In vitro and in silico cholinesterase inhibitory and antioxidant effects of essential oils and extracts of two new Salvia fruticosa mill. cultivars (Turgut and Uysal) and GC-MS analysis of the essential oils.

The EtOH extracts of the leaves of two new cultivars (Uysal-SFU and Turgut-SFT) of Salvia fruticosa Mill. was tested against acetylcholinesterase (IC50: 30.62 ± 3.27 and 32.97 ± 2.33 µg/mL for SFU and SFT, respectively) and butyrylcholinesterase (IC50: 69.91 ± 1.08 µg/mL and 86.55 ± 1.26 µg/mL), respectively, relevant to Alzheimer's disease. The essential oils showed a stumpy inhibition against AChE and no inhibition against BChE. DPPH radical scavenging activity of the extracts (86.70 ± 0.17% and 86.14 ± 1.13% for SFU and SFT, respectively) was stronger than that of quercetin (85.51 ± 0.17%): Their (1.24 ± 0.05 and 1.04 ± 0.16 for SFU and SFT, respectively) ferric-reducing antioxidant power were close to that of the reference (e.g. quercetin, 1.42 ± 0.14). Molecular docking simulations were performed on their major monoterpenes. Our findings revealed that the leaf EtOH extracts of two cultivars are promising inhibitors of both AChE and BChE.

Reactivity of free N-heterocyclic carbenes in dichloromethane.

The reactivity of free 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene (MeIPr) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IDipp) in dichloromethane was investigated. MeIPr reacts relatively slowly and selectively with the solvent under the formation of imidazolium salt [MeIPrH]Cl, which was characterised through NMR and IR spectroscopy as well as single crystal X-ray diffraction. Through deuterium labelling experiments the reaction rate was determined. In contrast IDipp reacts unselectively to various imidazolium salts. Due to the slow decomposition rates of MeIPr and IDipp in CH2Cl2, reactions of the free carbenes with BeBr2 to [(MeIPr)BeBr2], [(MeIPr)2BeBr2] and [(IDipp)BeBr2] can be performed.

A Preference for Heterolepticity - Schlenk Type Equilibria in Organometallic Beryllium Systems.

The reaction of homoleptic beryllium halide with diphenyl beryllium complexes leads to the clean formation of heteroleptic beryllium Grignard compounds [(L)1-2 BePhX]1-2 (X=Cl, Br, I; L=C-, N-, O-donor ligand). The influence of ligands and solvent on these compounds, their formation and exchange equilibria in solution were investigated, together with the factors determining the complex constitution.

Cholinesterase Inhibitory and In Silico Toxicity Assessment of Thirty-Four Isoquinoline Alkaloids - Berberine as the Lead Compound.

