carried out more often if the patient has diabetes, obesity, alcoholism, cardiovascular risk factors, lipid metabolism disorders, or a family history of any such conditions (26). Daily treatment doses should be reduced in the event of a more than twofold increase in the results of liver function tests and should be stopped when they increase threefold. Treatment may be stopped for some time as necessary and then started again at a lower dose. Diet and lifestyle changes should be applied before starting a course of lipid-lowering drugs in the event of increased lipid levels. Patients who have been administered acitretin should not donate blood during treatment and for 3 years after the cessation of treatment due to the possibility of acitretin being metabolically converted to etretinate. Patients should refrain from alcohol during treatment, and female patients should not consume alcohol for 2 months following the cessation of treatment. The drug should be administered at least 8 weeks prior to evaluation of the efficacy of treatment, with 204 the highest response rate observed to occur after a mean of 3 months of treatment. Hyperlipidemia and hypothyroidism develop in the majority of patients being treated with bexarotene. Hyperlipidemia is frequently seen in doses higher than 300 mg/m2/daily, and it is more frequently characterized with an increase in triglyceride levels (55). Central hypothyroidism may develop secondary to the drug intake during bexarotene treatment (57), having been reported in 40% of cases in clinical studies. Preventive treatment methods should be started early in order to prevent the development of side effects, and patients should be closely followed up (58). Hyperlipidemia and central hypothyroidism are the most frequently reported side effects among patients receiving bexarotene (54). The other side effects occurring during oral bexarotene treatment are lethargy, myalgia, anemia, neutropenia, leukopenia, elevated liver enzymes, hepatitis, nausea, vomiting, diarrhea, exfoliation, itching, cataract, and extracutaneous lymphoma (54,60). Pregnant patients or patients looking to become pregnant should refrain from all types of retinoid treatments including bexarotene due to their teratogenic effects (58). The side effects of topical bexarotene are limited to the area of application in general, and the reported side effects to date are rashes, irritation, itching, pain at the application site, and asymptomatic retinoid erythema (61). Starting on antihyperlipidemic drugs prior to treatment will permit long-term use of bexarotene in optimal doses, and using topical bexarotene rather than oral bexarotene in cases with localized lesions is a safer alternative. Retinoids in Dermatology As in the case of other retinoids, any woman of childbearing potential must not become pregnant while taking alitretinoin and for at least 1 month after its discontinuation. Alitretinoin does not appear to pose a risk to female partner or to fetus in the case of pregnant partner of a male patient (62). Alitretinoin treatment is associated with an overall 23% rate of development of side effects, headache (7. Treatment discontinuation was mostly due to headache or increased triglyceride levels (63). This is especially prevalent in patients with obesity, diabetes, alcohol intake, and a family history of dyslipidemia. Therefore, fasting glucose, total cholesterol, and triglyceride levels should be checked before and after the start of treatment. If triglyceride levels rise to uncontrollable high levels or signs of pancreatitis develop, treatment should be discontinued (62). Treatment with any systemic retinoid, including alitretinoin, can be associated with transient and reversible increases in liver transaminases. Reduction of the dose or discontinuation of alitretinoin treatment should be considered in the case of persistent and clinically relevant elevation of transaminases to more than two- to threefold increase of the normal levels (62). Like all other retinoids, alitretinoin can cause xerosis, cheilitis, photosensitivity, dry eye, arthralgia, and myalgia (62). Prior to initiation of alitretinoin treatment and at each visit during therapy, patients should be asked about depression, mood disturbance, or any psychiatric disorder (62). Alitretinoin treatment should be regularly followed up and pregnancy test, serum transaminases, blood lipid levels, and fasting blood glucose levels should be obtained before treatment and at 1 month after start of treatment. Adverse events related to topical treatment with alitretinoin gel tend to be mild to moderate in severity and are limited to the site of application. The most frequent adverse event is skin irritation occurring at the application site (32%) followed by paresthesia, itch, pain, and peeling (65). Alitretinoin Alitretinoin is indicated for the treatment of chronic hand dermatitis that is refractory to potent topical corticosteroids in adults (over 18 years) (62). Conclusions Isotretinoin, acitretin, bexarotene, and alitretinoin have important mucocutaneous, metabolic, and teratogenic side effects. Accordingly, patients should be questioned in detail about the Laboratory and Clinical Follow-Up various side effects at each clinical visit and appropriate tests should be run prior to the start of treatment and during treatment to identify the possible side effects that may develop. All retinoids are teratogenic; appropriate precautions and close followup should be undertaken in women of childbearing potential. Bexarotene treatment requires close follow-up to identify important side effects of hyperlipidemia and hypothyroidism. When appropriate clinical and laboratory follow-up is performed, retinoids can be safely and effectively used in the treatment of various dermatologic disorders. Isotretinoin is not associated with inflammatory bowel disease: A population-based case-control study. A populationbased analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. A proposed set of new guidelines for routine blood tests during isotretinoin therapy for acne vulgaris. Is it necessary to have routine blood tests in patients treated with isotretinoin Is there a reproductive safety risk in male patients treated with acitretin (Neotigason/Soriatane) Review of treatment options for psoriasis in pregnant or lactating women: From the Medical Board of the National Psoriasis Foundation. Extraspinal tendon and ligament calcification associated with long-term therapy with etretinate. Bone mineral density of the lumbar spine in psoriatic patients with long term etretinate therapy. Prolonged treatment with oral retinoids in adults: No influence on the frequency and severity of spinal abnormalities. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. A double-blind comparison of acitretin and etretinate in the treatment of severe psoriasis-Results of a Nordic multicenter study. Advice on the safe introduction and continued use of isotretinoin in acne in the U. Facial edema induced by isotretinoin use: A case and a review of the side effects of isotretinoin. Clinical side-effects and results of systemic isotretinoin treatment in patients with nodulocystic acne. The results and side effects of systemic isotretinoin treatment in 100 patients with acne vulgaris. A prospective study of the responsiveness of depression and suicidal ideation in acne patients to different phases of isotretinoin therapy. Serum-lipid changes during acitretin (etretin) treatment of psoriasis and palmoplantar pustulosis. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: An 8-week, randomized, double-blind, placebo-controlled study. Fish oil supplementation results in decreased hypertriglyceridemia in patients with psoriasis undergoing etretinate or acitretin therapy. Effect of acitretin on the response to an intravenous glucose-tolerance test in healthy volunteers. Toxic hepatitis due to combination therapy with methotrexate and etretinate in psoriasis. Bexarotene-induced hypothyroidism: Bexarotene stimulates the peripheral metabolism of thyroid hormones. Bexarotene treatment of late-stage mycosis fungoides and Sezary syndrome: Development of extracutaneous lymphoma in 6 patients. Phase1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Tollefson Introduction and History Vitamin A and its bioactive metabolite, retinoic acid, are vital to mammalian embryogenesis. The role of vitamin A in embryonic development is made possible through enzymes that control the conversion of retinol, the alcohol form of vitamin A, to an aldehyde (retinaldehyde) and then to retinoic acid, a carboxylic acid. Through binding to retinoid receptors, retinoic acid plays a crucial role in signal transduction and gene transcription pathways that regulate the development of many organs (1). Both deficient and excess levels of vitamin A during embryogenesis can cause congenital malformations (2,3). It has been well established through studies in animals that large doses of vitamin A and its related compounds are teratogenic. The congenital malformations that were observed in the pregnant rats exposed to excess vitamin A included exencephaly, brachygnathia, macroglossia, cleft lip, cleft palate, and gross defects of the eye, while the control group of pregnant rats did not experience these malformations. It was also observed that the highest number of fetal abnormalities occurred with more vitamin A intake on days two through six of gestation (4). Synthetic retinoids are very similar in chemical composition to vitamin A and have been shown to cause birth defects in humans when taken orally (5,6).

