Long-Term Safety Profile and Off-Label Use of JAK Inhibitors in Dermatological Disorders / Perfil de seguridad a largo plazo y usos fuera de indicación de los inhibidores de JAK en dermatología

JAK inhibitors target specific inflammatory cytokines involved in various inflammatory diseases. Four molecules have been approved for dermatological use: upadacitinib, baricitinib, abrocitinib and topical ruxolitinib. Off-label prescriptions for other dermatological conditions have been reported. We conducted a narrative review of the literature to assess the long-term safety profile of currently approved JAK inhibitors in dermatology, and their off-label use in skin disorders. We performed literature searches with Pubmed and Google Scholar from January 2000 to January 2023, using the keywords “Janus kinase inhibitors”, “JAK inhibitors”, “off-label”, “dermatology”, “safety”, “adverse events”, “ruxolitinib”, “upadacitinib”, “abrocitinib” and “baricitinib”. Our search yielded a total of 37 dermatological disorders with studies supporting the use of these JAK inhibitors. Preliminary studies indicate that JAK inhibitors generally have a favorable safety profile and can be considered as an option in many dermatological disorders (AU)

Los inhibidores de JAK actúan bloqueando la acción de ciertas citoquinas inflamatorias involucradas en varias enfermedades inflamatorias. Cuatro moléculas han sido aprobadas para uso en dermatología: upadacitinib, baricitinib, abrocitinib y ruxolitinib tópico. Se han reportado usos fuera de indicación para diferentes enfermedades dermatológicas. Se realizó una revisión narrativa de la literatura sobre la seguridad a largo plazo de los inhibidores de JAK aprobados en dermatología y su uso fuera de indicación en enfermedades dermatológicas, mediante búsquedas bibliográficas en Pubmed y Google Scholar desde enero de 2000 hasta enero de 2023, incluyendo las palabras clave: «Janus kinase inhibitors», «JAK inhibitors», «off-label», «dermatology», «safety», «adverse events», «ruxolitinib», «upadacitinib», «abrocitinib» y «baricitinib». Se encontraron un total de 37 trastornos dermatológicos con estudios que respaldan el uso de estos fármacos. Los estudios preliminares indican que los inhibidores de JAK tienen un perfil de seguridad generalmente favorable y pueden considerarse una opción en muchas enfermedades dermatológicas (AU)

[Artículo traducido] Perfil de seguridad a largo plazo y usos fuera de indicación de los inhibidores de JAK en dermatología / Long-Term Safety Profile and Off-Label Use of JAK Inhibitors in Dermatological Disorders

Los inhibidores de JAK actúan bloqueando la acción de ciertas citoquinas inflamatorias involucradas en varias enfermedades inflamatorias. Cuatro moléculas han sido aprobadas para uso en dermatología: upadacitinib, baricitinib, abrocitinib y ruxolitinib tópico. Se han reportado usos fuera de indicación para diferentes enfermedades dermatológicas. Se realizó una revisión narrativa de la literatura sobre la seguridad a largo plazo de los inhibidores de JAK aprobados en dermatología y su uso fuera de indicación en enfermedades dermatológicas, mediante búsquedas bibliográficas en Pubmed y Google Scholar desde enero de 2000 hasta enero de 2023, incluyendo las palabras clave: «Janus kinase inhibitors», «JAK inhibitors», «off-label», «dermatology», «safety», «adverse events», «ruxolitinib», «upadacitinib», «abrocitinib» y «baricitinib». Se encontraron un total de 37 trastornos dermatológicos con estudios que respaldan el uso de estos fármacos. Los estudios preliminares indican que los inhibidores de JAK tienen un perfil de seguridad generalmente favorable y pueden considerarse una opción en muchas enfermedades dermatológicas (AU)