BACKGROUND: Cholinesterase (ChE) inhibitors used currently in clinics for the treatment of Alzheimer's disease (AD) are the most prescribed drug class with nitrogen-containing chemical formula. Galanthamine, the latest generation anti-ChE drug, contains an isoquinoline structure. OBJECTIVE: The aim of the current study was to investigate the inhibitory potential of thirty-four isoquinoline alkaloids, e.g. (-)-adlumidine, ß-allocryptopine, berberine, (+)-bicuculline, (-)-bicuculline, (+)-bulbocapnine, (-)-canadine, (±)-chelidimerine, corydaldine, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, dehydrocavidine, (+)-fumariline, (-)-fumarophycine, (+)-α-hydrastine, (+)-isoboldine, 13-methylcolumbamine, (-)-norjuziphine, norsanguinarine, (-)-ophiocarpine, (-)-ophiocarpine-N-oxide, oxocularine, oxosarcocapnine, palmatine, (+)-parfumine, protopine, (+)-reticuline, sanguinarine, (+)-scoulerine, (±)-sibiricine, (±)-sibiricine acetate, (-)-sinactine, and (-)-stylopine isolated from several Fumaria (fumitory) and Corydalis species towards acetyl- (AChE) and butyrylcholinesterase (BChE) by microtiter plate assays. The alkaloids with strong ChE inhibition were proceeded to molecular docking simulations as well as in silico toxicity screening for their mutagenic capacity through VEGA QSAR (AMES test) consensus model and VEGA platform as statistical approaches. The inputs were evaluated in a simplified molecular input-line entry system (SMILES). RESULTS: ChE inhibition assays indicated that the highest AChE inhibition was caused by berberine (IC50: 0.72 ± 0.04 µg/mL), palmatine (IC50: 6.29 ± 0.61 µg/mL), ß-allocryptopine (IC50: 10.62 ± 0.45 µg/mL), (-)-sinactine (IC50: 11.94 ± 0.44 µg/mL), and dehydrocavidine (IC50: 15.01 ± 1.87 µg/mL) as compared to that of galanthamine (IC50: 0.74 ± 0.01 µg/mL), the reference drug with isoquinoline skeleton. Less number of the tested alkaloids exhibited notable BChE inhibition. Among them, berberine (IC50: 7.67 ± 0.36 µg/mL) and (-)-corydalmine (IC50: 7.78 ± 0.38 µg/mL) displayed a stronger inhibition than that of galanthamine (IC50: 12.02 ± 0.25 µg/mL). The mutagenic activity was shown for ß-allocryptopine, (+)- and (-)-bicuculline, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, (-)-fumarophycine, (-)-norjuziphine, (-)-ophiocarpine-N-oxide, (+)-scoulerine, (-)-sinactine, and (-)-stylopine by means of in silico experiments. The results obtained by molecular docking simulations of berberine, palmatine, and (-)-corydalmine suggested that the estimated free ligand-binding energies of these compounds inside the binding domains of their targets are reasonable to make them capable of establishing strong polar and nonpolar bonds with the atoms of the active site amino acids. CONCLUSION: Our findings revealed that berberine, palmatin, and (-)-corydalmine stand out as the most promising isoquinoline alkaloids in terms of ChE inhibition. Among them, berberine has displayed a robust dual inhibition against both ChEs and could be evaluated further as a lead compound for AD.

Inducing Nucleophilic Reactivity at Beryllium with an Aluminyl Ligand.

The reactions of anionic aluminium or gallium nucleophiles {K[E(NON)]}2 (E = Al, 1; Ga, 2; NON = 4,5-bis(2,6-diisopropylanilido)-2,7-ditert-butyl-9,9-dimethylxanthene) with beryllocene (BeCp2) led to the displacement of one cyclopentadienyl ligand at beryllium and the formation of compounds containing Be-Al or Be-Ga bonds (NON)EBeCp (E = Al, 3; Ga, 4). The Be-Al bond in the beryllium-aluminyl complex [2.310(4) Å] is much shorter than that found in the small number of previous examples [2.368(2) to 2.432(6) Å], and quantum chemical calculations suggest the existence of a non-nuclear attractor (NNA) for the Be-Al interaction. This represents the first example of a NNA for a heteroatomic interaction in an isolated molecular complex. As a result of this unusual electronic structure and the similarity in the Pauling electronegativities of beryllium and aluminium, the charge at the beryllium center (+1.39) in 3 is calculated to be less positive than that of the aluminium center (+1.88). This calculated charge distribution suggests the possibility for nucleophilic behavior at beryllium and correlates with the observed reactivity of the beryllium-aluminyl complex with N,N'-diisopropylcarbodiimide─the electrophilic carbon center of the carbodiimide undergoes nucleophilic attack by beryllium, thereby yielding a beryllium-diaminocarbene complex.

Evaluation of Anti-Alzheimer Activity of Synthetic Coumarins by Combination of in Vitro and in Silico Approaches.

