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1.
Acta Neuropathol ; 147(1): 60, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38526612

RESUMO

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.


Assuntos
Neuropatias Diabéticas , Antagonistas Muscarínicos , Animais , Humanos , Camundongos , Ratos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/patologia , Ácidos Mandélicos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Qualidade de Vida , Receptores Muscarínicos , Diabetes Mellitus Tipo 1
2.
Urogynecology (Phila) ; 30(3): 214-222, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38484234

RESUMO

IMPORTANCE: There is strong evidence for long-term cognitive effects with anticholinergic use. Differences in insurance coverage of anticholinergics and beta-3 agonists hinder individualization of overactive bladder (OAB) treatment. OBJECTIVES: The aims of the study were to assess individual and family health insurance plan coverage for select OAB medications and to compare coverage of preferred medications to those with a greater risk of cognitive dysfunction. STUDY DESIGN: This cross-sectional study analyzed formularies for the top 7 U.S. medical insurers. Coverage tiers were assessed for the following 7 OAB medications: (1) oxybutynin instant-release 5 mg, (2) oxybutynin extended-release 5 mg, (3) solifenacin 5 mg, (4) trospium instant-release 20 mg, (5) trospium extended-release 60 mg, (6) mirabegron 25 mg, and (7) vibegron 75 mg. Coverage was compared between nonpreferred (oxybutynin, solifenacin) and preferred medications (trospium, mirabegron, vibegron). Coverage scores, representing a weighted average based on coverage tier frequency relative to the number of plans investigated for each state or insurer, were generated with a lower coverage score indicating better coverage (range, 0.2-1.0). RESULTS: A total of 2,780 insurance plans from 41 states representing a 47% market share for the individual and family marketplace were evaluated. Oxybutynin IR had the best coverage score across insurers (0.2) while vibegron had the worst (0.92). Preferred medications were more often designated to higher tiers with worse coverage compared with nonpreferred medications (P < 0.001). Less concordance in coverage between insurers was noted for anticholinergics with greater bladder specificity and for extended-release formulations. CONCLUSIONS: Despite risks with anticholinergics, beta-3 agonists were more expensive across all insurers highlighting the need for expanded coverage of preferred medications to avoid cognitive dysfunction when undergoing treatment for OAB.


Assuntos
Acetanilidas , Ácidos Mandélicos , Tiazóis , Bexiga Urinária Hiperativa , Humanos , Bexiga Urinária Hiperativa/tratamento farmacológico , Succinato de Solifenacina/uso terapêutico , Estudos Transversais , Antagonistas Muscarínicos/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico
3.
Environ Pollut ; 346: 123628, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38395129

RESUMO

Epidemiological evidence concerning effects of simultaneous exposure to noise and benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS) on renal function remains uncertain. In 2020, a cross-sectional study was conducted among 1160 petrochemical workers in southern China to investigate effects of their co-exposure on estimated glomerular filtration rate (eGFR) and mild renal impairment (MRI). Noise levels were assessed using cumulative noise exposure (CNE). Urinary biomarkers for BTEXS were quantified. We found the majority of workers had exposure levels to noise and BTEXS below China's occupational exposure limits. CNE, trans, trans-muconic acid (tt-MA), and the sum of mandelic acid and phenylglyoxylic acid (PGMA) were linearly associated with decreased eGFR and increased MRI risk. We observed U-shaped associations for both N-acetyl-S-phenyl-L-cysteine (SPMA) and o-methylhippuric acid (2-MHA) with MRI. In further assessing the joint effect of BTEXS (ß, -0.164 [95% CI, -0.296 to -0.033]) per quartile increase in all BTEXS metabolites on eGFR using quantile g-computation models, we found SPMA, tt-MA, 2-MHA, and PGMA played pivotal roles. Additionally, the risk of MRI associated with tt-MA was more pronounced in workers with lower CNE levels (P = 0.004). Multiplicative interaction analysis revealed antagonisms of CNE and PGMA on MRI risk (P = 0.034). Thus, our findings reveal negative dose-effect associations between noise and BTEXS mixture exposure and renal function in petrochemical workers. With the exception of toluene, benzene, xylene, ethylbenzene, and styrene are all concerning pollutants for renal dysfunction. Effects of benzene, ethylbenzene, and styrene exposure on renal dysfunction were more pronounced in workers with lower CNE.


