Pharmacological hyperprolactinemia: a retrospective analysis of 501 hyperprolactinemia cases in primary care setting.

PURPOSE: To describe a series of cases with pharmacological hyperprolactinemia in primary care setting and the prolactin levels, clinical implications of different causes of pharmacological hyperprolactinemia. METHODS: A retrospective study of all patients with detected hyperprolactinemia in hormonal studies was performed between 2019 and 2020 in 20 Spanish primary care centers. Hyperprolactinemia is defined as a serum prolactin >19.4ng/ml in men and >26.5ng/ml in women. Four pharmacological causes of hyperprolactinemia were established: (i) oral contraceptives (OCPs) and other hormonal treatments; (ii) antipsychotics and antidepressants; (iii) other drugs (calcium antagonists, antiemetics, H2 antihistamines, opioids, and anabolic agents); and (iv) hyperprolactinemia due to several drugs. RESULTS: From a sample of 501 patients with elevated serum prolactin, 39.4% (n=162) had pharmacological hyperprolactinemia. The most common cause of pharmacological hyperprolactinemia in women was OCPs (n=61) while in men antipsychotics/antidepressants (n=21). In the cases of hyperprolactinemia due to antipsychotics/antidepressants, the prolactin levels were significantly higher in patients taking classical antipsychotics than in those taking second-generation antipsychotics (80.0±43.17 vs. 50.7±28.66 ng/dL, P=0.035). The antidepressant/antipsychotic group showed hyperprolactinemia-related symptoms more frequently than the group of other treatments (58.9% vs. 32%, P=0.001). The concomitant use of several drugs caused hyperprolactinemia-related symptoms more frequently than one drug alone (73% vs. 44%, P=0.031). CONCLUSION: In this series of cases, drugs represented the 39.4% of the causes of hyperprolactinemia. The most common drugs were OCPs in women and antipsychotics/antidepressants in men. Antidepressants/antipsychotics were drugs that caused the greatest elevation of the prolactin levels and showed hyperprolactinemia-related symptoms more frequently.

Unravelling hip-spine bone mineral density discordance in people living with HIV.

INTRODUCTION: In people living with HIV (PLWH), bone mineral density (BMD) discordance between the lumbar spine (LS) and femoral neck (FN) could be frequent given the high frequency of secondary osteoporosis, including HIV-related factors for bone disease. MATERIALS AND METHODS: Retrospective cohort of PLWH with a dual X-ray absorptiometry scan. Hip-spine BMD discordance was defined as different T-score or Z-scores categories at LS and FN. RESULTS: Overall, 865 individuals (mean 49.5 years, female 27%) were included. Osteoporosis diagnosis was four-to-seven times lower when both skeletal sites were affected than when considering the lowest T-score at any site (overall, 21% vs 4%). Hip-spine BMD discordance was observed in 381 (44%) individuals, it increased with age (from 43 to 52%, P = 0.032), and it was mainly due to lower LS-BMD. A lower FN-BMD was associated with older age, lower BMI (P < 0.01), and HIV-related factors, such as low CD4 + T-cell counts, duration of HIV infection, and time on antiretroviral therapy (ART). In a multivariate regression analysis, sex male (Odds Ratio, OR 4.901), hyperparathyroidism (OR, 2.364), and time on ART (OR 1.005 per month) were independently associated with discordance. A higher estimated fracture risk by FRAX equation was observed in individuals with BMD discordance due to lower FN-BMD compared to those with lower LS-BMD (+ 36% for major osteoporotic fracture, P = 0.04; + 135% for hip fracture, P < 0.01). CONCLUSION: Hip-spine BMD discordance is highly prevalent in PLWH and it is associated with classical and HIV-related risk factors, modifying the rate of osteoporosis and fracture risk estimation.

Stress Hyperglycemia and Osteocalcin in COVID-19 Critically Ill Patients on Artificial Nutrition.