Series of synthetic coumarin derivatives (1-16) were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes linked to the pathology of Alzheimer's disease (AD). Compound 16 was the most active AChE inhibitor with IC50 32.23±2.91 µM, while the reference (galantamine) had IC50 =1.85±0.12 µM. Compounds 9 (IC50 75.14±1.82 µM), 13 (IC50 =16.14±0.43 µM), were determined to be stronger BChE inhibitors than the reference galantamine (IC50 =93.53±2.23 µM). The IC50 value of compound 16 for BChE inhibition (IC50 =126.56±11.96 µM) was slightly higher than galantamine. The atomic interactions between the ligands and the key amino acids inside the binding cavities were simulated to determine their ligand-binding positions and free energies. The three inhibitory coumarins (9, 13, 16) were next tested for their effects on the genes associated with AD using human neuroblastoma (SH-SY5Y) cell lines. Our data indicate that they could be considered for further evaluation as new anti-Alzheimer drug candidates.

Ino-Chloridolithates from Ionothermal Synthesis.

Anionic lithium-containing species were predicted to impact ionic liquid-based electrochemical applications but have hitherto never been isolated from ionic liquid systems. Here, we report the first representatives of this class of compounds, ino-chloridolithates, comprising [LiCl2]- and [Li2Cl3]- polyanions from ionothermal reactions. Such compounds are obtained at moderate temperatures with imidazolium-based ionic liquids and LiCl. The addition of an auxiliary ammonium salt enhances the lattice energy to yield an ammonium lithate in good yields, which enables extensive investigations including solid-state nuclear magnetic resonance, infrared, and Raman spectroscopy. The structural motifs of ino-lithates are related to ino-silicates, as 1D-extended anionic substructures are formed. Despite this analogy, according to density functional theory calculations with periodic boundary conditions, no evidence of covalent bonding in the anionic moieties is found-indicating packing effects to be the main cause for the formation. Based on an in-depth analysis of the different synthetic parameters, this class of compounds is discussed as an intermediate in ionic liquid applications and could serve as a model system for electrochemical lithium-based systems.

Outlining In Vitro and In Silico Cholinesterase Inhibitory Activity of Twenty-Four Natural Products of Various Chemical Classes: Smilagenin, Kokusaginine, and Methyl Rosmarinate as Emboldening Inhibitors.

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.

Natural Products as Potential Leads Against Coronaviruses: Could They be Encouraging Structural Models Against SARS-CoV-2?

New coronavirus referred to SARS-CoV-2 has caused a worldwide pandemic (COVID-19) declared by WHO. Coronavirus disease 2019 (COVID-19) is an infectious disease with severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2). SARS-CoV-2 is akin to SARS-CoV, which was the causative agent of severe acute respiratory syndrome (SARS) in 2002 as well as to that of Middle East respiratory syndrome (MERS) in 2012. SARS-CoV-2 has been revealed to belong to Coronaviridiae family as a member of ß-coronaviruses. It has a positive-sense single-stranded RNA with the largest RNA genome. Since its genomic sequence has a notable similarity to that of SARS-CoV, antiviral drugs used to treat SARS and MERS are now being also applied for COVID-19 treatment. In order to combat SARS-CoV-2, many drug and vaccine development studies at experimental and clinical levels are currently conducted worldwide. In this sense, medicinal plants and the pure natural molecules isolated from plants have been reported to exhibit significant inhibitory antiviral activity against SARS-CoV and other types of coronaviruses. In the present review, plant extracts and natural molecules with the mentioned activity are discussed in order to give inspiration to researchers to take these molecules into consideration against SARS-CoV-2.

Norditerpenoids with Selective Anti-Cholinesterase Activity from the Roots of Perovskia atriplicifolia Benth.