Assuntos
Glioxilatos , Nefropatias , Ácidos Mandélicos , Exposição Ocupacional , Humanos , Benzeno/análise , Xilenos/análise , Tolueno/análise , Estireno/análise , Estudos Transversais , Derivados de Benzeno/análise , Exposição Ocupacional/análise
4.
J Clin Sleep Med ; 20(1): 169-172, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38163944

RESUMO

Sleep hyperhidrosis is defined as profuse nocturnal sweating that disrupts sleep. Although the mechanism is unknown, some cases are secondary to hot flushes during the menopausal period, medical, mental and sleep disorders, and medication, while dysregulation of thermoregulation during sleep is suspected in primary cases. We present the case of a woman with severe primary sleep hyperhidrosis, occurring nightly for 23 years, which definitively resolved after brief treatment with oxybutynin (a muscarinic receptor-blocking anticholinergic). An ammoniacal odor in the sweat and a sensation of coldness on awakening during sweating episodes suggest that the mechanism of her night sweating was not an exacerbation of thermoregulation during the night but shares the mechanical properties of emotional/psychological sweating. This extreme case of sleep hyperhidrosis was treated with excellent efficacy and minimal side effects using oxybutynin, which could benefit other patients with nighttime discomfort. CITATION: Dias L, Martinot C, Vaillant G, Arnulf I. Severe night sweating treated by oxybutynin. J Clin Sleep Med. 2024;20(1):169-172.


Assuntos
Hiperidrose , Sudorese , Feminino , Humanos , Hiperidrose/tratamento farmacológico , Hiperidrose/induzido quimicamente , Antagonistas Muscarínicos/uso terapêutico , Ácidos Mandélicos/uso terapêutico
5.
J Biochem Mol Toxicol ; 38(1): e23584, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38009396

RESUMO

Urinary tract infection (UTI) mainly results from bacterial infections in the urinary tract and markedly impacts the normal lives of millions of patients worldwide. The infection and damage to urethral epithelial cells is the first and key step of UTI development and is a critical target for treating clinical UTI. Oxybutynin, an agent for treating urinary incontinence, is recently claimed with protective effects on bladder ultrastructure. Our study will assess the impact of Oxybutynin on inflammation in lipopolysaccharide (LPS)-stimulated bladder epithelial cells. Bladder epithelial T24 cells were treated with 1 µg/mL LPS with or without 10 and 20 µM Oxybutynin for 24 h. Increased levels of oxidative stress (OS) biomarkers, such as reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, as well as upregulated inducible nitric oxide synthase and promoted release of nitric oxide, were observed in LPS-managed T24 cells, all of which were signally suppressed by Oxybutynin. Furthermore, severe inflammatory responses, including enhanced release of cytokines, upregulated matrix metallopeptidase-2 (MMP-2) and MMP-9, and raised monocyte chemoattractant protein-1 level, were found in LPS-challenged T24 cells, which were markedly reversed by Oxybutynin. Moreover, the activated toll-1ike receptor 4/nuclear factor-κB pathway observed in LPS-managed T24 cells was repressed by Oxybutynin. Collectively, Oxybutynin mitigated LPS-induced inflammatory response in human bladder epithelial cells.


Assuntos
Lipopolissacarídeos , Ácidos Mandélicos , Bexiga Urinária , Humanos , Lipopolissacarídeos/toxicidade , Bexiga Urinária/metabolismo , Citocinas/metabolismo , NF-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/metabolismo , Células Epiteliais/metabolismo
6.
CNS Neurosci Ther ; 30(1): e14398, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37553527

RESUMO

OBJECTIVE: Adrenocorticotropic hormone (ACTH) is the first-line treatment of infantile epileptic spasm syndrome (IESS). Its reported effectiveness varies, and our current understanding regarding the role of gut microbiota composition in IESS treatment response is limited. This study assessed the microbiome-metabolome association to understand the role and mechanism of gut microbiota composition in IESS treatment outcomes. METHODS: Children with IESS undergoing ACTH treatment were enrolled. Pre-treatment stool and serum samples were collected for 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. The children were divided into "responsive" and "non-responsive" groups, and gut microbiota and serum metabolome differences were analyzed. RESULTS: Of the 30 patients with IESS, 14 responded to ACTH and 16 did not. The "non-responsive" group had larger maleficent Clostridioides and Peptoclostridium_phage_p630P populations (linear discriminant analysis >2; false discovery rate q < 0.05). Ten metabolites were upregulated (e.g., xanthurenic acid) and 15 were downregulated (e.g., vanillylmandelic acid) (p < 0.05). Association analysis of the gut microbiome and serum metabolome revealed that Clostridioides and Peptoclostridium_phage_p630P2 were positively correlated with linoleic and xanthurenic acids, while Clostridioides was negatively correlated with vanillylmandelic acid (p < 0.05). A classifier using differential gut bacteria and metabolites achieved an area under the receiver operating characteristic curve of 0.906 to distinguish responders from non-responders. CONCLUSION: This study found significant differences in pre-treatment gut microbiota and serum metabolome between children with IESS who responded to ACTH and those who did not. Additional exploration may provide valuable information for treatment selection and potential interventions. Our results suggest that varying ACTH responses in patients with IESS may be associated with increased gut Clostridioides bacteria and kynurenine pathway alteration, but additional experiments are needed to verify this association.


