Новости эндокринологии, записная книжка

[FilippovaYulia]

Во-первых, инсулин сам по себе легкоусваиваемый белок а во-вторых, так анаболическое же действие у инсулина... а учитывая повышенную проницаемость кишечника у новорожденных, особенно недоношенных, и несовершенство ферментных систем, вполне возможно, что микроколичества доходят в кровоток "непереваренными" и малость стимулируют все, что только могут...

[Melnichenko]

Dramatic, Durable Hair Growth With Oral JAK Inhibitor
— Oral baricitinib superior to placebo at 36 weeks in BRAVE-AA1 and BRAVE-AA2 trials
by Charles Bankhead, Senior Editor, MedPage Today March 27, 2022


BOSTON -- An oral Janus kinase (JAK) inhibitor produced significant, durable hair growth, including scalp, eyebrows, and eyelashes in patients with severe alopecia areata, according to long-term data from two randomized trials.

Almost 40% of patients achieved a Severity of Alopecia Tool (SALT) score ≤20 (total percentage of hair loss) at 52 weeks with a higher dose of baricitinib (Olumiant), and almost 30% had a SALT score ≤10. The patients had a mean SALT score >80 at baseline. Almost half of the patients had met response criteria for eyebrow and eyelash regrowth, reported Brett King, MD, PhD, of Yale School of Medicine in New Haven, Connecticut.

Adverse events (AEs) that occurred more often with baricitinib than with placebo were acne, elevated creatinine kinase levels, and increased LDL and HDL cholesterol, King said in a presentation at the American Academy of Dermatology (AAD) meeting.

The 52-week results showed continued improvement as compared with results after 36 weeks of follow-up, which were reported simultaneously in the New England Journal of Medicine.

"Continued treatment with baricitinib after 36 weeks resulted in further increases in the proportion of patients who achieved scalp, eyebrow, and eyelash hair regrowth," said King. "The proportion of patients achieving a SALT score <20 and/or a SALT score <10 -- and that's kind of a high bar -- continued to increase. The proportion of patients achieving ClinRO [Clinician Reported Outcome] for eyebrow and eyelash hair loss ... also continued to increase, restoring to nearly normal or normal."

"This is truly transformational for patients," he added. "These patients start out looking nothing like themselves, and they finish study, at least when it works, looking like themselves again, restored to normal."

Limited Treatment Options

An autoimmune condition with no approved therapies, alopecia areata affects men and women alike and causes rapid hair loss in the scalp, eyebrows, and eyelashes. The pathogenesis of the condition involves genetic and immune factors. Cytokines implicated in alopecia areata depend on the JAK pathway for intracellular signaling, providing a rationale for evaluating the therapeutic potential of JAK inhibition.

King reported findings from 52 weeks of follow-up in the BRAVE-AA1 and BRAVE-AA2 randomized, placebo-controlled evaluations of baricitinib in adults with active alopecia areata associated with a SALT score ≥50 (at least 50% hair loss). Investigators at 169 centers in 10 countries randomized 1,200 patients 2:2:3 to placebo, baricitinib 2 mg, or baricitinib 4 mg.

The primary endpoint was the proportion of patients achieving a SALT score ≤20 at 36 weeks. Secondary endpoints included a SALT score ≤10 and a ClinRO of 0 or 1 (full eyebrow/eyelash coverage or minimal gaps) with at least a 2-point improvement from baseline. The 52-week assessment focused on the same three outcomes. Patients allocated to the JAK inhibitor remained in their assigned dose groups, and placebo-treated patients with SALT score >20 switched to baricitinib after 36 weeks.

The study population had a median age of about 37, and women accounted for about 60% of all patients. About two-thirds of the patients had an alopecia duration of <4 years, and >40% had alopecia universalis. Baseline SALT score averaged about 85 across the placebo and baricitinib groups.

Key Results

The 36-week results showed that 34% of patients in the baricitinib 4-mg arm had a SALT score ≤20, as compared with 19.7% of the 2-mg arm, and 4.1% of the placebo group. At 52 weeks, the proportion of patients with SALT score ≤20 had increased to 39% with the 4-mg baricitinib dose and 22.6% with the lower dose.

For the more stringent SALT score ≤10, response rates at 36 weeks were 24.9%, 11.8%, and 2.3%, respectively for baricitinib 4 mg, baricitinib 2 mg, and placebo. Rates increased to 28.9% and 15.3% for the baricitinib arms at 52 weeks.

Rates of ClinRO response for eyebrows increased from 33.0% at 36 weeks to 44.1% at 52 weeks with the higher dose of baricitinib and from 15.8% to 22.9% with the 2-mg dose. In the placebo group, 3.8% of patients met ClinRO response criteria at 36 weeks.