Inhibition of cholinesterases remains one of a few available treatment strategies for neurodegenerative dementias such as Alzheimer's disease and related conditions. The current study was inspired by previous data on anticholinesterase properties of diterpenoids from Perovskia atriplicifolia and other Lamiaceae species. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by the three new natural compounds-(1R,15R)-1-acetoxycryptotanshinone (1), (1R)-1-acetoxytanshinone IIA (2), and (15R)-1-oxoaegyptinone A (3)-as well as, new for this genus, isograndifoliol (4) were assessed. Three of these compounds exhibited profound inhibition of butyrylcholinesterase (BChE) and much weaker inhibition of acetylcholinesterase (AChE). All compounds (1-4) selectively inhibited BChE (IC50 = 2.4, 7.9, 50.8, and 0.9 µM, respectively), whereas only compounds 3 and 4 moderately inhibited AChE (IC50 329.8 µM and 342.9 µM). Molecular docking and in silico toxicology prediction studies were also performed on the active compounds. Natural oxygenated norditerpenoids from the traditional Central Asian medicinal plant P. atriplicifolia are selective BChE inhibitors. Their high potential makes them useful candidate molecules for further investigation as lead compounds in the development of a natural drug against dementia caused by neurodegenerative diseases.

Novel pyridazinone derivatives as butyrylcholinesterase inhibitors.

In the current study, forty-four new [3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (EeAChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl heptylcarbamate (16c, eqBuChE, IC50 = 12.8 µM; EeAChE, no inhibition at 100 µM) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC50 = 3.25 µM; EeAChE, IC50 = 0.11 µM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC50 = 35 µM; EeAChE, no inhibition at 100 µM) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl (4-methylphenyl)carbamate 7c (eqBuChE, IC50 = 34.5 µM; EeAChE, 38.9% inhibition at 100 µM) was the most active derivative against EeAChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2H)-one scaffold is important for the inhibitory activity and compounds 7c, 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer's disease treatment.

Profiling Auspicious Butyrylcholinesterase Inhibitory Activity of Two Herbal Molecules: Hyperforin and Hyuganin C.

Cholinergic therapy based on cholinesterase (ChE) inhibitory drugs is the mainstay for the treatment of Alzheimer's disease. Therefore, an extensive research has been continuing for the discovery of drug candidates as inhibitors of acetyl- and butyrylcholinesterase. In this study, two natural molecules, e. g. hyperforin and hyuganin C were tested in vitro for their AChE and BChE inhibitory activity. Both of the compounds were ineffective against AChE, whereas hyperforin (IC50 =141.60±3.39 µm) and hyuganin C (IC50 =38.86±1.69 µm) were found to be the highly active inhibitors of BChE as compared to galantamine (IC50 =46.58±0.91 µm) which was used as the reference. Then, these molecules were further proceeded to molecular docking experiments in order to establish their interactions at the active site of BChE. The molecular docking results indicated that both of them are able to block the access to key residues in the catalytic triad of the enzyme, while they complement some of the hydrophobic residues of the cavity, what is consistent with our in vitro data. While both compounds were predicted as mutagenic, only hyuganin C showed hepatotoxicity in in silico analysis. According to whole outcomes that we obtained, particularly hyuganin C besides hyperforin are the promising BChE inhibitors, which can be the promising compounds for AD therapy.

Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives.

Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC50 = 46.58 ±â€¯0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC50 = 7.01 ±â€¯0.28 µM - 43.31 ±â€¯3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC50 = 7.01 ±â€¯0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC50 = 8.18 ±â€¯0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies.

Antifungal consumption, indications and selection of antifungal drugs in paediatric tertiary hospitals in Turkey: Results from the first national point prevalence survey.