Assuntos
Hormônio Adrenocorticotrópico , Clostridioides , Ácidos Mandélicos , Criança , Humanos , Hormônio Adrenocorticotrópico/uso terapêutico , RNA Ribossômico 16S , Ácido Vanilmandélico , Espasmo
7.
Int J Mol Sci ; 24(20)2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37894730

RESUMO

Frequently, a good chiral separation is the result of long trial and error processes. The three-point interaction mechanisms require the fair geometrical fitting and functional group compatibility of the interacting groups. Structure-chiral selectivity correlations are guidelines that can be established via trough systematic studies using model compounds. The enantiorecognition of the test compounds was studied on an octakis 2,3-Di-O-acetyl-6-O-tert-butyldimethylsilyl-gamma-cyclodextrin (TBDMSDAGCD) chiral selector. In our work, mandelic acid and its variously substituted compounds were used as model compounds to establish adaptable rules for other enantiomeric pairs. The mandelic acid and its modified compounds were altered at both their carboxyl and hydroxyl positions to test the key interaction forces of the chiral recognition processes. Ring- and alkyl-substituted mandelic acid derivatives were also used in our experiments. The chiral selectivity values of 20 test compounds were measured and extrapolated to 100 °C. The hydrogen donor abilities of test compounds improved their chiral selectivities. The inclusion phenomenon also played a role in chiral recognition processes in several cases. Enantiomer elution reversals were observed for different derivatives of hydroxyl groups, providing evidence for the multimodal character of the selector. The results of our research can serve as guidelines to achieve appropriate chiral separation for other enantiomeric pairs.


Assuntos
Ciclodextrinas , gama-Ciclodextrinas , gama-Ciclodextrinas/química , Ciclodextrinas/química , Ácidos Mandélicos , Cromatografia Gasosa/métodos , Estereoisomerismo
8.
Artigo em Chinês | MEDLINE | ID: mdl-37805429

RESUMO

Objective: To develop a method for the analysis of phenylglyoxylic acid (PGA) and mandelic acid (MA) in urine by ultra-high performance liquid chromatography tandem mass spectrometry. Methods: The study was conducted in April 2022. Urine samples were directly diluted with the initial mobile phase, separated by Waters HSS T3 column after passing through the membrane, and analyzed under negative ionization mode (ESI(-)) and multiple reaction monitoring (MRM) conditions, the contents of PGA and MA in human urine were quantitatively determined by external standard method. Results: The determination of PGA and MA showed a good linear relationship within the range of 10-1000 ng/ml, with a correlation coefficient of 0.9999. The linear regression equation of PGA was y=1141.4x+2157.3, the detection limit and lower limit of quantification of the method were 0.081 ng/ml and 0.269 ng/ml, and the recovery rate was 90.47%-99.83%. The linear regression equation of MA was y=62.8x+140.3, the detection limit and lower limit of quantification of the method were 0.551 ng/ml and 1.836 ng/ml, and the recovery rate was 92.75%-101.09%. The intra and inter batch precision of PGA and MA were both<5%. Conclusion: An ultra-high performance liquid chromatography tandem mass spectrometry method for the analysis of PGA and MA in urine was established.The sample pretreatment operation is simple, and the accuracy and precision of the method meet the standard requirements. It can be used for monitoring and evaluating PGA and MA in urine of the general population and occupational contact population.