JAK inhibitors target specific inflammatory cytokines involved in various inflammatory diseases. Four molecules have been approved for dermatological use: upadacitinib, baricitinib, abrocitinib and topical ruxolitinib. Off-label prescriptions for other dermatological conditions have been reported. We conducted a narrative review of the literature to assess the long-term safety profile of currently approved JAK inhibitors in dermatology, and their off-label use in skin disorders. We performed literature searches with Pubmed and Google Scholar from January 2000 to January 2023, using the keywords “Janus kinase inhibitors”, “JAK inhibitors”, “off-label”, “dermatology”, “safety”, “adverse events”, “ruxolitinib”, “upadacitinib”, “abrocitinib” and “baricitinib”. Our search yielded a total of 37 dermatological disorders with studies supporting the use of these JAK inhibitors. Preliminary studies indicate that JAK inhibitors generally have a favorable safety profile and can be considered as an option in many dermatological disorders (AU)

Long-Term Safety Profile and Off-Label Use of JAK Inhibitors in Dermatological Disorders. / [Artículo traducido] Perfil de seguridad a largo plazo y usos fuera de indicación de los inhibidores de JAK en dermatología.

JAK inhibitors target specific inflammatory cytokines involved in various inflammatory diseases. Four molecules have been approved for dermatological use: upadacitinib, baricitinib, abrocitinib and topical ruxolitinib. Off-label prescriptions for other dermatological conditions have been reported. We conducted a narrative review of the literature to assess the long-term safety profile of currently approved JAK inhibitors in dermatology, and their off-label use in skin disorders. We performed literature searches with PubMed and Google Scholar from January 2000 to January 2023, using the keywords "Janus kinase inhibitors", "JAK inhibitors","off-label", "dermatology", "safety", "adverse events", "ruxolitinib", "upadacitinib","abrocitinib" and "baricitinib". Our search yielded a total of 37 dermatological disorders with studies supporting the use of these JAK inhibitors. Preliminary studies indicate that JAK inhibitors generally have a favorable safety profile and can be considered as an option in many dermatological disorders.

Long-Term Safety Profile and Off-Label Use of JAK Inhibitors in Dermatological Disorders.

JAK inhibitors target specific inflammatory cytokines involved in various inflammatory diseases. Four molecules have been approved for dermatological use: upadacitinib, baricitinib, abrocitinib and topical ruxolitinib. Off-label prescriptions for other dermatological conditions have been reported. We conducted a narrative review of the literature to assess the long-term safety profile of currently approved JAK inhibitors in dermatology, and their off-label use in skin disorders. We performed literature searches with Pubmed and Google Scholar from January 2000 to January 2023, using the keywords "Janus kinase inhibitors", "JAK inhibitors", "off-label", "dermatology", "safety", "adverse events", "ruxolitinib", "upadacitinib", "abrocitinib" and "baricitinib". Our search yielded a total of 37 dermatological disorders with studies supporting the use of these JAK inhibitors. Preliminary studies indicate that JAK inhibitors generally have a favorable safety profile and can be considered as an option in many dermatological disorders.

Clozapine-induced interstitial nephritis in a patient with schizoaffective disorder in the forensic setting: a case report and review of the literature.

We present a rare case of Acute Interstitial Nephritis (AIN) that occurred following a re-trial of clozapine in a 56-year-old lady with schizoaffective disorder. On initial trial of clozapine, this patient felt generally unwell with respiratory symptoms. Her inflammatory markers were raised and her renal function showed a mild, transient deterioration which normalised on the day of cessation of clozapine. Two years later, clozapine was re-trialled due the refractory nature of her psychiatric symptoms. She subsequently developed renal failure and AIN was confirmed by renal biopsy. Renal function improved after cessation of clozapine; however, she never fully regained normal renal function.

Report of two cases of mucous membrane pemphigoid with frontal fibrosing alopecia: a variant of lichen planus pemphigoides or an incidental finding?

