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Cardiac involvement is the most severe manifestation of neonatal lupus. It is usually diagnosed as an advanced (second or third degree) atrio-ventricular (AV) congenital heart block (CHB) starting around 20 weeks of gestation. At this gestational time, a window of opportunity might exist, and fluorinated corticosteroids (FS) have been attempted as a therapeutic option. Unfortunately the quality of the studies is methodologically low, due to the retrospective design and to the rarity of autoimmune CHB. Some case reports and small case series basically suggested a possible utility of FS, mainly in the context of incomplete CHB, while larger observational retrospective studies did not find any efficacy of FS either on mortality, on the rate of pacemaker implantation, to reduce the degree of incomplete CHB or to reduce the development of cardiomyopathy. Of note the distinction between complete and incomplete AV block may be very difficult and time consuming in utero. Overall FS should not be recommended in CHB, but might be considered for a short time for a recent incomplete CHB.

Summary In around 1% of exposed pregnancies, anti-Ro/SSA and anti-La/SSB antibodies lead to congenital heart block, the main feature of neonatal lupus syndrome. As such, echocardiographic screening to detect congenital heart block, done every other week from 16 weeks to at least 24 weeks gestation, is widely recommended for anti-SSA-positive pregnant women. Such screening is now routinely done in many centres worldwide. In this Viewpoint, we call this dogma into question for several reasons. Even if congenital heart block is discovered (which is rare), the usefulness of treatment with fluorinated steroids has not been shown, whereas the associated side-effects are well known. The discovery of congenital heart block very early in the pregnancy does not modify obstetric management, and at least 500 ultrasounds are needed to find one case of congenital heart block, which would ultimately be found by other means. Finally, this screening strategy misses most cases of congenital heart block because most affected women are not known to have anti-SSA antibodies, and thus are not screened. Accordingly, except in the context of research protocols, which are certainly needed and are outside the scope of this Viewpoint, overturning the dogma of routine repeated screenings for congenital heart block could save money and health-care staff time and prevent maternal stress without substantial clinical consequences.

Objective: Neonatal Lupus (NL) is a rare syndrome caused by placental transfer of maternal anti-SSA/Ro and anti-La/SSB autoantibodies to the fetus. The rarity of this condition requires the establishment of multidisciplinary registries in order to improve our knowledge.Method: Inclusion criteria in this retrospective study were the maternal confirmed positivity for anti-SSA/Ro and/or anti-SSB/La antibodies, and the presence of II or III degree congenital heart block (CHB) in utero or neonatal period (up to 27 days after birth).Result: Eighty-nine cases of CHB were observed in 85 women with 88 pregnancies that occurred between 1969 and 2017. CHB was mostly detected in utero (84 cases, 94.2%), while five cases were observed in the neonatal period. A permanent pacemaker was implanted in 51 of 73 children born alive (69.8), whereas global mortality rate was 25.8% (23 cases): 16 in utero, five perinatal, and two during childhood. By univariate analysis, factors associated with fetal death were pleural effusion (p = 0.005, OR > 100; CI 95% 2.88->100 and hydrops (p = 0.003, OR = 14.09; CI 95% 2.01–122). Fluorinated steroids (FS) were administered in 71.4% pregnancies, and its use was not associated with better survival. Some centers treated all cases with fluorinated steroids and some centers did not treat any case. CHB was initially incomplete in 24 fetuses, and of them five cases of II degree block reverted to a lower degree block after treatments. Recurrence rate in subsequent pregnancies was 17.6% (3 out of 17). A prophylactic treatment was introduced in 10 of these 16 subsequent (58.8%) pregnancies, mostly with FS or high dose intravenous immunoglobulins.Conclusion: This is the first report from the Italian Registry of neonatal lupus/CHB. The live birth rate was nearly 80%, with nearly two thirds of the children requiring the implantation of a pacemaker. The management of fetuses diagnosed with CHB was heterogeneous across Italian Centers. The registry at present is mainly rheumatological, but involvement of pediatric cardiologists and gynecologists is planned.

Fluorinated steroids have found entry into the list of important pharmaceuticals. Fluorinated corticosteroids are being used as topical drugs against rheumatism and inflammatory skin diseases or as inhalation drugs again asthma. A number of fluorinated steroids bind strongly to the estrogen or the progesterone receptor. With the availability of [ 18 F]fluorine as a radiolabel, radiofluorinated steroids are being developed as potential positron emission tomography (PET) imaging agents. This article presents an overview of preparative methods to fluorinated steroids as well as of the uses of these compounds.