Changes in ClinRO response for eyelashes from 36 to 52 weeks were 33.6% to 45.3% with baricitinib 4 mg and from 12.0% to 25.5% with baricitinib 2 mg. The placebo group had a 4.3% ClinRO response at 36 weeks.

In response to a question from the audience, King said patients with longstanding alopecia areata are not good candidates for treatment with the JAK inhibitor. A patient with a 10-year history of the hair loss is unlikely to benefit, although outliers do exist.

Similar results emerged from a subgroup analysis of phase IIb/III placebo-controlled study of a different JAK inhibitor. An analysis of 105 adolescents (mean age 15) included in the overall study population showed that the JAK3/TEC inhibitor ritlecitinib led to SALT score ≤20 responses in 17%-28% of patients treated for 24 weeks with one of five doses of the drug. Additionally, 17%-28% of patients met criteria for SALT ≤10 responses.

From 22%-61% of patients treated with ritlecitinib rated results as improved or much improved on Patient Global Impression of Change index. The best results occurred in patients randomized to a 200-mg loading dose of the drug followed by 50 or 30 mg daily, reported Maria Hordinsky, MD, of the University of Minnesota in Minneapolis, and colleagues, in an AAD poster presentation. The most common AEs (including the placebo group) were headache, nasopharyngitis, and upper respiratory infection.

[Melnichenko]

The FDA has approved a new oral testosterone undecanoate capsule (Tlando) for hypogonadism, Antares Pharma announced.

This androgen is indicated for testosterone replacement therapy in adult men for conditions associated with a deficiency or absence of endogenous testosterone, including congenital or acquired primary hypogonadism, as well as congenital or acquired hypogonadotropic hypogonadism.

"The FDA approval of Tlando brings to market an oral formulation of testosterone that we believe will prove beneficial to physicians and their patients," said Robert F. Apple, president and CEO of Antares Pharma.

The approval was based on a phase III trial in which about 80% of participants achieved 24-hour average serum testosterone concentrations within the normal range between 300 to 1,080 ng/dL with Tlando, meeting the primary efficacy endpoint.

Prior to treatment initiation, diagnosis of hypogonadism must be confirmed via morning measurements of serum testosterone concentrations on at least two separate days to see if levels are below the normal range.

The recommended dosage is 225 mg orally twice daily with food. It does not require dose titration.

"We believe Tlando's oral formulation and convenient dosing, which requires no titration, differentiates it from other treatment options," noted Apple.

The drug was also deemed a Schedule III controlled substance, due to risks of abuse and misuse of testosterone.

[FilippovaYulia]

Отлично. Давно не хватало хорошего перорального тестостерона. Хотя посмотрим еще, сколько будет стоить...

[Melnichenko]

BOSTON -- About half of patients with longstanding vitiligo obtained significant repigmentation that persisted for at least a year with the topical Janus kinase (JAK) inhibitor ruxolitinib (Opzelura), two randomized trials showed.

In one trial, 52.6% of patients randomized to ruxolitinib cream had at least 75% improvement in the Facial Vitiligo Area Scoring Index (F-VASI75) at 52 weeks. In the second trial, 48% of patients met F-VASI75 response criteria at 52 weeks. Patients in the trials who switched from placebo to ruxolitinib after 24 weeks also had substantial improvement at 52 weeks.

The most common treatment-related adverse events (TRAEs) with ruxolitinib were application-site acne and pruritus, reported David Rosmarin, MD, of Tufts Medical Center in Boston, during the American Academy of Dermatology (AAD) meeting here.

"Half of patients who applied ruxolitinib cream from day 1 achieved F-VASI75 and T-VASI50 [trunk] responses by week 52," said Rosmarin. "Efficacy at week 52 in crossover patients, after 28 weeks of ruxolitinib cream, was consistent with week-24 data in patients who applied ruxolitinib cream from day 1. Ruxolitinib cream was well tolerated, and no serious treatment-related adverse events were reported."

Also at AAD, preliminary data from a trial of oral JAK inhibitor ritlecitinib, presented by Yuji Yamaguchi, MD, PhD, of Pfizer, provided evidence that the drug halted progression of active vitiligo lesions and induced repigmentation in stable lesions, with consistent results for up to 48 weeks across the range of Fitzpatrick skin types.

Long-Term Ruxolitinib Outcomes

Rosmarin previously reported the primary outcome for the TRuE-V1 and TRuE-V2 trials, which showed that ruxolitinib 1.5% cream BID significantly increased the F-VASI75 response rate at 24 weeks versus vehicle. The updated report included ruxolitinib-treated patients who continued the JAK inhibitor to week 52, as well as placebo-treated patients who switched to ruxolitinib after completing the 24-week randomized trial.