However muscle spasms yahoo answers discount imuran 50mg without prescription, these drugs have shown little therapeutic success since the beginning of their use (McMullan et al spasms synonyms discount imuran 50mg visa. Despite this spasms during sleep generic imuran 50mg otc, reports of cure of some cases of canine spasms right upper quadrant cheap imuran 50 mg visa, equine and human pythiosis with antifungal drugs (Shenep et al muscle relaxant kava buy imuran 50mg on-line. However muscle spasms 7 little words buy generic imuran online, monotherapy with antifungal drugs can be considered ineffective for the treatment of pythiosis, especially in humans (Krajaejun et al. Pythium species differentiate from true fungi because they are quite sensitive to antibacterial drugs that inhibit protein synthesis, such as tetracycline, chloramphenicol, streptomycin, and erythromycin (Marchant and Smith 1968, Rawn and Vanetten 1978, Guo and Ko 1994), and these antimicrobials are likely to inhibit the growth of the microorganism by interfering with cytoplasmic and mitochondrial protein synthesis (Rawn and Vanetten 1978). In this context, several classes of antibacterial drugs were reported for their in vitro anti-P. In this model, complete remission or reduction of subcutaneous lesions was observed in all treatments, except for clarithromycin. Additionally, one case of ocular pythiosis was successfully treated with surgery and minocycline (Ros Castellar et al. Miller (1981) and Miller and Campbell (1982) were the first investigators to report the use of P. Vaccine (immunotherapy) produced from macerated cells of Pythium insidiosum (PitiumVac). Considering the higher incidence of pythiosis in horses, most of the efficacy data of immunotherapy are described for these species. However, there is also the description of its use in canines (Thitithanyanont et al. Immunotherapy in human pythiosis has been described both in successful treatments and in therapeutic failures - and in association with surgical procedures and the use of various antimicrobial drugs (Thitithanyanont et al. However, the use of immunotherapy against pythiosis does not induce a protective response against reinfections. Animals with pythiosis that evolved to cure through immunotherapy are susceptible to reinfections if kept in an aquatic environment that contains zoospores of P. Other antimicrobial compounds and therapeutic proposals Iodides, as agents proposed in pythiosis control, have been used since the earliest descriptions of the treatment of this disease (Hutchins and Johnston 1972, Murray et al. Other adjuvant treatments include (i) the use of neodymium: yttrium-aluminum-pomegranate laser in pythiosis granulomas in equines (Sedrish et al. Prevention Most cases of pythiosis are associated with previous exposure of the host, with lesions or microlesions on the skin, in aquatic or to soil and grass in endemic areas, which contain the infective propagules of P. In endemic areas, susceptible hosts should avoid these sites, especially if skin lesions are observed. However, it is recommended that health care professionals and persons in direct contact with pythiosis hosts use personal protective equipment, such as gloves and goggles, to manipulate the lesions. Contact lens wearers should be aware of the correct contact lens and hand sanitizer procedures, even if they do not reside in endemic areas of the disease. The difficulty in diagnosis is related to the morphological similarities of this species with true fungi and the fact that few physicians and clinical laboratories are familiar with this pathological agent. Moreover, standardization of antimicrobial susceptibility testing and definition of clinical breakpoints are required for more effective pharmacological support. Despite the morphological similarity with filamentous fungi, the antifungal drugs have little or no antimicrobial action against P. Noteworthy, several classes of antibacterial drugs that act by inhibiting protein synthesis of microorganisms have demonstrated anti-P. Further clinical studies are needed and should expand the knowledge of the therapeutic potential of these drugs. However, the use of these drugs, even if proven effective, may be limited by the high financial cost for the treatment of animal pythiosis, particularly for large animals and in the epizootic cases of the disease. Immunotherapy has been widely used in the treatment of pythiosis in horses and has favorable results. The identification and the in vitro and in vivo evaluation of immunodominant antigens should stimulate the development of more effective immunotherapies and adjuvants that may result in protective vaccination strategies. Clinical profile, risk factors and outcome of medical, surgical and adjunct interventions in patients with Pythium insidiosum keratitis. Pythium insidiosum: Inhibitory effects of propolis and geopropolis on hyphal growth. In vitro activities of voriconazole, itraconazole, and terbinafine alone or in combination against Pythium insidiosum isolates from Brazil. In vitro and in vivo susceptibility of two-drug and three-drug combinations of terbinafine, itraconazole, caspofungin, ibuprofen and fluvastatin against Pythium insidiosum. Long-term follow-up after successful treatment of Pythium insidiosum keratitis in Israel. Granulomatous pneumonia caused by Pythium insidiosum in a central American jaguar, Panthera onca. In vitro activity of terbinafine combined with caspofungin and azoles against Pythium insidiosum. Performance comparison of immunodiffusion, enzymelinked immunosorbent assay, immunochromatography and hemagglutination for serodiagnosis of human pythiosis. Inferring putative virulence factors for Pythium insidiosum by proteomic approach. Interleukin-10 and immunity against prokaryotic and eukaryotic intracellular pathogens. Evaluation of intravenous regional perfusion with