The number of compounds with fluorine or trifluoromethyl groups present on a stereogenic carbon in pharmaceutical targets on the market is small, especially when compared with pharmaceuticals containing fluorinated and trifluoromethylated aromatic rings. This is despite the beneficial physical properties and possibilities to probe the mechanism and function. The discrepancy in numbers is highly likely due to the fact that there are only a few methods for the incorporation of fluoro- and trifluoromethyl groups, especially in an asymmetric manner. The majority of fluorinated or trifluoromethylated stereogenic centers are formed by using fluorinated building blocks rather than utilizing a C-F or a C-CF3 bond-forming process. Indeed, this is still the case even for aromatic fluorination and trifluoromethylation. © 2012 Elsevier Ltd. All rights reserved.

Controversies in the therapy of congenital complete heart block are reviewed in terms of the timing of pacemaker implantation, the type and complications of pacing and its role in the presence of myocardial dysfunction. Drug treatment may be useful in selected cases in the presence of pleural effusions, ascites and hydrops of the fetus, but have no effect on complete heart block. Administration of fluorinated steroids in anti-Ro antibody-positive mothers with the aim of preventing complete heart block has given controversial results. Because of the variety of the clinical presentations, especially in regard to pacing therapy, it is mandatory to refer patients with congenital complete heart block to specialized centers with adequate resources and experienced personnel.

Resume Les blocs auriculoventriculaires congenitaux d’origine immunologique sont lies au passage transplacentaire d’anticorps anti-SS-A/Ro et/ou anti-SS-B/La maternels pouvant s’integrer dans le cadre d’une connectivite. L’echographie avec Doppler est essentielle pour le depistage de ces blocs auriculoventriculaires au cours des grossesses a risque. Elle permet le diagnostic des blocs du premier ou deuxieme degre qui constituent probablement des etapes preliminaires dans l’atteinte des voies de conduction. Un traitement maternel par corticoides peut dans cette situation etre propose au couple, en raison d’un possible effet de cette therapeutique sur les blocs du premier ou deuxieme degre. En tant que signes precoces d’une lesion nodale, ils peuvent toutefois manquer : certains fœtus developpent un bloc complet sans qu’aucun bloc de degre inferieur n’ait ete identifie prealablement. De meme, la valeur semiologique du bloc du premier degre n’est pas totalement claire puisqu’il semble pouvoir etre spontanement reversible. D’autres marqueurs de lesion nodale seraient donc precieux. En cas de bloc complet, l’echographie est utile pour identifier des signes de decompensation cardiaque et guider la conduite obstetricale et l’extraction fœtale sur la base de signes pronostiques defavorables.

In this paper we report the synthesis of four fluorinated analogues of brassinosteroids in which fluorine was introduced stereoselectively at C-2. The bioactivity of these new compounds was evaluated using the rice lamina inclination test. The results show that two of these analogues elicit high bioactivity, suggesting the involvement of hydrogen bond interactions between the active brassinosteroids and their cellular receptor.

Steroidal 3-fluoroderivatives were prepared from corresponding tosylates using tetrabutylammonium difluorodimethylphenylsilicate as fluorinating agent. The reaction was tested on all four possible C-3 and C-5 stereoisomers of cholestane and 17-oxoandrostane skeletons. In this reaction only one isomer was always formed with opposite configuration at C-3 to starting tosylate. The reaction is accompanied by elimination which affords a mixture of corresponding olefines.

Background: We have previously shown that some synthetic hydroxylated stigmastanes derived from plant sterols inhibit in vitro HSV-1 replication in ocular cell lines and decrease cytokine production in stimulated macrophages, suggesting that these steroids might combine antiviral and immunomodulating properties. In this paper we report the synthesis of some analogues fluorinated at C-6 in order to study the effect of this modification on bioactivity.Methods: The following methods were used: organic synthesis of fluorinated analogs, cytotoxicity determination with MTT assays, cytokine production quantification with ELISAs, glucocorticoid activity determination by displacement assays, immunofluorescence and transcriptional activity assays, studies of the activation of signaling pathways by Western blot, antiviral activity evaluation through virus yield reduction assays.Results: We report the chemical synthesis of new fluorinated stigmastanes and show that thisfamily of steroidal compounds exerts its immunomodulating activity by inhibiting ERK and Akt signaling pathways, but do not act as glucocorticoids. We also demonstrate that fluorination enhances the antiviral activity.Conclusions: Fluorination on C-6 did not enhance the anti-inflammatory effect, however, an increase in the in vitro antiviral activity was observed. Thus, our results suggest that it is possible to introduce chemical modifications on the parent steroids in order to selectively modulate one of the effects.General significance: This family of steroids could allow the development of an alternative treatment for ocular immunopathologies triggered by HSV-1, without the undesirable side effects of the currently used drugs. Fil: Michelini, Flavia Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Bueno, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Molinari, Alejandro Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Galagovsky, Lydia Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Alche, Laura Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Ramirez, Javier Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina

SUMMARY Five commercially available corticosteroid creams were compared with respect to their thinning action on mouse tail epidermis. The greatest effects were produced by Synalar and Sintisone; hydrocortisone had the least action. In addition it was shown that the epidermal thickening induced by vitamin A could be significantly reduced by Ledercort cream. The thinning action of the fluorinated steroids on the epidermis is an important property of these agents when used for the treatment of dermatoses having a hyperactive epidermis. The mouse tail test is considered to be a useful screening test for new topical applications of these substances.

A new formulation of hydrocortisone with vasoconstrictor activity has been shown to be effective clinically and was more effective in a 0.1% concentration than 1.0% Hydrocortisone Cream BPC. Its use should obviate the adverse effects of fluorinated steroids.

Rationale: We report a case of acute steroid myopathy in a patient with eczema receiving one dose of intra-muscular injection of Compound betamethasone. Patient concerns: Acute steroid myopathy (ASM) is usually caused by exogenous corticosteroids, and typically, occurs with therapy using intravenous corticosteroids at high doses. Diagnoses: The patient was considered as a diagnosis of acute steroid myopathy. Interventions: The patient was treated with non-steroid anti-inflammatory drug and other symptomatic therapy. Outcomes: ASM was gradually improved after 2 weeks symptomatic treatment and completely recovered after one-month treatment. Lessons: The diagnosis of steroid myopathy is a clinical diagnosis based on characteristic symptoms. Higher dose of steroids, especially fluorinated steroids, for longer periods of time increases the risk of steroid-induced myopathy.

Isolated congenital complete heart block (CCHB) is a rare disease with significant associated morbidity and mortality. A diagnosis is often made in fetal life, but data regarding long-term outcomes are limited, and fetal therapy to improve prognosis is controversial. In our institution, 85 fetuses were diagnosed with CCHB from 1981 to 2013 in 80 mothers. There were 37 anti-Ro-positive pregnancies, 36 both anti-Ro and anti-La positive, 10 antibody negative, and 2 of unknown antibody status. Antenatal treatments were given in 14 fetuses, with 8 given fluorinated steroids, 4 beta sympathomimetics, and both in 2. Of the original 85, 74 babies survived to delivery. Fetal hydrops was the only risk factor found to be significantly associated with intrauterine death (p0.001). Four babies died before pacemaker implantation, 56 have had pacemakers implanted, and 14 are pacemaker free. The Kaplan-Meier estimate for median time to pacemaker implantation was 2.6 years, with 15 implanted in the neonatal period. There have been 14 postnatal deaths, with a Kaplan-Meier estimate of survival at 30 years of 76.8% (95% confidence interval 65% to 90%). Dilated cardiomyopathy was uncommon, occurring in 6 patients. Prematurity and hydrops were associated with increased postnatal mortality (p = 0.02 and 0.005, respectively). In conclusion, we present the largest single-unit experience of prenatally diagnosed CCHB in the published literature. Our cohort was conservatively managed, with survival similar to those previously published. These data offer insight into the long-term natural history of CCHB.

Granuloma Gluteale Infantum (GGI) is a rare condition of unclear etiology, [1] presenting as asymptomatic cherry red nodules in the diaper area appearing in the setting of primary irritant contact dermatitis. [2] A 50 day old infant with GGI is presented to emphasize that the condition may be easily missed, and that it may result from the misuse of fluorinated topical steroids used to treat a rash in the diaper area. This is the first case reported from Saudi Arabia.

Solid-state {1H}13C cross-polarization/magic angle spinning (CP/MAS) NMR spectroscopy was performed to analyze two fluorinated steroids, i.e., betamethasone (BMS) and fludrocortisone acetate (FCA), that have fluorine attached to C9, as well as two non-fluorinated analogs, i.e., prednisolone (PRD) and hydrocortisone 21-acetate (HCA). The 13C signals of BMS revealed multiplet patterns with splittings of 16–215 Hz, indicating multiple ring conformations, whereas the 13C signals of FCA, HCA, and PRD exhibited only singlet patterns, implying a unique conformation. In addition, BMS and FCA exhibited substantial deviation (>3.5 ppm) in approximately half of the 13C signals and significant deviation (>45 ppm) in the 13C9 signal compared to PRD and HCA, respectively. In this study, we demonstrate that fluorinated steroids, such as BMS and FCA, have steroidal ring conformation(s) that are distinct from non-fluorinated analogs, such as PRD and HCA.