Assuntos
Ácidos Mandélicos , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Ácidos Mandélicos/urina
9.
J Dermatol ; 50(11): 1459-1472, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37605375

RESUMO

The long-term safety and efficacy of 52-week application of oxybutynin hydrochloride 20% lotion (20% OL) for the treatment of primary palmar hyperhidrosis (PPHH) in Japanese patients aged ≥12 years were evaluated in an open-label extension (OLE) of a 4-week, randomized, double-blind (DB) study. The OLE included 114 patients who completed the DB study and wished to continue treatment and 12 new patients. In the safety analysis population (125 patients), the incidence of adverse events (AEs) and adverse drug reactions (ADRs) was 79.2% and 36.0%, respectively. Serious AEs were observed in two patients but were considered unrelated to the investigational drug. The incidence of AEs that led to study discontinuation was 1.6%. The incidence of application site AEs and ADRs was 35.2% and 26.4%, respectively. The severity of most events was mild. The incidence of anticholinergic AEs related to dry mouth was 3.2% for thirst and 0.8% for dry throat. The long-term efficacy of 20% OL was confirmed by a long-lasting reduction in sweat volume and improvement in the Hyperhidrosis Disease Severity Scale and Dermatology Life Quality Index. This study has several limitations: First the results may include some bias because most of the participants were from the prior DB study; second, the results may not be generalizable because only a few participants were in the age group most susceptible to PPHH (i.e., < 15 years old); and third, the study did not obtain safety information from treatment for more than 52 weeks, so this information must be collected in clinical practice in the future. No reduced therapeutic effect was observed in patients with PPHH in this study after 52-week application of 20% OL. Also, few patients experienced serious AEs or AEs that led to study treatment discontinuation.


Assuntos
Hiperidrose , Ácidos Mandélicos , Humanos , Adolescente , Resultado do Tratamento , Ácidos Mandélicos/efeitos adversos , Hiperidrose/tratamento farmacológico , Método Duplo-Cego
10.
Int Urol Nephrol ; 55(9): 2139-2144, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37314647

RESUMO

PURPOSE: Pollakiuria is defined as a change in the pattern of daily urination. Students have mentioned wetting their pants at school as the third tragic event after the death of a parent or going blind. In this study, the effect of adding Montelukast to oxybutynin on the improvement of urinary symptoms of patients with pollakiuria was studied. MATERIALS AND METHODS: This study was a pilot clinical trial in which children with pollakiuria aged 3-18 years old were included. These children were randomly divided into two groups of intervention (Montelukast plus oxybutynin) and the control group (only oxybutynin). At the beginning and the end of the study (after 14 days), mothers were asked about the frequency of daily urination. Finally, the gathered data were compared between two groups. RESULTS: In the present study, 64 patients were examined in two intervention and control groups (32 in each group). The results revealed that although significant changes were observed in both groups before and after intervention, the average changes in the intervention group were significantly higher (p = 0.014). CONCLUSION: The results of this study showed that adding montelukast to oxybutynin has a significant decrease in frequency of daily urination in patients with pollakiuria, although further studies are recommended in this area.


Assuntos
Antagonistas Muscarínicos , Micção , Humanos , Criança , Pré-Escolar , Adolescente , Antagonistas Muscarínicos/farmacologia , Ácidos Mandélicos/uso terapêutico , Ácidos Mandélicos/farmacologia , Método Duplo-Cego , Resultado do Tratamento
11.
J Agric Food Chem ; 71(20): 7631-7641, 2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-37179490

RESUMO

To investigate the effect of spatial configuration on the biological activity of the compounds, a series of chiral mandelic acid derivatives with a moiety of 1,3,4-oxadiazole thioether have been designed and synthesized. Bioassay results demonstrated that most title compounds with the S-configuration exhibited better in vitro antifungal activity against three plant fungi, such as H3' (EC50 = 19.3 µg/mL) against Gibberella saubinetii, which was approximately 16 times higher than that of H3 (EC50 = 317.0 µg/mL). CoMFA and CoMSIA models were established for 3D-QSAR analysis and provided an important support for further optimization of this series of compounds. Comparing the preliminary mechanism studies between enantiomers (H3 and H3') found that the S-configuration compound (H3') exhibited a stronger ability to destroy the surface structure of G. saubinetii mycelia, causing the leakage of intracellular substances to accelerate and the growth of the hyphae to be inhibited. The results provided a novel view for the further optimization of this series of active compounds and deep mechanism study of chiral pesticides.