amphotericin B and dimethylsulfoxide to treat horses for pythiosis of a limb. Treatment of experimental pythiosis with essential oils of Origanum vulgare and Mentha piperita singly, in association and in combination with immunotherapy. Cutaneous pythiosis in cattle in the Southern region of Rio Grande do Sul, Brazil. Development of a nested polymerase chain reaction assay for the detection and identification of Pythium insidiosum. Development and evaluation of an enzyme-linked immunosorbent assay for the serodiagnosis of pythiosis in dogs. Evaluation of microbial culture techniques for the isolation of Pythium insidiosum from equine tissues. Growth rate and antibiotic sensitivities of conidium and selfed-oospore progenies of heterothallic Pythium splendens. Suprainguinal vascular pythiosis: Effective long-term outcome of aggressive surgical eradication. Sterol induction of reproduction and stimulation of growth of Pythium and Phytophthora. Six new species of Pythiogeton in Taiwan, with an account of the molecular phylogeny of this genus. Successful management of gastrointestinal pythiosis in a dog using itraconazole, terbinafine, and mefenoxam. In vitro activity of carvacrol and thymol combined with antifungals or antibacterials against Pythium insidiosum. In vitro and in vivo antimicrobial activities of minocycline in combination with azithromycin, clarithromycin, or tigecycline against Pythium insidiosum. Pythiosis presenting with digital gangrene and subcutaneous nodules mimicking medium vessel vasculitis. Expressed sequence tags reveal genetic diversity and putative virulence factors of the pathogenic oomycete Pythium insidiosum. Transcriptome analysis reveals pathogenicity and evolutionary history of the pathogenic oomycete Pythium insidiosum. Equine pythiosis in the Brazilian Pantanal region: Clinical and pathological findings of typical and atypical cases. Characterization of the specificity of the humoral response to Pythium insidiosum antigens. Dendritic cells pulsed with Pythium insidiosum (1,3)(1,6)-beta-glucan, Heat-inactivated zoospores and immunotherapy prime naive T cells to Th1 differentiation in vitro. Imported Pythium insidiosum keratitis after a swim in Thailand by a contact lens-wearing traveler. Evolution of the sterol biosynthetic pathway of Pythium insidiosum and related oomycetes contributes to antifungal drug resistance. Diphenyl diselenide in vitro and in vivo activity against the oomycete Pythium insidiosum. Efficacy of azithromycin and miltefosine in experimental systemic pythiosis in immunosuppressed mice. In vitro activities of miltefosine and antibacterial agents from the macrolide, oxazolidinone, and pleuromutilin classes against Pythium insidiosum and Pythium aphanidermatum. Confirmation of Pythium insidiosum as an etiologic agent of enzootic bovine granulomatosis by sequence analysis. Biomechanical interaction between hyphae of two Pythium species (Oomycota) and host tissues. Potential distribution of Pythium insidiosum in Rio Grande do Sul, Brazil, and projections to neighbour countries. The effect of chloramphenicol on growth and mitochondrial structure of Pythium ultimum. A comparative study of the histopathology and immunohistochemistry of pythiosis in horses, dogs and cattle. Amphotericin B for the treatment of localized subcutaneous phycomycosis in the horse. Actin dynamics in Phytophthora infestans; rapidly reorganizing cables and immobile, long-lived plaques. Immunoblot analysis of the humoral immune response to Pythium insidiosum in horses with pythiosis. An improved Pythium insidiosum-vaccine formulation with enhanced immunotherapeutic properties in horses and dogs with pythiosis. Orbital pythiosis: A non-fungal disease mimicking orbital mycotic infections, with a retrospective review of the literature. Immunotherapy of equine pythiosis: Testing the efficacy of a biological and evaluation of the leukocytic response to the treatment in horses naturally infected with Pythium insidiosum. Nasal cavity diseases of small ruminants in Federal District and Goias State, Brazil. Pythium insidiosum as a new opportunistic fungal pathogen for Pacific white shrimp, Litopenaeus vannamei. Caspofungin in vitro and in vivo activity against Brazilian Pythium insidiosum strains isolated from animals. Comparison between immunotherapy and caspofungin as agents to treat experimental pythiosis in rabbits. Environmental sampling reveals that Pythium insidiosum is ubiquitous and genetically diverse in North Central Florida. Anatomopathological and immunohistochemical study of pythiosis in naturally infected horse. Microevolutionary analyses of Pythium insidiosum isolates of Brazil and Thailand based on exo-1,3-beta-glucanase gene. Probing the phylogenomics and putative pathogenicity genes of Pythium insidiosum by Oomycete genome analyses. Hepatic and renal analysis in horses with pythiosis treated with potassium iodate, through the detection of serum proteins, nitrogenated substances and enzymes. Does immunotherapy protect equines from reinfection by the oomycete Pythium insidiosum Contribution to the study of cutaneous pythiosis in equidae from northern Pantanal, Brazil. Epidemiological survey of equine pythiosis in the Brazilian Pantanal and nearby areas: Results of 76 cases. Three types of immunotherapics against pythiosis insidiosi developed and evaluated. Fatal disseminated Pythium insidiosum infection in a child with Diamond-Blackfan anemia. Evidence for geographic clusters: Molecular genetic differences among strains of Pythium insidiosum from Asia, Australia and the America are explored. Development of a species-specific probe for Pythium insidiosum and the diagnosis of pythiosis. Adjunctive use of a neodymium: Yttrium-aluminum-garnet laser for treatment of pythiosis granulomas in two horses. A domain-centric analysis of oomycete plant pathogen genomes reveals unique protein organization.