The regiospecific synthesis of two A-ring fluorinated steroids is described. Treatment of a 4-trimethylstannyl Δ4,3-keto steroid with caesium fluoroxysulfate gave the corresponding fluorinated steroid in good yield; use of the N-fluorodiazabicyclic reagent, Selectfluor, as the fluorine source provides the same compounds in lower yield. The fluorination was found to be sufficiently rapid to be potentially useful in the synthesis of 18F labelled steroids for PETT applications.

Analyses of the 1 H, 13 C and 19 F NMR spectra of 15 mono-, di-, tri- or tetrafluorosubstituted steroids were carried out by two-dimensional 1 H- 1 H and 1 H- 13 C shift correlation experiments

The regiospecific synthesis of two A-ring fluorinated steroids is described. Treatment of a 4-trimethylstannyl Δ4,3-keto steroid with caesium fluoroxysulfate gave the corresponding fluorinated steroid in good yield; use of the N-fluorodiazabicyclic reagent, Selectfluor, as the fluorine source provides the same compounds in lower yield. The fluorination was found to be sufficiently rapid to be potentially useful in the synthesis of 18F labelled steroids for PETT applications.

Small unilamellar liposomes containing fluorinated steroids (flumethasone and dexamethasone) were obtained. A physicochemical evaluation was conducted based on photon correlation spectroscopy (PCS) and fluorine-19 (19F) nuclear magnetic resonance (NMR) spectroscopy compared with standard biochemical methods (HPLC). The PCS method provides a fast and adequate evaluation of some critical features of liposomes (size, physical stability). In addition, 19F NMR spectroscopy gives substantial information, in a nondestructive manner, on steroid behavior in the membrane upon encapsulation and also when the temperature of liposomes is increased. The combined spectroscopic approach proposed here might prove useful in (1) the management of liposomal formulation, especially in the documentation of physicochemical properties, (2) pharmaceutical control in the industrial production line, and (3) control preceding injection at the clinical site. Spectroscopic techniques might offer a complementary approach to classical biochemical methods in the evaluation of the properties of a liposomal formulation and could be usefully integrated into quality control procedures.

Steroidal 3-fluoroderivatives were prepared from corresponding tosylates using tetrabutylammonium difluorodimethylphenylsilicate as fluorinating agent. The reaction was tested on all four possible C-3 and C-5 stereoisomers of cholestane and 17-oxoandrostane skeletons. In this reaction only one isomer was always formed with opposite configuration at C-3 to starting tosylate. The reaction is accompanied by elimination which affords a mixture of corresponding olefines.

To determine the feasibility and effectiveness of prenatal therapy of congenital heart block (CHB), information was sought regarding the timing of identification of CHB in 72 pregnancies and the outcome of those pregnancies in which the mothers were administered corticosteroids. Mailed questionnaires with telephone follow-up, data from primary physicians and chart review were utilized. In 38 (53%) of affected pregnancies CHB was identified between 16 and 24 weeks of gestation, in 17 (24%) between 25 and 30 weeks of gestation, in 8 (11%) between 31 and 37 weeks, and in 5 (7%) between 38 and 40 weeks. In four pregnancies the timing was unknown. Five women were taking prednisone for disease activity prior to the discovery of CHB and in six other women prednisone therapy was initiated at or about the time CHB was identified. In 19 pregnancies, women were given fluorinated steroids (available to the fetus in an active form) as attempted therapy after the discovery of CHB. Of these, one fetus with second degree block reverted to sinus rhythm and two with third degree block exhibited an improvement in the degree of block. In eight fetuses pleural and/or pericardial effusions resolved. In conclusion, the gestational period of heightened fetal vulnerability for the development of heart block is in the mid second to early third trimester. Although there is no evidence that maternal prednisone should be used prophylactially, fluorinated steroids may be efficacious after the identification of heart block, particularly with regard to an associated myocarditis.

Topical corticosteroids may have adverse systemic effects and/or adverse local effects. Many of the adverse reactions seen with topical corticosteroids are related to their potency. Thus, side effects may frequently be avoided by using low-potency topical agents. Generally, fluorinated steroids are more potent than nonfluorinated steroids.