OBJECTIVES: The aim of this point prevalence survey was to evaluate the consumption, indications and strategies of antifungal therapy in the paediatric population in Turkey. METHODS: A point prevalence study was performed at 25 hospitals. In addition to general data on paediatric units of the institutes, the generic name and indication of antifungal drugs, the presence of fungal isolation and susceptibility patterns, and the presence of galactomannan test and high-resolution computed tomography (HRCT) results were reviewed. RESULTS: A total of 3338 hospitalised patients were evaluated. The number of antifungal drugs prescribed was 314 in 301 patients (9.0%). Antifungal drugs were mostly prescribed in paediatric haematology and oncology (PHO) units (35.2%), followed by neonatal ICUs (NICUs) (19.6%), paediatric services (18.3%), paediatric ICUs (PICUs) (14.6%) and haematopoietic stem cell transplantation (HSCT) units (7.3%). Antifungals were used for prophylaxis in 147 patients (48.8%) and for treatment in 154 patients (50.0%). The antifungal treatment strategy in 154 patients was empirical in 77 (50.0%), diagnostic-driven in 29 (18.8%) and targeted in 48 (31.2%). At the point of decision-making for diagnostic-driven antifungal therapy in 29 patients, HRCT had not been performed in 1 patient (3.4%) and galactomannan test results were not available in 12 patients (41.4%). Thirteen patients (8.4%) were receiving eight different antifungal combination therapies. CONCLUSION: The majority of antifungal drugs for treatment and prophylaxis were prescribed in PHO and HSCT units (42.5%), followed by ICUs. Thus, antifungal stewardship programmes should mainly focus on these patients within the availability of diagnostic tests of each hospital.

Deprivación andrógenica en cáncer de próstata y riesgo de fractura a largo plazo / Androgen deprivation in prostate cancer and the long-term risk of fracture

Objetivos: Determinar el porcentaje de pérdida de masa ósea y el riesgo de fractura inducido por la terapia de deprivación androgénica en pacientes con cáncer de próstata. Material y métodos: Estudio prospectivo en 2 fases. En la primera se recogieron variables demográficas, FRAX(R), densidad mineral ósea y fracturas clínicas antes de iniciar la terapia y hasta un año después de finalizada. En la segunda se realizó una entrevista telefónica una media de 8,5 años después del inicio del estudio para evaluar nuevas fracturas. Resultados: Se incluyeron 150 pacientes con una edad media de 67 años y duración media de la terapia de 24 meses. Antes del inicio del tratamiento 62 pacientes (41%) presentaban osteoporosis o baja masa ósea en la densitometría. Después del primer año de tratamiento la densidad mineral ósea descendió una media de 3,7% y 2,1% en la columna lumbar y el cuello femoral, respectivamente. Al final del segundo y tercer año el porcentaje de pérdida fue menor. Durante la primera fase del estudio 4 pacientes (2,7%) sufrieron una fractura. En la entrevista telefónica a 80 pacientes (53%) solo uno había sufrido una fractura. Conclusiones: En los pacientes con cáncer de próstata y terapia de deprivación androgénica la mayor pérdida ósea se produce durante el primer año. Cuando el tratamiento no supera los 2 años el riesgo absoluto de fractura es bajo, y la fractura clínica infrecuente a corto y a largo plazo

Objectives: To determine the rate of bone mass loss and the risk of fracture induced by androgen deprivation therapy in patients with prostate cancer. Material and methods: Prospective study in 2 phases. In the first phase, demographic variables, FRAX(R), bone mineral density and clinical fractures were collected, before starting the therapy and up to 1 year after ending the therapy. In the second phase, we conducted a telephone interview a mean of 8.5 years after the start of the study to assess new fractures. Results: We included 150 patients with a mean age of 67 years and a mean therapy duration of 24 months. Before starting the treatment, 62 patients (41%) showed osteoporosis or low bone mass in the densitometry. After the first year of treatment, the bone mineral density decreased a mean of 3.7% and 2.1% in the lumbar spine and femoral neck, respectively. At the end of the second and third year, the loss rate was lower. During the first phase of the study, 4 patients (2.7%) experienced a fracture. In the telephone interviews with 80 patients (53%), only 1 had experienced a fracture. Conclusions: In the patients with prostate cancer and androgen deprivation therapy, greater bone loss occurred during the first year. When the treatment did not exceed 2 years, the absolute risk of fracture was low, and clinical fractures were uncommon in the short and long term

Androgen deprivation in prostate cancer and the long-term risk of fracture. / Deprivación andrógenica en cáncer de próstata y riesgo de fractura a largo plazo.