Lichen planus pemphigoides (LPP) is a rare autoimmune subepidermal blistering disease characterized by the coexistence of both lichen planus and either bullous pemphigoid or mucous membrane pemphigoid (MMP) features. Frontal fibrosing alopecia (FFA) is a scarring alopecia, generally considered a form of lichen planopilaris. We report two patients with concomitant FFA and MPP. Patient 1 was a 73-year-old woman with the clinical and histological diagnosis of oral lichen planus. In addition, she presented alopecic plaques in the parietal area with blisters, immunohistologically compatible with Brunsting-Perry pemphigoid, a variant of MMP. During follow-up, the patient also developed FFA. Patient 2 was a 70-year-old woman with a history of ocular inflammation and desquamative gingivitis, who was diagnosed with MMP based on a conjunctival biopsy. She also had clinical features of FFA. ELISA and frontal biopsy confirmed the diagnoses of MMP and FFA. In conclusion, we report two patients with MMP associated with FFA, and discuss whether this association is a new variant of LPP or an incidental finding.

Growth and field emission properties of ZnO nanostructures deposited by a novel pulsed laser ablation source on silicon substrates.

Zinc oxide (ZnO) nanostructures were produced using a novel pulsed laser ablation apparatus comprising in-situ analysis of the plume by reflection time-of-flight mass spectrometry. Various morphologies of nano and microstructures were obtained for laser wavelengths of 1064 and 355nm, and oxygen ambient pressures of 10(-6) and 10(-2)mbar, respectively. None of the produced structures exhibited a particular type of self-organisation whereas all of them showed low aspect ratios and good field emission properties. Optimum values of 5.2Vmicrom(-1) and 2060 were obtained for the turn-on field and Fowler-Nordheim enhancement factor, respectively, for deposited nano-tipped microstructures presenting a high coverage of the substrate. The experimental data showed that for a given laser wavelength, higher field enhancement factors were obtained for the samples grown at the lower pressure of 10(-6)mbar. In these conditions, the deposited materials showed distinct nanostructuring and comparison with existing data showed the corresponding ablation plumes to contain (ZnO)(n) clusters, up to n=13. This work also shows that the electronic properties of the nanostructured ZnO produced in our conditions, as determined by the oxygen concentration during deposition, have an influence on the field emission properties in addition to the nanostructure morphology.

Glycogen synthase kinase 3beta negatively regulates both DNA-binding and transcriptional activities of heat shock factor 1.

Stress activation of heat shock factor (HSF1) involves the conversion of repressed monomers to DNA-binding homotrimers with increased transcriptional capacity and results in transcriptional up-regulation of the heat shock protein (hsp) gene family. Cells tightly control the activity of HSF1 through interactions with hsp90 chaperone complexes and through integration into a number of different signaling cascades. A number of studies have shown that HSF1 transcriptional activity is negatively regulated by constitutive phosphorylation in the regulatory domain by glycogen synthase kinase (GSK3) isoforms alpha/beta. However, previous studies have not examined the ability of GSK3 to regulate the DNA-binding activity of native HSF1 in vivo under heat shock conditions. Here we show that GSK3beta inhibits both DNA-binding and transcriptional activities of HSF1 in heat-shocked cells. Specific inhibition of GSK3 increased the levels of DNA binding and transcription after heat shock and delayed the attenuation of HSF1 during recovery. In contrast, the overexpression of GSK3beta resulted in significant reduction in heat-induced HSF1 activities. These results confirm the role of GSK3beta as a negative regulator of HSF1 transcription in cells during heat shock and demonstrate for the first time that GSK3beta functions to repress DNA binding.

Myasthenia gravis and recurrent falls in an elderly patient.

PRESENTATION: An elderly man had recurrent hospital admissions with falls. OUTCOME: Acetylcholine receptor antibodies and single-fibre electromyogram were useful in the diagnosis of myasthenia gravis. Treatment prevented further hospital admissions.

Anaesthesia for caesarean section in the presence of severe primary pulmonary hypertension.