We aimed to study the possible association of stress hyperglycemia in COVID-19 critically ill patients with prognosis, artificial nutrition, circulating osteocalcin, and other serum markers of inflammation and compare them with non-COVID-19 patients. Fifty-two critical patients at the intensive care unit (ICU), 26 with COVID-19 and 26 non-COVID-19, were included. Glycemic control, delivery of artificial nutrition, serum osteocalcin, total and ICU stays, and mortality were recorded. Patients with COVID-19 had higher ICU stays, were on artificial nutrition for longer (p = 0.004), and needed more frequently insulin infusion therapy (p = 0.022) to control stress hyperglycemia. The need for insulin infusion therapy was associated with higher energy (p = 0.001) and glucose delivered through artificial nutrition (p = 0.040). Those patients with stress hyperglycemia showed higher ICU stays (23 ± 17 vs. 11 ± 13 days, p = 0.007). Serum osteocalcin was a good marker for hyperglycemia, as it inversely correlated with glycemia at admission in the ICU (r = -0.476, p = 0.001) and at days 2 (r = -0.409, p = 0.007) and 3 (r = -0.351, p = 0.049). In conclusion, hyperglycemia in critically ill COVID-19 patients was associated with longer ICU stays. Low circulating osteocalcin was a good marker for stress hyperglycemia.

Serum zinc and copper in people with COVID-19 and zinc supplementation in parenteral nutrition.

OBJECTIVES: Zinc and copper are important to protect cells from oxidative stress and to enhance immunity. An association between low zinc levels and the severity of acute respiratory distress syndrome has been shown for people with COVID-19. We aimed to study serum zinc and copper concentrations in people with severe COVID-19 and zinc supplementation in parenteral nutrition (PN). METHODS: Thirty-five people with COVID-19 in need of PN were studied in a retrospective design. Serum samples were collected at three time points: at the start of PN, between 3 and 7 d after, and at the end of PN. RESULTS: Participants were on PN for a mean of 14 d, with a mean (± SD) daily supplemental zinc of 14.8 ± 3.7 mg/d. Serum zinc increased during PN administration from 98.8 ± 22.8 to 114.1 ± 23.3 µg/dL (Wilks' λ = 0.751, F = 5.459, P = 0.009). Conversely, serum copper did not vary from baseline (107.9 ± 34.2 µg/dL) to the end of the study (104.5 ± 37.4 µg/dL, Wilks' λ = 0.919, F = 1.453, P = 0.248). Serum zinc within the first week after starting PN and at the end of PN inversely correlated with total hospital stay (r = -0.413, P = 0.014, and r = -0.386, P = 0.022, respectively). Participants in critical condition presented lower serum copper (z = 2.615, P = 0.007). Mortality was not associated with supplemental zinc or with serum zinc or copper concentrations at any time of the study (P > 0.1 for all analyses). CONCLUSIONS: Serum zinc concentrations during PN support were inversely associated with length of hospital stay but not with mortality. Serum copper concentrations were lower in participants in critical condition but not associated with prognosis.

Bone mineral density decline according to renal tubular dysfunction and phosphaturia in tenofovir-exposed HIV-infected patients.

INTRODUCTION: The mechanisms underlying the effect of tenofovir disoproxil fumarate (TDF) on the decline of bone mineral density (BMD) have not been established, especially the effect of renal tubular dysfunction. METHODS: Longitudinal study of 90 patients with two successive dual X-ray absorptiometry scans after evaluation of serum and urinary parameters (proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria, ß-2-microglobulin, and retinol-binding protein). RESULTS: After a median of 38 months on TDF, osteopenia at spine and hip was observed in 49 and 48%, and osteoporosis in 9 and 2%, respectively. There was a lineal correlation between BMD at femoral neck and time on TDF (Spearman's rho = -0.27; P = 0.01). One or more tubular abnormalities were observed in 80% of cases (hyperphosphaturia, 50%). A lower BMD correlated with phosphaturia (r = -0.25; P = 0.03), even with phosphataemia within normal limits. In fact, patients with previous improvement in phosphaturia had better BMD at inclusion (Spearman's rho = -0.33; P < 0.01). A second dual X-ray absorptiometry, after a median of 40.8 months (33.8-45.1; 627.7 patients-year on TDF), showed additional BMD reduction at hip in 50% of cases (36% with bone loss >3%), a decline associated with phosphaturia (ß, -0.31; P = 0.01) or number of tubular abnormalities (ß, -0.41; P = 0.01), but also with use of boosted protease inhibitors (ß, -0.47; P = 0.03) and BMD at inclusion (ß, -0.33; P = 0.03). CONCLUSION: Chronic abnormal phosphaturia explains, at least in part, progressive bone loss during TDF therapy. These data suggest that tubular dysfunction leads to an altered equilibrium between phosphataemia, phosphaturia, and bone as mechanism of progressive BMD decline.