OBJECTIVES: To determine the rate of bone mass loss and the risk of fracture induced by androgen deprivation therapy in patients with prostate cancer. MATERIAL AND METHODS: Prospective study in 2 phases. In the first phase, demographic variables, FRAX®, bone mineral density and clinical fractures were collected, before starting the therapy and up to 1 year after ending the therapy. In the second phase, we conducted a telephone interview a mean of 8.5 years after the start of the study to assess new fractures. RESULTS: We included 150 patients with a mean age of 67 years and a mean therapy duration of 24 months. Before starting the treatment, 62 patients (41%) showed osteoporosis or low bone mass in the densitometry. After the first year of treatment, the bone mineral density decreased a mean of 3.7% and 2.1% in the lumbar spine and femoral neck, respectively. At the end of the second and third year, the loss rate was lower. During the first phase of the study, 4 patients (2.7%) experienced a fracture. In the telephone interviews with 80 patients (53%), only 1 had experienced a fracture. CONCLUSIONS: In the patients with prostate cancer and androgen deprivation therapy, greater bone loss occurred during the first year. When the treatment did not exceed 2 years, the absolute risk of fracture was low, and clinical fractures were uncommon in the short and long term.

Thyroid Hormone Replacement Therapy Improves Olfaction and Taste Sensitivity in Primary Hypothyroid Patients: A Prospective Randomised Clinical Trial.

Smell and taste are known to be influenced by thyroid function changes. However, many hypothyroid patients and physicians are unaware of their dysosmia and dysgeusia. The present study was performed to shed more light on the relation between hypothyroidism and olfactory loss. 32 primary hypothyroid patients and 31 controls enrolled in the prospective randomized interventional study. Newly diagnosed Primary hypothyroid patients were treated with L-thyroxine for 3-6 months. The control group was selected on the basis of the biochemical evidence of a normal thyroid function. Psychophysiological olfactory testing was performed using odor dispensers similar to felt-tip pens ("Sniffin' Sticks", Burghart, Wedel, Germany). Taste function tests were made using "Taste Strips" (Burghart, Wedel, Germany) which are basically tastant adsorbed filter paper strip. Smell identification, threshold, discrimination, TDI scores, bitter and sweet taste scores were significantly lower in untreated hypothyroid patients compared to controls (12.31±1.09 vs. 14.03±1.05, p<0.001; 7.09±1.15 vs. 8.89±1.12, p<0.001; 11.47±0.95 vs. 13.06±0.85, p<0.001; 30.90±2.70 vs. 35.89±2.07, p<0.001; 4.88±1.6 vs. 6.64±0.96, p<0.001; and 5.5±2.22 vs. 6.58±1.28, p=0.021) respectively. Comparison of scores at the third month of treatment and before treatment of hypothyroid patients revealed significant improvement in smell and taste functions in terms of identification, threshold, discrimination, TDI scores, bitter, sweet and salty tastes (12.31±1.09 vs. 13.84±1.22, p<0.001; 7.09±1.15 vs. 8.02±1.16, p<0.001; 11.47±0.95 vs. 12.41±1.21, p<0.001; 30.90±2.70 vs. 34.27±3.25, p<0.001; 4.88±1.6 vs. 6.06±1.4, p<0.001; 5.5±2.22 vs. 6.38±1.28, p<0.001; and 6.12±2.32 vs. 6.62±1.48, p=0.044) respectively. On correlation analysis, there was a negative correlation between TPO-Ab levels and discrimination, identification and TDI scores (r=-0.409, p=0.02; r=-0.424, p=0.016; r=-0.532, p=0.002), and also between Tg-Ab levels and identification, TDI, and bitter scores (r=-0.423, p=0.016; r=-0.468, p=0.007; r=-0.409, p=0.02) respectively. Primary hypothyroidism was found to have a negative effect on smell and taste. RAI treatment was found to be most destructive on smell and taste compared to surgical and autoimmune hypothyroidism. Treatment of hypothyroidism was positively correlated with an improvement of both senses. Thus, the future workup of patients with smell/taste loss should include investigations for thyroid functions.