We describe the case of a pregnant woman, 35 weeks' gestation, with primary pulmonary hypertension and coarctation of the aorta requiring emergency Caesarean section under general anaesthesia. The patient had a pulmonary artery catheter inserted before operation which revealed pulmonary artery pressures in excess of 80/40 mm Hg. These were lowered using an infusion of glyceryl trinitrate. After delivery of the baby and administration of oxytocin, pulmonary artery pressures were more difficult to control. An infusion of prostacyclin was substituted which stabilized pulmonary pressures. After operation, she was transferred to the intensive care unit where prostacyclin was administered by an "aerosolized" route. Her trachea was extubated after 48 h and she made an uneventful recovery.

Anaesthesia for caesarean section in a patient with systemic amyloidosis secondary to familial Mediterranean fever.

The anaesthetic management of a 33-year-old primigravid woman at 29 + 5 weeks' gestation with familial Mediterranean fever (FMF), secondary amyloidosis, renal allograft with deteriorating renal function and cardiac impairment for emergency caesarean section is described. Pathophysiology and management options are discussed. Cautious induction of epidural anaesthesia together with continuous invasive monitoring produced a good outcome for mother and baby.

Accomplishments during young adulthood of children originally diagnosed with minimal cerebral dysfunction: a ten-year follow-up study.

To gather data about the adult accomplishments of persons diagnosed with minimal cerebral dysfunction this retrospective study evaluated 57 subjects at ten-year follow-up. Two-thirds of the subjects graduated from high school with an average of 11.8 years of education. Factors correlating with educational outcome included intelligence quotient, age at initial evaluation, and parental socioeconomic status. Adult accomplishments appear related to intelligence and to the presence of family or behavior problems.

School psychologists' knowledge of children's legal rights.

School psychologists need a working knowledge of laws affecting children. This investigation was done to discover whether members of Ohio's school psychological association, including intern school psychologists who were functioning in a supervised capacity, are as knowledgeable about law as they need to be to avoid lawsuits. Participants completed a custom-designed questionnaire. Survey of Children's Legal Rights, including questions assessing knowledge of children's rights in relation to child abuse, suspension and expulsion, corporal punishment, rights in juvenile court, special education, freedom of religion and speech, search and seizure within school, divorce and child custody, school vandalism, and school attendance. Analysis indicated significant misconceptions about legal decisions; however, these school psychology practitioners have adequate legal knowledge about most of the surveyed themes excepting provisions for special education.

Generalization and maintenance of treatment gains using self-management procedures with behaviorally disordered adolescents.

Using reversal design (A-B-A-B) we investigated the effectiveness of self-management strategies to reduce disruptive, off-task behavior for three students from a self-contained classroom for behaviorally disordered students. Two were boys (ages 13 yr., 2 mo. and 14 yr., 4 mo.) and one a girl (age 13 yr., 3 mo.). The study investigated the maintenance and generalizability of treatment gains in a regular education setting. Parallel changes of self-concept influenced by the self-management procedures were also measured. Results strongly support that self-management techniques reduce off-task behavior, generalize to regular education settings, and help maintain treatment gains. Also, behavioral self-concept was markedly improved to within normal limits with the implementation of self-management procedures.

The pharmacodynamics and pharmacokinetics of the metabolite 3-desacetylvecuronium (ORG 7268) and its parent compound, vecuronium, in human volunteers.