Ожидаемый прорыв

[Melnichenko]

Men taking metformin were more likely to have offspring with birth defects, a Danish study found.

Newborns with fathers who took metformin during the development of fertilizing sperm had a 40% higher frequency of birth defects compared with newborns whose fathers used insulin (adjusted OR 1.40, 95% CI 1.08-1.82), reported Maarten J. Wensink, MD, PhD, of the University of Southern Denmark, and colleagues.

The same did not hold true for offspring with fathers who took sulfonylureas versus insulin (aOR 1.34, 95% CI 0.94-1.92), they pointed out in the Annals of Internal Medicine.

Неприятно... Мб, что-то не так посчитали?

[FilippovaYulia]

Как-то с трудом верится. А поправки на длительность диабета, метаболический синдром, прием препаратов от АГ, наличие осложнений?.. надо будет вчитаться в трайл.

[Dr.Vad]

это не трайл, а ретро-наблюдение [Ссылки доступны только зарегистрированным пользователям ]

[Dr.Vad]

простой пример, как выводы зависят от статистики:

и на метформине и на сульф-мочевине был прирост на 35-40%, по сравнению с инсулином, НО на метФ было в 2 раза больше пациентов, поэтому 40% прирост оказался стат. состоверным, на на СуМо 34% повышение - нет, лишь потому, что метф прописывали в 2 раза чаще: Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92).

прямо скажем, что из-за редкости назначения сульфМ она статистически не дотянула до 1/3 избыточных врожденных проблем, а метформин - оказался инфант-террибль

[Melnichenko]

очень хочется думать так.

[Melnichenko]

Targeting 11-Beta Hydroxylase With [131I]IMAZA: A Novel Approach for the Treatment of Advanced Adrenocortical Carcinoma Get access Arrow
Stefanie Hahner, Philipp E Hartrampf, Patrick W Mihatsch, Marc Nauerz, Britta Heinze, Heribert Hänscheid, Carmina Teresa Fuß, Rudolf A Werner, Christina Pamporaki, Matthias Kroiss ... Show more
The Journal of Clinical Endocrinology & Metabolism, Volume 107, Issue 4, April 2022, Pages e1348–e1355, [Ссылки доступны только зарегистрированным пользователям ]

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options. Theranostic approaches with adrenal specific radiotracers hold promise for improved diagnostics and treatment.

Objective
Here, we report a new theranostic approach to advanced ACC applying (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinyl amide ([123I]IMAZA) for diagnostic imaging and [131I]IMAZA for radionuclide therapy.

Methods
Sixty-nine patients with nonresectable, metastatic ACCs were screened using a diagnostic [123I]IMAZA scan. Patients with significant uptake in all tumoral lesions were offered treatment with [131I]IMAZA. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), and adverse effects were assessed by Common Toxicity Criteria (version 5.0).

Results
After screening, 13 patients were treated with a median of 25.7 GBq [131I]IMAZA (range 18.1-30.7 GBq). Five individuals received a second treatment course. Best response was a decrease in the RECIST target lesions of –26% in 2 patients. Five patients with disease stabilization experienced a median progression-free survival of 14.3 months (range 8.3-21.9). Median overall survival in all patients was 14.1 months (4.0-56.5) after therapy. Treatment was well tolerated, in other words no severe toxicities (CTCAE grade ≥3) were observed.

Conclusion
In patients with advanced ACC refractory to standard therapeutic regimens, [131I]IMAZA treatment was associated with disease stabilization and nonsignificant tumor size reduction in a significant patient fraction and only limited toxicities. High [131I]IMAZA-uptake in tumor lesions was observed in 38.5% of patients with advanced ACC, rendering [131I] IMAZA a potential treatment option in a limited, well-defined patient fraction. Further clinical trials will be necessary to evaluate the full potential of this novel theranostic approach.

[Melnichenko]

Как-то напряжно...Ther Clin Risk Manag. 2020; 16: 245–259.
Published online 2020 Apr 8. doi: 10.2147/TCRM.S243462
PMCID: PMC7152545
PMID: 32308402
Hypophosphatemia Associated with Intravenous Iron Therapies for Iron Deficiency Anemia: A Systematic Literature Review
John A Glaspy,1 Michelle Z Lim-Watson,2 Michael A Libre,3 Swagata S Karkare,3 Nandini Hadker,3 Aleksandra Bajic-Lucas,2 William E Strauss,2 and Naomi V Dahl2
Author information Article notes Copyright and License information

Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed condition with a significant impact on quality of life. Oral iron supplementation is often poorly tolerated or yields inadequate response, requiring the use of intravenous iron (IVI) in some patients. Administration of certain IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to adverse events including serious fatigue and osteomalacia.