Effect of a monthly dose of calcidiol in improving vitamin D deficiency and secondary hyperparathyroidism in HIV-infected patients.

There are no data about the optimal supplementation therapy in HIV-infected patients with vitamin D (25OHD) deficiency. The aim of this study was to assess the effect of an oral monthly dose of 16,000 IU calcidiol. We performed a longitudinal cohort study of 365 HIV-infected patients (24 % females) was with sequential determinations of 25OHD, serum parathyroid hormone (PTH), calcium, and alkaline phosphatase. The efficacy and safety of supplementation in 123 patients were compared against dietary and sun exposure advice. Overall, mean baseline 25OHD levels were 19.1 ng/ml (IQR 12-23.6), 63 % of patients had 25OHD deficiency and 27 % secondary hyperparathyroidism. After a median time of 9.3 months (95.61 patients-year on-treatment), 25OHD levels increased in comparison with non-supplemented patients (+16.4 vs. +3.2 ng/ml; p < 0.01), decreasing the rate of 25OHD deficiency (from 84 to 24 %), and decreasing serum PTH (-4.9 pg/ml) and the rate of secondary hyperparathyroidism (from 43 to 31 %; p < 0.001). This improvement was observed irrespective of HIV/HCV coinfection or the use of efavirenz. In a regression analysis, adjusting by seasonality, a lower baseline 25OHD was associated with persistence of deficiency (relative risk, RR 1.07; 95 % CI 1.03-1.1; p < 0.001), whereas calcidiol supplementation was the only factor associated with significant improvement (RR 0.38; 95 % CI 0.12-0.46; p < 0.001). This monthly dose showed no clinical toxicity, and no patient had 25OHD levels above 100 ng/ml, nor hypercalcemia. The use of monthly calcidiol is safe, easy to take, and largely effective to improve vitamin D deficiency and secondary hyperparathyroidism in HIV-infected patients.

Chromium arene complexes in organic synthesis.

The complexation of an arene to a chromium tricarbonyl unit changes its chemical behavior, giving rise to unprecedented transformations. The electron-withdrawing effect of the unit allows efficient nucleophilic attack (S(N)Ar and dearomatization reactions), stabilizes negative charges in benzylic positions and activates C(Ar)-halogen bonds for cross-coupling reactions. In addition, the Cr(CO)(3) moiety exerts great facial control so it can be used as an auxiliary that can easily be removed. The 1,2- and 1,3-unsymmetrically disubstituted complexes are planar chiral and there are various ways to prepare them in enantiomerically pure form. Planar chiral chromium complexes are becoming useful intermediates and ligands for asymmetric catalysis. This mature field of organometallic chemistry has given rise to several synthetic applications of chromium arene complexes in the synthesis of natural products. This chemistry is overviewed in this tutorial review, giving special attention to the most recent and outstanding contributions in the area.

Arene-chromium tricarbonyl complexes in the Pauson-Khand reaction.

[reactions: see text] We show the use of arene-chromium tricarbonyl complexes in intra- and intermolecular Pauson-Khand reactions. Both styrene and ethynylbenzene complexes react with alkynes and olefins. The synthesis of enynes connected through chromium-complexed aromatic rings is developed. The intramolecular Pauson-Khand reaction occurs in a totally diastereoselective manner.

Tandem enyne metathesis-Diels-Alder reaction for construction of natural product frameworks.

Enynes connected through aromatic rings are used as substrates for metathesis reactions. The reactivity of three ruthenium carbene complexes is compared. The resulting 1,3-dienes are suitable precursors of polycyclic structures via a Diels-Alder process. Some domino RCM-Diels-Alder reactions are performed, suggesting a possible beneficial effect of the ruthenium catalyst in the cycloaddition process. Other examples require Lewis acid cocatalyst. When applied to aromatic ynamines or enamines, a new synthesis of vinylindoles is achieved. Monitorization of several metathesis reactions with NMR shows the different behavior for ruthenium catalysts. New carbenic species are detected in some reactions with an important dependence on the solvent used.

Tandem RCM-Pauson-Khand reaction for access to tricycles in one step.

Starting from conveniently designed dienynes complexed to cobalt, a tandem RCM-intramolecular Pauson-Khand reaction yields tricyclic compounds. The methodology allows the synthesis of 6,5,5 and 7,5,5 systems.