Bufexamac2 is a new topically active non-steroidal anti-inflammatory agent incorporated into a cream base for use in eczema and other inflammatory dermatoses. Comparative studies have shown the efficacy of bufexamac 5% cream to be indistinguishable from that of commonly used topical fluorinated corticosteroids in eczema and various other inflammatory dermatoses, but its relative efficacy in psoriasis has yet to be determined. Bufexamac has not been compared with hydrocortisone but it would appear to be at least as effective in eczema (which responds readily to all topical steroids), and is perhaps without the problems associated with long-term or inappropriate use of the more potent fluorinated steroids. It is well tolerated by most patients.

Nine cases of perioral dermatitis and 16 cases of rosacea-like dermatitis have been treated for the last 3 years at our clinic. These cases were all females whose ages ranged from 18 to 61 years with a mean of 45 years. All had been under treatment with fluorinated steroids for a period of from 3 months to 10 years, about 3 years on the average. Tetracyclines were beneficial as remedies for these conditions, bringing about healing or remission in approximately 3 months. About 1 year was required for the recovery from atrophy of the skin and telangiectasia. Hydrocortisone 17-butyrate was more useful as a topical medication than hydrocortisone acetate but gave rise to withdrawal rebound eruptions in some cases.

The synthesis of polyfluorinated desmosterols by a Wittig condensation between a steroidal triphenylphosphonium ylid and polyfluorinated acetones is described. The mass spectra of these fluorinated steroids show significant differences from the unsubstituted parent compounds.

The application of hypofluorites (fluoroxy-compounds), especially tri- fluoromethyl hypofluorite, in the synthesis of fluorinated steroids is described. Hypofluorites are powerful but selective fluorinating agents with unusual electrophilic character. They should find considerable application not only in the synthesis of fluorinated steroids, but for preparation of fluorinated compounds of many different types.

1. By the reaction of boron trifluoride etherate with 5α,6α-epoxy-17α-vinylandrostane-3β, 17β -diol 3-acetate (I) the fluorohydrin (VI) was obtained, and from this 6α-fluoro-17α-vinyltestosterone (VIII) was prepared for the first time. 2. The reaction of boron trifluoride etherate with the C-20 epimers of 5α,6α ∶ 20e,21-diepoxypregnane-3β, 17β-diol (II) and (HI) gives more than one product. In both cases the main products are the monofluorohydrins (XI) and (XIII), which are formed as a result of the opening of the 5α,6α-epoxide ring.

The 13C NMR spectra of tertiary fluorinated steroids possessing no functional groups in the vicinity of the fluorine have been measured. All α- and β-carbons are deshielded by the fluorine atom. The γ-carbons, however, are divided into two groups. The carbons gauche to the fluorine atom are all shielded by 1–8 ppm, whereas the γ-carbons anti to the halogen are all deshielded by 2–5 ppm. Apart from the α-Carbons, which have coupling constants of 170–180 Hz, all β-Carbons are also coupled to the fluorine with a 2J(CF) value of approximately 20 Hz. The γ-carbons gauche to the fluorine have a very small coupling constant (usually 0-3 Hz), while the anti γ-carbons are split by the fluorine by 6–8 Hz. Both chemical shifts and coupling constants can be used for the Stereochemical evaluation of fluorosteroids.

SummaryThe cytotoxicity of a number of steroids to Earle's L cells (NCTC 929), Gey's adrenal cells (3G29), and Ehrlich ascites cells (Squibb #2) was determined using cells grown in suspension culture in serum-containing media. The L cells were much more sensitive to fluorinated steroids than they were to the non-fluorinated parent compounds; progesterone derivatives were more toxic than corticosteroids. The adrenal cells were quite insensitive to the fluorinated steroids, while the Ehrlich ascites cells were less sensitive than the L cells but more sensitive than the adrenal cells. The adrenal cells were found to convert progesterone to: Δ4-pregnene-20α-ol-3-one; Δ4-pregnene-20β/-ol-3-one; Δ4-pregnene-6α-ol-3,20-dione; and Δ4-pregnene-6β-ol-3,20-dione, as determined by filter paper chromatographic methods and spot tests. A similar series of compounds was formed from 11α-hydroxyprogesterone by this cell line.

Two patients with contact allergy to Ultralan® preparations are reported. Each Ultralan preparation contains two of three related fluocortolone derivatives. The first patient reacted to all three derivatives. The second patient reacted to fluocortolone and when retested 4 months later also to fluocortolone pivalate but not to fluocortolone caproate. The negative reaction to fluocortolone pivalate at the first examination was probably false negative due to a too low test concentration. In order to avoid false negative patch test reactions the fluorinated steroids should possibly be applied in concentrations higher than 1%. No cross sensitivity to the other steroids for topical use was found.