The pharmacology of 3-desacetylvecuronium, the principal metabolite of vecuronium, was investigated. We studied 12 healthy volunteers, each on two occasions. First they received 3-desacetylvecuronium alone and then, on a later occasion, vecuronium. Six subjects received a large dose of each drug (pharmacokinetic study), the remaining six received a small dose (pharmacodynamic study). Drug concentrations in plasma and urine were measured using capillary gas chromatography. Neuromuscular block was assessed by measuring force of contraction of the adductor pollicis. Drug plasma concentration vs. time and neuromuscular effect data were analyzed by nonlinear mixed-effects modeling. 3-Desacetylvecuronium, compared with vecuronium (median, range in parentheses), had a smaller plasma clearance, 3.51 (2.11-6.57) vs. 5.39 (5.04-7.19) ml.kg-1.min-1; a larger steady-state distribution volume, 254 (215-410) vs. 152 (111-170) ml.kg-1; a longer terminal elimination half-life 116 (44-672) vs. 34 (25-61) min and a longer mean residence time, 67 (42-145) vs. 26 (18-32) min (P < .05). Renal clearances of 3-desacetylvecuronium and vecuronium were 0.85 (0.15-1.24) and 0.58 (0.16-0.66) ml.kg-1.min-1, respectively (P < .05). Conversion to 3-desacetylvecuronium accounted for 12% of vecuronium's clearance. Concentrations of 3-desacetylvecuronium and vecuronium that produced 50% neuromuscular block were 123 (109-154) and 102 (71-123) ng.ml-1, respectively (P < .05). 3-Desacetylvecuronium is a potent neuromuscular blocking drug and may be responsible for episodes of prolonged paralysis after long-term administration of vecuronium to patients in intensive care units.

Influence of dose on suxamethonium-induced muscle damage.

We have examined postoperative muscle pain and early increases in serum concentrations of myoglobin after administration of suxamethonium to see if these changes were dependent on the dose of drug. Thirty ASA I and II adult patients undergoing day-case surgery received a standard anaesthetic technique, including one of three doses of suxamethonium: 0.5, 1.5 or 3.0 mg kg-1. The incidence of postoperative myalgia and the severity of fasciculations were greater after suxamethonium 1.5 mg kg-1 than after a dose of 0.5 or 3.0 mg kg-1. Serum concentrations of myoglobin increased in a dose-dependent manner. Intubating conditions were significantly better with suxamethonium 1.5 or 3.0 mg kg-1 than with 0.5 mg kg-1. Changes in serum concentrations of calcium and potassium were small and similar in the three groups. We conclude that a dose of 3.0 mg kg-1 of suxamethonium provided a better combination of intubating conditions and minimal postoperative myalgia than the two lower doses.

Neuromuscular effects of succinylcholine following different pretreatments.

STUDY OBJECTIVE: To study the neuromuscular effects (onset, intensity, and duration of block) of succinylcholine following different pretreatments. DESIGN: Randomized open study. SETTING: University-affiliated hospital. PATIENTS: Fifty ASA physical status I and II adult inpatients undergoing elective ophthalmic surgery. INTERVENTIONS: Succinylcholine 0.5 mg/kg was administered after no pretreatment or after pretreatment with d-tubocurarine 0.05 mg/kg intravenously (IV) 3 minutes before, chlorpromazine 0.1 mg/kg i.v. 3 minutes before, alpha-tocopherol (vitamin E) 600 mg in three divided doses orally at 6-hour intervals, or aspirin 600 mg orally 1 hour before in groups of ten patients each. MEASUREMENTS AND MAIN RESULTS: Neuromuscular block by stimulation of the ulnar nerve at the wrist by application of train-of-four stimuli at 2 Hz every 12 seconds and recording the force of contraction of the adductor pollicis muscle. There was no significant difference in the time to occurrence of maximum block (49 to 53 seconds), reappearance of the twitch response (254 to 307 seconds), or complete recovery of twitch response (532 to 607 seconds) between the groups receiving no pretreatment and those pretreated with chlorpromazine, alpha-tocopherol, or aspirin. However, the time to maximum block (71 seconds) was significantly longer and the time to reappearance of the response (172 seconds) was significantly shorter (both p < 0.05) in the d-tubocurarine pretreated group in comparison with the control group. The time to complete recovery (420 seconds) also was shorter but not significantly different. CONCLUSIONS: Of the pretreatments used, only d-tubocurarine interferes with the neuromuscular blocking effects of succinylcholine. Chlorpromazine, which attenuates the muscle pains as well as the increase in creatine kinase and can be administered with the same convenience, may be a better pretreatment in the prevention of side effects of succinylcholine.