In addition 303 muscle relaxant reviews discount imuran 50 mg free shipping, two case reports stated that oral isotretinoin triggered bronchospasm (23 muscle relaxant properties of xanax buy imuran now,24) spasms just below ribs order 50 mg imuran amex. In another report spasms or twitches imuran 50 mg line, allergic pneumonia developed while the subject was taking isotretinoin (25) spasms 1983 youtube order imuran 50mg visa. Other Retinoids the pulmonary side effects associated with retinoids other than oral isotretinoin are quite limited muscle relaxant in india order cheapest imuran. A previous study on human patients with emphysema suggested that definitive clinical improvement could not be achieved with the administration of retinoids (26). It is characterized by fever, acute renal failure, respiratory distress, hypotension, pleural effusion, and weight gain (30). A 63-year-old patient with significant psoriasis who developed a drug fever attributed to acitretin was reported (31). The package insert also indicates that sinusitis, coughing, increased sputum, and laryngitis may occur (19). In light of the current literature, we believe that retinoids are not associated with respiratory side effects. Large controlled studies of respiratory side effects are essential for a definitive conclusion to be made. Thirty-eight acne patients were evaluated with audiometric tests before treatment and after the first, second, and third weeks of treatment initiation. Another study with the use of oral isotretinoin for 3 weeks due to acne caused subclinical changes in auditory brainstem response (33). An additional study of 32 patients showed that isotretinoin use caused significant changes in the audiologic and ocular nerve (or retinal) functions (34). In another study, a positive effect on spermatogenesis was seen in patients using oral isotretinoin for acne conglobata 6 months after the beginning of treatment; however, it was determined that the values returned to the pretreatment baseline levels 1 year after cessation of treatment (59). The effect of oral isotretinoin on female fertility and ovarian reserve and functions is not clear. In some studies, it has been shown that isotretinoin negatively affects ovarian reserve and functions (60,61). One study found that isotretinoin did not affect ovarian functions (62), while another study reported that ovarian reserve and functions were impaired at the end of 6 months of oral isotretinoin treatment, but returned to the pretreatment baseline level 1 year after cessation of treatment. The authors suggested that the disruptive effect of oral isotretinoin on ovarian reserve was transient (63). Retinoids have antiproliferative, anti-inflammatory, and immunomodulatory effects. A 17-year-old girl developed acute renal failure and a 16-year-old boy developed eosinophilic tubulointerstitial nephritis after isotretinoin use (64,65). Perinuclear antineutrophil cytoplasmic antibody-positive vasculitis, oligoarthritis, tendinitis, and myositis developed in a 15-year-old boy 6 weeks after the initiation of oral isotretinoin treatment (66). Because the number of case reports is limited, it is possible that these side effects are coincidental rather than causal. The available data on the effects of systemic isotretinoin on the urinary system are limited. In a controlled study, there was no statistically significant difference in the prevalence of hematuria between acne patients using isotretinoin and the control group (67). A 16-year-old boy developed terminal hematuria following 1 month of isotretinoin treatment (68). Isotretinoin treatment may also cause urethritis (69) and dermatitis affecting the urinary meatus (70). Although the effects of isotretinoin on uric acid levels were first mentioned 30 years ago, current information on this topic is limited (7,71). Hyperuricemia, hypercalcemia, and nephrolithiasis developed after isotretinoin use in one patient (7). Uric acid levels were measured before treatment and 1 and 2 months after treatment in 51 acne patients taking 0. The uric acid levels at 1 and 2 months after treatment began were significantly higher than pretreatment levels (71). Spontaneous abortions occurred in six women, while two other women had induced abortions; only one woman carried to term and gave birth (74). In light of the current data, it is recommended that partners of men who use acitretin use contraception, but the risk of fetal anomalies is very low when their partners do become pregnant. The literature on the effects of retinoids other than isotretinoin on uric acid levels are limited. In one patient, gouty tophi developed with very high uric acid levels after acitretin use (75). A population-based study showed a positive correlation between retinol levels and uric acid levels (76). The limited data available show that large, comprehensive studies of renal side effects are necessary for a definitive conclusion to be made. Retinoids and Hypersensitivity Reactions Allergic reactions, such as urticaria and angiedema related to retinoid use, are extremely rare. Conclusions Retinoids are essential drugs that are successfully used to treat many skin conditions. Because isotretinoin is currently the most commonly used oral retinoid, most reported side effects are associated with isotretinoin. Retinoids: A journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. Does isotretinoin therapy have any effects on electrocardiography, heart rate and blood pressure Other Retinoids Acitretin is believed to have no effect on spermatogenesis; however, the evidence is limited. In one study, acitretin did not affect spermatogenesis in rats at standard and high doses (72). In another study conducted with 10 men receiving acitretin treatment for 3 months, acitretin did not affect spermatogenesis, sperm motility, or sperm morphology (73). An unknown side effect of isotretinoin: Pericardial effusion with atrial tachycardia. Vascular complications after treatment with low-dose isotretinoin in two elderly patients. Isotretinoin and the risk of cardiovascular, cerebrovascular and thromboembolic disorders. Influence of isotretinoin on nasal mucociliary clearance and lung function in patients with acne vulgaris. Acceleration of lung maturation in a human fetus following maternal isotretinoin intake. Incidence, clinical features, and outcome of all-trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The effect of oral isotretinoin (13-cis retinoic acid) on hearing systems in patients with acne vulgaris: A prospective study. Neurological and neurophysiological effects of oral isotretinoin: A prospective investigation using auditory and visual evoked potentials. The effects of oral isotretinoin (13-cis retinoic acid) on the inner ear: A prospective clinical study. Improved simultaneous determination method of beta-carotene and retinol with saponification in human serum and rat liver. Effect of systemic isotretinoin therapy on mucociliary clearance and nasal surface mucosa in acne patients. Efficacy of oral isotretinoin in the control of skin and nasal colonization by antibiotic-resistant propionibacteria in patients with acne. Evaluation of nasal and oropharyngeal flora in patients with acne vulgaris according to treatment options. The effects of systemic isotretinoin and antibiotic therapy on the microbial floras in patients with acne vulgaris. Isotretinoin embryopathy and the cranial neural crest: An in vivo and in vitro study. Development of canal cholesteatoma in a patient with prenatal isotretinoin exposure. A case of suspected isotretinoin-induced malformation in a baby of a mother who became pregnant one month after discontinuation of the drug. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. Light microscopic studies of spermatogenesis in rats following the admisitration of high doses of 13-cis-retinoic acid. Spermatological investigations in patients treated with etretinate and isotretinoin. Perinuclear antineutrophil cytoplasmic antibody-positive vasculitis, oligoarthritis, tendinitis, and myositis associated with isotretinoin in a 15-year-old boy: Case report and review of literature. The frequency of hematuria in acne vulgaris patients during isotretinoin treatment. Terminal hematuria associated with oral isotretinoin treatment in a patient with acne vulgaris. An unusual side effect of isotretinoin: Retinoid dermatitis affecting external urethral meatus. Isotretinoin use for acne vulgaris is associated with increased serum uric acid levels. Zouboulis Introduction Acne vulgaris is a chronic inflammatory disorder of the pilosebaceous follicles. Being one of the most commonly diagnosed skin diseases worldwide, acne remains a challenging dermatologic disease scientifically, extending into the pathogenetic pathways and therapeutic choices, as well as in daily clinical practice. For patients suffering from acne, this is a disease noticeable to everyone around. The chronic wavy manifestations of acne can lead to dramatic inflammation, rapid scarring, and permanent dyspigmentation if not treated. Acne has adverse emotional consequences and profound negative effects on psychosocial functioning that have been associated with increased rates of depression, anxiety, suicidal ideation, and suicidal attempts (1,2). Acne is not a temporary problem, but it shows persistence over years and has been reclassified according to the criteria of the World Health Organization as a chronic inflammatory disease, similar in scope with atopic dermatitis (7). In addition, acne can be an essential component of several systemic diseases or syndromes (8). This is accompanied by the homing microbiome, the proliferation of Propionibacterium acnes (P. Retinoids act to normalize desquamation by reducing keratinocyte proliferation and promoting differentiation through their immunomodulatory effects. Topical retinoids have been shown to both reduce visible lesions and inhibit the development of microcomedones and additional new lesions. Tretinoin, isotretinoin, adapalene, and tazarotene are effective comedolytic agents, while adapalene seems less irritative than tretinoin (18). Consensus guidelines (13) for topical retinoid indications recommend early use to obtain best results in most patients with acne vulgaris. As monotherapy, topical retinoids have been mainly used in apparently noninflammatory comedonal acne. In inflammatory acne, the concomitant use of a topical retinoid with other topical or systemic antibiotics can enhance the beneficial effect (19,20). In addition to all benefits of local retinoids, systemic isotretinoin decreases sebum production and inhibits P. The major metabolites of isotretinoin in blood are 4-oxo- and 4-hydroxy-isotretinoin. Isotretinoin crosses the placenta (26) and is more than 99% bound to plasma proteins, primarily albumin. Serum albumin has a critical function as a retinoidbinding protein in reducing the concentration of active retinoids and restricting the biological effects on sebaceous gland cells (22,27). Oral bioavailability can be increased, especially by fatty acids, which prevent the binding of retinoids with albumin and hence improve the clinical effect (29). Isotretinoin undergoes first-pass metabolism in the liver and subsequent enterohepatic recycling. Excretion of the drug is equal both in feces after conjugation and in urine after metabolization to water-soluble glucuronides (30). Its epidermal concentrations are rather low, and no progressive accumulation in serum, epidermis, or the subcutis has been found (31). After discontinuation of therapy, increased levels of isotretinoin disappear from the serum and skin within 4 weeks (in a few cases within 3 months). It seems likely that isotretinoin therapy interferes with the endogenous metabolism of vitamin A in the skin because vitamin A levels increased by about 50% and dehydrovitamin A levels decreased by around 80% in some patients (15).

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For instance spasms during mri cheap 50 mg imuran amex, with examining more than 10 muscle relaxant g 2011 50mg imuran overnight delivery,000 Pythium isolates from 2100 soil samples spasms in colon buy imuran with american express, Hendrix and Campbell (1970) concluded that P spasms near tailbone best buy for imuran. Other species likewise proved better subjects for species complexes than pointless exercises attempting to determine which of the several names to use muscle relaxant pregnancy category generic imuran 50 mg on line. Besides muscle relaxant 2632 discount imuran 50mg fast delivery, environmental and laboratory conditions might have considerable influence on morphology. This has been shown by Biesbrock and Hendrix (1967) that how morphological features of the oogonia, antheridia, and sporangia varied with differences in temperature, light, and nutrient media in a taxonomic study of P. Some of these complications were related to the biology of these microorganisms and some of them had something to do with the scientific tools and software availability. It is possible to add some phytosterols in the form of sterol-rich plant materials such as hemp seed extract or pure sterols, for instance, -sitosterol, into media (Mostowfizadeh-Ghalamfarsa 2015). However, for some isolates, it takes a long time to produce any sexual or asexual organs and some of them never produce anything but a mycelial mat of coenocytic hyphae. Additionally, some sexual organs, such as antheridia may disappear soon after fertilization. As it was discussed previously, some Pythium species produce more than one type of sporangia or antheridia. To avoid any confusion related to this pleomorphism, the cultures must be absolutely pure. There is a high level of morphological overlapping among convergent species, especially phylogenetically related ones, which makes them an identification challenge. It is not that easy to find a compatible mating type for a heterothallic Pythium isolates to stimulate oospore production. Therefore, the identification must be solely based on asexual morphology, which is error-prone. The biology of Pythium species is not the only issue in the course of identification and there are several software-based concerns which have something to do with the accessible tools for the identification. The most comprehensive Pythium species identification key available (van der Plaats-Niterink 1981) only covers 120 out of 250 reported species. On the other hand, there are also no descriptive sheets, no web-based database and no molecular barcode metadatabase for Pythium species. There were some attempts for generating web-based interactive keys based on Lucid Builder platform (Moorman et al. Nevertheless, it is a modification of van der Plaats-Niterink (1981) identification key and not all the species in the original key are included. This is mainly due to the availability of a vast number of sequences in public databases. Although using these regions might help for more accurate identification, this might prompt researchers with less experiences in oomycete taxonomy to sequence genes that might not resolve some species. Application of cox1 and cox2 as mitochondrial markers should be with regard to their maternal evolution, due to which they might produce incongruent phylogenies (Hyde et al. Although Btub region can be amplified and sequenced in most of Pythium species and can be easily used in concatenated datasets, it is not a powerful marker to resolve species-level phylogenies (Hyde et al. Some would suggest that such species might have the chance to be formally synonymized using multiple hypervariable genes in further investigations (Hyde et al. Furthermore, such approach might be useful to resolve species complexes such as P. As a consequence, it might be possible to use a single locus for identification; however, it is crucial to examine two or more loci before identifying or describing a new species (Schroeder et al. As a result, separate sampling of many possible independent genes and their comparison with each other to study whether they support each other or not is important (Villa et al. They also suggested that clade H species occupy an intermediate position (Villa et al. Submission of a Pythium species into GenBank database for molecular identification might result in matching with multiple species (Schroeder et al. This is mainly due to the submission of erroneous data entered into GenBank or the regions being similar. Some other molecular techniques have also been employed for the identification of Pythium species. Although molecular techniques have significantly assisted in the identification of unknown Pythium species, morphological features are still essential in supporting the identifications defined by molecular techniques (Zitnick-Anderson 2013). On the other hand, in order to describe a new species, Pythium taxonomy based on morphological characteristics has been increasingly supplemented with molecular techniques (Paul 2003). Possible strategies for resolving taxonomic challenges in the genus Pythium Since pathologists encounter Pythium species only in culture, when attempting identification, laboratory environment requires careful standardization for comparative studies (Benfradj et al. Considering both morphological and molecular identification methods and their