Assuntos
Antifúngicos , Relação Quantitativa Estrutura-Atividade , Antifúngicos/farmacologia , Fungos , Ácidos Mandélicos , Relação Estrutura-Atividade
12.
Int J Mol Sci ; 24(10)2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37240243

RESUMO

Plant diseases caused by phytopathogenic fungi are a serious threat in the process of crop production and cause large economic losses to global agriculture. To obtain high-antifungal-activity compounds with novel action mechanisms, a series of 4-substituted mandelic acid derivatives containing a 1,3,4-oxadiazole moiety were designed and synthesized. In vitro bioassay results revealed that some compounds exhibited excellent activity against the tested fungi. Among them, the EC50 values of E13 against Gibberella saubinetii (G. saubinetii), E6 against Verticillium dahlia (V. dahlia), and E18 against Sclerotinia sclerotiorum (S. sclerotiorum) were 20.4, 12.7, and 8.0 mg/L, respectively, which were highly superior to that of the commercialized fungicide mandipropamid. The morphological studies of G. saubinetii with a fluorescence microscope (FM) and scanning electron microscope (SEM) indicated that E13 broke the surface of the hyphae and destroyed cell membrane integrity with increased concentration, thereby inhibiting fungal reproduction. Further cytoplasmic content leakage determination results showed a dramatic increase of the nucleic acid and protein concentrations in mycelia with E13 treatment, which also indicated that the title compound E13 could destroy cell membrane integrity and affect the growth of fungi. These results provide important information for further study of the mechanism of action of mandelic acid derivatives and their structural derivatization.


Assuntos
Antifúngicos , Fungicidas Industriais , Antifúngicos/química , Fungicidas Industriais/farmacologia , Ácidos Mandélicos/farmacologia , Oxidiazóis , Relação Estrutura-Atividade
13.
Angew Chem Int Ed Engl ; 62(20): e202300906, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36929048

RESUMO

The development of mild, efficient, and enantioselective methods for preparing chiral building blocks from simple, renewable carbon units has been a long-term goal of the sustainable chemical industry. Mandelate derivatives are valuable pharmaceutical intermediates and chiral resolving agents, but their manufacture relies heavily on highly toxic cyanide. Herein, we report (S)-4-hydroxymandelate synthase (HmaS)-centered biocatalytic cascades for the synthesis of mandelates from benzaldehydes and glycine. We show that HmaS can be engineered to perform R-selective hydroxylation by single-point mutation, empowering the stereodivergent synthesis of both (S)- and (R)-mandelate derivatives. These biocatalytic cascades enabled the production of various mandelate derivatives with high atom economy as well as excellent yields (up to 98 %) and ee values (up to >99 %). This methodology offers an effective cyanide-free technology for greener and sustainable production of mandelate derivatives.


Assuntos
Aldeídos , Ácidos Mandélicos , Biocatálise , Hidroxilação , Benzaldeídos , Estereoisomerismo
14.
J Am Acad Dermatol ; 89(1): 62-69, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36990320

RESUMO

BACKGROUND: No previous controlled studies have been specifically designed or adequately powered to show the efficacy of topical oxybutynin for palmar hyperhidrosis by using quantitative measures. OBJECTIVE: To evaluate efficacy of 20% oxybutynin hydrochloride lotion (20% OL) in reducing palmar sweat volume in patients with primary palmar hyperhidrosis (PPHH). METHODS: In a randomized controlled trial, Japanese patients with PPHH aged 12 years and older received either 20% OL (n = 144) or placebo (n = 140) on both palms once daily for 4 weeks. Palmar sweat volume was measured by the ventilated capsule method. For the primary outcome, response was defined as a reduction of sweat volume of at least 50% from baseline. RESULTS: At week 4, the responder rate for sweat volume was significantly higher in the 20% OL arm than in the placebo arm (52.8% vs 24.3%, respectively; treatment difference, 28.5% [95% CI, 17.7% to 39.3%]; P < .001). No serious adverse events occurred, and no adverse events led to treatment discontinuation. LIMITATIONS: The treatment period was only 4 weeks. CONCLUSIONS: In patients with PPHH, 20% OL is superior to placebo in reducing palmar sweat volume.