Objective
The purpose of this study was to systematically assess the prevalence, clinical consequences, and reporting of treatment-emergent hypophosphatemia within literature investigating IVI therapies marketed in the United States (US).

Methods
A systematic literature review (SLR) was conducted using the PubMed database to identify publications reporting serum phosphate levels or rates of hypophosphatemia within adult IDA patient populations receiving current US-marketed IVIs.

Results
The SLR yielded 511 unique publications, with 40 records meeting the final inclusion criteria. Most studies did not report phosphate monitoring methodology or an explicit definition of hypophosphatemia. Hypophosphatemia rates ranged from 0.0% to 92.1% for ferric carboxymaltose (FCM), 0.0% to 40.0% for iron sucrose, 0.4% for ferumoxytol, and 0.0% for low-molecular-weight (LMW) iron dextran. Randomized controlled studies described hypophosphatemia as “asymptomatic” or did not report on other associated sequelae. Eleven case reports detailed treatment-emergent hypophosphatemia in patients treated with FCM. Patients with acute hypophosphatemia primarily developed severe fatigue; those with repeated FCM dosing developed chronic hypophosphatemia associated with osteomalacia and bone deformities.

Conclusion
Studies analyzed in this SLR reported a range of hypophosphatemia rates, with the highest consistently seen in patients treated with FCM. Across the clinical literature, there appeared to be minimal standardization of phosphate monitoring and definitions of hypophosphatemia. Although multiple cases have documented serious clinical consequences of hypophosphatemia associated with certain IVIs, current trials neither consistently nor adequately assess the frequency and severity of treatment-emergent hypophosphatemia and may underestimate its prevalence.

[FilippovaYulia]

По большому счету не очень напрягает, главное, помнить об этом, отслеживать и при необходимости корректировать.
Конечно, в России сейчас чаще применяют внутривенное введение железа, но все равно это ничтожно мало, особенно вдали от "центров цивилизации", коими являются Москва и Питер.

[Melnichenko]

Примерно так же ответил и наш гематолог , доктор Шкляев Большое спасибо за интересную статью о том, что терапия внутривенным Карбоксимальтозатом Железа может вызывать тяжелую гипофосфатемию и даже иногда остеомаляции!

Пока с такими проблемами мы не сталкивались, но хорошо знаем о том, что снижение уровня фосфора является наиболее частым побочным эффектом (в инструкции к препарату (Феринжект) это чётко прописано).

На мой взгляд основная причина того, что пока нам не доводилось сталкиваться с развитием выраженной гипофосфатемии и тем более остеомаляциями заключается в используемой нами дозе этого препарата внутривенного железа. В присланной Вами статье в США используют дозу 750 мг в/в 1 раз в неделю (N2). Мы же назначаем этот препарат по 100 мг/сутки (в/в капельно в 100 мл физ. р-ра очень медленно!) и за неделю, таким образом, набираем 500 мг. Далее обязательный перерыв на выходные дни и, если есть необходимость далее продолжаем проводить ещё 5 инфузий железа, т.о. чтобы доза достигла суммарно 1000 мг (за 12 дней).

В любом случае следует по возможности мониторировать уровень фосфора в сыворотке крови хотя бы после каждых 2-3 инфузий.

[Dr.Vad]

немного по диагностике этого осложнения:
In symptomatic patients a test panel including ionized calcium, total and bone-specific alkaline phosphatase, PTH, 25 (OH) vitamin D and 1,25 (OH)2 vitamin D is recommended. Typical findings in patients with intravenous iron-induced hypophosphatemia include mild hypocalcemia, normal or mildly reduced 25 (OH) vitamin D and markedly reduced 1,25 (OH)2 vitamin D with hyperparathyroidism and elevated total and bone-specific alkaline phosphatase. These changes can persist beyond the resolution of hypophosphatemia...

по ведению-профилактике:
Delay further intravenous iron doses and switch to iron formulations with lower hypophosphatemia risk in patients with hypophosphatemia.
It is unknown if vitamin D supplementation before FCM administration reduces hypophosphatemia and fracture risk.
...treatment was started in the majority of patients including oral (n = 36) or intravenous (n = 20) phosphate, activated vitamin D (n = 21),vitamin D (n = 9) or calcium (n = 10). Treatment outcome was highly variable and inconsistently reported. Considering the underlying pathogenesis driven by elevated intact FGF23, phosphate supplementation would not sustainably correct hypophosphatemia, but increase urinary phosphate excretion [[39], [40], [41]]. As clinical and biochemical changes apparently persist up to several months after the last FCM infusion, rational treatment approaches would include mitigation of secondary hyperparathyroidism with activated vitamin D, which was successfully used in some patients [40,42,43].
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Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management. 2022
[Ссылки доступны только зарегистрированным пользователям ]