advantages and defects, it is extremely recommended to use both morphological and molecular methods for an accurate identification of Pythium species (Benfradj et al. For instance, one should verify that the entire sequence (not a part of it) has high homology with other verified sequences in a database, when a given sequence shows high homology with one in the database (Kageyama 2014). Besides, confirmation of a verified species in a database is a matter of importance, especially when the list of homologous sequences shows more than one species. Moreover, checking the known sequence variability in any species showing homology with the query sequence is a crucial step in molecular species identification. The phylogenetic analysis would be helpful to show the possible relationships between a given query isolate and its related species in a database. Resolving the systematic status of the Pythium genus and concordance between Taxonomic Challenges in the Genus Pythium 193 taxonomists on keeping Pythium as a single genus or splitting the genus into four separate genera, would deeply help those who are involved in Pythium identification, especially plant pathologists, and prevent any confusion. Finally, constructing a molecular identification database, at least for pathogenic species, to foster accurate and faster identification of the species would be an important step for tackling the challenges of Pythium taxonomy. Conclusion the genus Pythium includes a number of recognized species with wide distributions and host ranges (Majeed et al. Identification of Pythium species traditionally has been conducted based on morphological features such as sporangia, oogonia, and antheridia, the type and size of oospores, homothallism vs. These features can also vary under different cultural conditions and many species show similar morphological characters. However, it is recommended to use more than one gene to describe a new species (Robideau et al. Convergent morphological features as well as molecular similarities existing between two distinct Pythium species urge taxonomists to adopt both morphological and molecular identification for accurate species identification. A new species of Pythium producing multiple oospores isolated from bentgrass in North Carolina. Phylogenetic relationships among Phytopythium species, and re-evaluation of Phytopythium fagopyri comb. Phylogenomic analysis supports multiple instances of polyphyly in the oomycete peronosporalean lineage. Morphological, pathogenic and molecular characterization of Pythium aphanidermatum: A casual pathogen of coriander damping-off in India. Isozyme variation in heterothallic species and related asexual isolates of Pythium. Occurrence of Pythium and Phytophthora species isolated from citrus trees infected with gummosis disease in Tunisia. Transcriptome and secretome of two Pythium species during infection and saprophytic growth. Effect of potassium and manganese phosphites in the control of Pythium damping-off in soybean: A feasible alternative to fungicide seed treatment. A pathogen of New Zealand Pyropia plicata (Bangiales, Rhodophyta), Pythium porphyrae (Oomycota). Effects of amino acids and sugars on zoospore taxis, encystment and cyst germination in Pythium aphanidermatum (Edson) Fitzp. Identification and characterization of Pythium graminicola, causal agent of kikuyu yellows in Argentina. Distribution of Phytophthora and Pythium species in soils in the continental United States. Physiochemical responses of Pythium porphyrae (Oomycota), the causative organism of red rot disease in Porphyra to acidification. Re-evaluation of Phytophthora citricola isolates from multiple woody hosts in Europe and North America reveals a new species, Phytophthora plurivora sp. Production and evaluation of monoclonal antibodies for the detection of Pythium sulcatum in soil. Distribution of Pythium porphyrae, the causal agent of red rot disease of Porphyrae spp. Host range and salinity tolerance of Pythium porphyrae may indicate its terrestrial origin. In vitro efficacy and population dynamics of fungal and bacterial antagonists against chilli damping off. Identification and characterization of Pythium species associated with greenhouse floral crops in Pynnsylvania. Characterization of border species among Pythiaceae: Several Pythium isolates produce elicitins, typical proteins from Phytophthora spp. Phytphthora database: A forensic database supporting the identification and monitoring of Phytophthora. Screening for a culture medium yielding optimal colony growth, zoospore yield and infectivity of different isolates of Leptolegnia chapmanii (Straminipila: Peronospromycetes). Taxonomy, phylogeny and pathogenicity of Pythium species in rice paddy fields of Fars Province. Molecular detection and quantification of Pythium species: Evolving taxonomy, new tools and challenges. Molecular phylogenetic analysis of Grifola frondosa (Maitake) and related species and the influence of selected nutrient supplements on mushroom yield. Molecular analyses of Pythium irregulare isolates from grapevines in South Africa suggest a single variable species. Comparative mitochondrial genome analysis of Pythium insidiosum and related oomycete species provides new insights into genetic variation and phylogenetic relationships. Molecular detection of Peronospora variabilis in quinoa seeds and phylogeny of the quinoa downy mildew pathogen in South America and the United States. A new species of Albugo parasitic to Arabidopsis thaliana reveals new evolutionary patterns in white blister rusts (Albuginaceae). Disentangling Peronospora on Papaver: Phylogenetics, taxonomy, nomenclature and host range of downy mildew of opium poppy (Papaver somniferum) and related species. Pathogenicity and virulence of Pythium species obtained from forest nursery soils on Douglas-Fir seedlings. Probability models based on soil properties for predicting presence-absence of Pythium in soybean roots. They infect a wide range of plant species or are confined to one or a few host species. Some of them are obligate parasites which require live host to grow and reproduce, but most of them being saprophytes survive in the soil, water and air without association with live host. Isolates of pathogenic fungi could be differentiated by morphological characteristics, host range (formae speciales), aggressiveness (pathotypes or races) or capability to establish stable vegetative heterokaryons by fusion of genetically different strains (Capote et al. Detection as well as accurate identification of plant pathogens is the most essential criteria to control or to initiate preventive or curative measures. Special attention should be given to early diagnosis of pathogens in seeds, mother plants and propagative plant material to prevent introduction and dissemination of pathogens to unaffected regions (Capote et al. To fulfill such criteria, rapid, sensitive and precise methods of detection and identification of fungal pathogens are increasingly necessary for making decision to control diseases. Traditionally, the most prevalent techniques employed to identify plant pathogens are dependent upon culture-based morphological approaches. Such methods are time-consuming, laborious and require extensive knowledge of the classical taxonomy of pathogen. Another limitation of early diagnosis includes difficulty in culturing some pathogens in vitro (Goud and Termorshuizen 2003). To overcome such limitations, to improve the accuracy and reliability, it is obvious to depend on the molecular approaches. A variety of molecular methods have been employed in detection, identification and quantification of several plant pathogenic fungi. Molecular methods are immensely valuable in understanding the genetic variability of pathogenic populations and also for the description of new fungal species/varieties. Overall, molecular methods are more rapid, specific, sensitive and accurate in diagnosis of plant pathogens. Plant pathogens like Phytophthora, Pythium, obligate biotrophic pathogens and soil inhabitants require special criteria for diagnosis and identification to enforce preventive measures. The genus Pythium is a well-known pathogen, which causes several diseases in plants as well as animals. Isolation and identification of these members results in array of complexities; hence, a wide range of molecular techniques have been followed for identification and diagnosis. Therefore, the main rationale of this chapter is to offer an overview of classical and *Corresponding author: mahadevakumars@gmail. Pythium the genus Pythium was established by Pringshein in 1858 (Pythium monospermum Pringsh.

A heart-healthy lifestyle spasms quadriplegic order imuran amex, including the role of diet and exercise muscle relaxant benzodiazepines cheap imuran amex, should be promoted as part of long-term follow-up care (6) yorkie spasms 50 mg imuran amex. For patients with symptoms concerning for cardiac dysfunction following completion of potentially cardiotoxic therapies back spasms 34 weeks pregnant order imuran 50 mg without prescription, recommended initial care includes serum cardiac biomarkers (troponins muscle relaxant drugs cyclobenzaprine discount imuran express, natriuretic peptides) and echocardiogram (with preferable consideration of cardiac magnetic resonance imaging if suboptimal echocardiogram) for diagnostic workup with referral to a cardiologist based on findings (6) spasms versus spasticity purchase imuran 50 mg mastercard. For asymptomatic patients considered to be at increased risk of developing cardiac dysfunction, similar imaging tests may be performed between 6 and 12 months after completion of cancer-directed therapy with referral to cardiology for further assessment and management if cardiac dysfunction is identified (6). Given the potential for a prolonged latent period following radiation therapy prior to the development of symptoms, survivors should be advised to seek medical attention if there is a change in their symptom status and to inform their caregivers of their prior treatments (4). Patients with significant prior radiation exposure should be given special consideration and considered as a unique population, particularly given the potential risk of harm arising because current standard preoperative risk testing grossly underestimates risk of cardiotoxicity, and because risks with interventions are significantly increased compared to the general population. It is hoped that better patient and physician awareness of these issues may lead to a more comprehensive preoperative assessment, improved informed consent, and a better selected surgical population. With increased survivorship comes additional emphasis on efforts to minimize, in particular, longer-term cardiac toxicity. Advances in radiation technology, techniques, dosimetry, precautions, and patient selection have led to reductions in cardiac radiation dose. Given the latency in cardiac sequelae with radiation exposure, the benefits of modern radiation therapy protocols will likely be observed over the next several years. Adjuvant hypofractionated versus conventional whole breast radiation therapy for early-stage breast cancer: Long-term hospital-related morbidity from cardiac causes. International guidelines for management of metastatic breast cancer: Can metastatic breast cancer be cured Effect of breast conservation therapy vs mastectomy on disease-specific survival for early-stage breast cancer. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark. Use of intensity modulated radiation therapy to reduce acute and chronic toxicities of breast cancer patients treated with traditional and accelerated whole breast irradiation. Early cardiac perfusion defects after left-sided radiation therapy for breast cancer: Is there a volume response Breast-conserving radiation therapy using combined electron and intensity-modulated radiotherapy technique. Cardiac dose reduction with deep-inspiratory breath hold technique of radiotherapy for left-sided breast cancer. Prone breast forward intensitymodulated radiotherapy for Asian women with early left breast cancer: Factors for cardiac sparing and clinical outcomes. Pilot study of feasibility and dosimetric comparison of prone versus supine breast radiotherapy. Prone versus supine positioning for whole and partial-breast radiotherapy: A comparison of non-target tissue dosimetry. Postmastectomy radiation therapy technique and cardiopulmonary sparing: A dosimetric comparative analysis between photons and protons with free breathing versus deep inspiration breath hold. Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery. Radiation exposure of the heart, lung and skin by radiation therapy References 65 43. Breast-conserving therapy with partial or whole breast irradiation: Tenyear results of the Budapest randomized trial. Definition of stereotactic body radiotherapy: Principles and practice for the treatment of stage I nonsmall cell lung cancer. Dosimetric comparison to the heart and cardiac substructure in a large cohort of esophageal cancer patients treated with proton beam therapy or Intensity-modulated radiation therapy. Mini-review on cardiac complications after mediastinal irradiation for Hodgkin lymphoma. Cardiac inflammation after local irradiation is influenced by the kallikrein-kinin system. Evaluation of left ventricular function in long-term survivors of childhood Hodgkin disease. Increased aorto-mitral curtain thickness independently predicts mortality in patients with radiation-associated cardiac disease undergoing cardiac surgery. Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Mitral and tricuspid valve repair in patients with previous mediastinal radiation therapy. Long-term outcomes of patients with mediastinal radiation-associated severe aortic stenosis and subsequent surgical aortic valve replacement: A matched cohort study. Percutaneous valve replacement in a young adult for radiation-induced aortic stenosis. However, cardiac-related adverse events are common complications and their prevention remains an important challenge for those with or surviving cancer. Prior to initiation of therapy, baseline assessment is crucial to identify patients who are at risk for cardiotoxicity (3). As the use of cardiotoxic treatments increases, dramatic improvements have been made to reduce the incidence of cardiotoxicity for various cancer treatments. This article will provide a brief overview of the evolution of cancer treatment as it pertains to mitigating the effects of cardiotoxic anticancer therapies. The four most common anthracyclines are doxorubicin, daunorubicin, epirubicin, and idarubicin (9,10). Note: +++ represents >10%; ++ represents 1%-10%; + represents <1% or rare; represents observed but precise incidence not well established; and - represents not well-recognized complication with no/minimal data. It is well documented in the literature that cumulative anthracycline dose is linked to irreversible cardiac dysfunction, left ventricle dysfunction, and heart failure (3,9). Anthracyclinerelated cardiotoxicity can present acutely and/or have a chronic effect, which can occur months, years, or decades after completion of therapy (1). Preventative management of anthracyclineinduced cardiotoxicity is classified into two approaches: (1) reduce cardiotoxic potency; and (2) use a cardioprotective agent concurrently with treatment (15). Pharmacodynamic and pharmacokinetic studies in animal models have reported 72 Overview of changes in cancer treatment strategies that increasing infusion duration reduces cardiotoxicity without compromising the oncologic efficacy of anthracycline therapy (8,16). In sarcoma and lymphoma patients, slow continuous doxorubicin infusions between 48 and 72 hours are often used (16). Infusions longer than 96 hours are associated with higher incidence of stomatitis, as well as a need for a prolonged infusion pump and an indwelling catheter (16). Another preventative strategy is using liposomal encapsulation to reduce cardiotoxicity from anthracyclines. By modifying pharmacokinetic and tissue distribution, the risk of cardiotoxicity diminishes without decreasing tumoricidal efficacy (19,20). Liposomal encapsulated doxorubicin has been shown to limit diffusion through the endothelial lining of the cardiac microvasculature (8,9,19). Additional concerns regarding the potential risk of secondary malignancies in childhood lymphoma have led to its restricted use (27). Nonanthracyclines While less common than anthracycline-induced cardiotoxicity, other chemotherapeutic agents used to treat cancer are also associated with cardiotoxicity. Capecitabine, its oral prodrug, is used for colorectal and metastatic breast cancer (3,29). However, this may be underestimated due to differences in the definition of cardiotoxicity and treatment schedules across studies (29). Continuous infusion is associated with a higher risk of cardiotoxicities compared to bolus administration (30). An early case series reported a 5% incidence of serious arrhythmias, ventricular tachycardia, and cardiac ischemia in patients who received paclitaxel (33). Preventative strategies include slow infusion of doxorubicin and paclitaxel, or increased time (24 hours) between doxorubicin and paclitaxel infusions (35,36). The cumulative dose of doxorubicin when combined with paclitaxel should not exceed 360 mg/m2 (37). Pharmacologic cardioprotective strategies during trastuzumab treatment are currently being explored to prevent future toxicity (38). However, these pharmacotherapies did not prevent trastuzumab-mediated left ventricular remodeling, a possible early marker of cardiotoxicity (38,43). Therefore, these results do not provide a solid basis of clinical decision-making, and larger studies are recommended. It is approved for the treatment of gastric, non-small cell lung, and colorectal cancer (52). Bevacizumab is associated with a spectrum of adverse events such as arterial hypertension, heart failure, pulmonary hemorrhage, gastrointestinal bleeding, pulmonary edema, and venous and arterial thromboembolic events (4,6,49). Bortezomib is typically used in the first-line setting while carfilzomib is used as second-line therapy in the relapsed setting (72). While relatively rare, proteasome inhibitors are associated with cardiac toxicities including heart failure and hypertension (72,73,76,77). Therefore, careful monitoring and a detailed history for cardiovascular risk factors and prior chemotherapy exposure (with particular attention to anthracyclines) are suggested (73). While there are no standard practice guidelines, Chari and Hajje published a set of recommendations for patients exposed to carfilzomib (83). In brief, screening echocardiograms should be obtained for all patients over the age of 60, with a history of amyloidosis, or other cardiovascular risk factors and repeated every two to three cycles (83). Immunotherapy the role of immunotherapies in oncology has substantially improved the management and survival of several advanced-stage malignancies (84). Although current literature remains limited to case reports and early clinical trials, strategies are proposed to prevent and manage potentially fatal complications. Other strategies include transfer to an intensive care unit to maintain adequate perfusion and treatment of any significant arrhythmias. Tocilizumab and glucocorticoids should be considered as first-line and second-line therapy in the event of cardiotoxicity, respectively (85,88). Studies have observed that patients may be concurrently diagnosed with other immune-related adverse events such as myositis autoimmune thyroiditis and hypophysitis with cardiotoxicity (85,89). From the limited literature, ipilimumab and/or nivolumab-induced myocarditis was reported in 0. Notably, the incidence may be underestimated as cardiac screening is not routinely performed in immunotherapy studies (84,85). Methods of cardiac dose protection and/or avoidance techniques are described in detail in Chapter 4 and are briefly summarized in Table 5. Cardiotoxicity related to radiation therapy is well studied and remains the most common nonmalignant cause of morbidity and mortality in survivors (1,96,98). Elderly patients (>70 years old) are at greater risk due to polypharmacy and use of cardiotoxic therapeutics (103). Studies and case reports have reported an association between high doses of corticosteriods and cardiac events such as atrial fibrillation and hypertension (103,107). This observation was noted in hematological malignancies and suggests that high doses of corticosteroids might mediate potassium outflow from cells, thereby inducing arrhythmias (103,108). However, the studies concluded that further validation is needed before routine clinical use. Both meta-analyses have some limitations and should be interpreted cautiously, as both these studies suffer from patient and treatment heterogeneity. Referral to a cardiologist for routine clinical heart failure (stage B) management is the standard of care. State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: A literature review. The field of cardio-oncology promotes optimal cancer treatment with a focus on limiting collateral cardiac damage (118,119). Along with the collaboration between cardiologists and oncologists, imaging specialists, clinical pharmacologists, nursing support, researchers, and educators are needed in this complex field (1). Cardio-oncology clinics allow clinicians to assess and prescribe appropriate therapeutic management if cardiac risk factors are present or if cardiotoxicity is identified (1). The creation of a specific cardio-oncology training program has been proposed by several experts to further advance this important therapeutic discipline (118). As the number of patients treated with cardiotoxic agents increases, it is imperative that we prevent cancer patients and survivors from becoming cardiac patients. As newer complex targeted therapies are 80 Overview of changes in cancer treatment strategies 13.