Assuntos
Hiperidrose , Ácidos Mandélicos , Humanos , Resultado do Tratamento , Ácidos Mandélicos/efeitos adversos , Hiperidrose/diagnóstico , Hiperidrose/tratamento farmacológico , Suor , Método Duplo-Cego
15.
Drug Deliv ; 30(1): 2180113, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36815245

RESUMO

Polymeric drug-releasing vaginal rings are useful for both local and systemic administration of drugs via the intravaginal route. Typically, they provide continuous sustained or controlled release of drug(s) over extended time periods, thereby avoiding overdose and improving adherence. This first-in-human study (EudraCT number: 2020-0050044-30) evaluated the pharmacokinetics, safety, and tolerability of a single dose of oxybutynin administered by a novel microprocessor-controlled vaginal ring (MedRing). Eight healthy female subjects received an electronically controlled single intravaginal dose of 3 mg oxybutynin hydrochloride (100 mg/mL) dissolved in 1:1 water/propylene glycol administered via MedRing. Following dosing, MedRing was kept in situ for up to 6 h. Blood samples were collected 1 h prior to oxybutynin dosing and subsequently at regular intervals post-dose for the assessment of plasma concentrations of oxybutynin and its active metabolite N-desethyloxybutynin. The results showed that MedRing efficiently administered oxybutynin via the intravaginal route, resulting in plasma oxybutynin levels comparable to orally administered oxybutynin. The mean ± standard deviation pharmacokinetic parameters for oxybutynin were Cmax 5.4 ± 2.7 ng/mL, AUCinf 34.9 ± 17.4 h ng/mL, t1/2 8.5 ± 3.5 h and for N-desethyloxybutynin were Cmax 3.9 ± 2.5 ng/mL, AUCinf 51.1 ± 43.1 h ng/mL, t1/2 7.7 ± 5.9 h. No serious adverse events were reported. The study demonstrates that intravaginal administration of oxybutynin hydrochloride using the MedRing device was well tolerated.


Assuntos
Antagonistas Colinérgicos , Ácidos Mandélicos , Humanos , Feminino , Antagonistas Colinérgicos/efeitos adversos , Estudos Cross-Over , Ácidos Mandélicos/metabolismo , Ácidos Mandélicos/uso terapêutico
17.
Anal Chim Acta ; 1239: 340725, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36628725

RESUMO

Because R/S-mandelic acids (MA) and their derivatives are critical starting materials or intermediates in the synthesis of chiral drugs, their chirality discrimination is important. In this study, R/S-MA and its derivatives, including R/S-2-phenylpropionic acid (2-PPA), R/S-methoxyphenylaceticacid (MPA), and R/S-2-hydroxy-4-phenylbutyric acid (HPBA), were accurate simultaneous mobility-discriminated by forming diastereomer complexes for the first time, which were obtained by simply mixing with cyclodextrins (α, ß, γ-CD) and transition-metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+). The mass spectra revealed non-covalent diastereomer complexes formed by CD, enantiomers, and metal ions, and ion-mobility spectrometry (IMS) was performed for 109 pairs of complexes. Significant chiral discrimination was observed in the formed diastereomeric complexes, and their separation peak-to-peak resolution (Rp-p) for the enantiomers depended on the transition metal ion type. In most cases, the Rp-p value gradually increases with CD size, with quaternary complexes having the largest Rp-p value. The greatest chiral distinctions of 2-PPA, MA, MPA, and HPBA were obtained by the diastereomeric complex ions of [(2-PPA)(α)2+Zn2+-H]+, [(MA)(α)2+Zn2+-H]+, [(MPA)2(ß)+Co2+-H]+, and [(HPBA)(α)2+Fe2+-H]+, with Rp-p values of 1.35, 1.57, 1.70, and 0.71, respectively. Furthermore, the favorable conformation and collisional cross section (CCS) value of the different [CD + R/S-MA + Cu-H]+ complexes were measured using chemical theoretical calculations to detail their intermolecular interaction, revealing that [α-CD + R/S-MA + Cu-H]+ has two favored gas complexes, and the CCS calculated were consistent with the TIMS observed. In addition, R2 > 0.99 was obtained for the relative quantification of the chiral enantiomers. Overall, the proposed method provides a promising strategy for distinguishing the enantiomers of MA and their derivatives, with the advantages of simplicity, speed, and accuracy, without the need for complex chemical derivatization or chromatographic separation.


Assuntos
Ciclodextrinas , Ácidos Mandélicos , Ácidos Mandélicos/química , Ciclodextrinas/química , Espectrometria de Massas , Íons , Estereoisomerismo
18.
Eur Urol Focus ; 9(1): 168-171, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35987891

RESUMO

Anticholinergic overactive bladder (OAB) medications have been studied in large observational studies to determine if they are associated with a greater risk of mortality (potentially because of their effects on the heart or the brain). Studies in different populations of old adults have shown that oxybutynin is associated with a significantly higher risk of mortality of 26-58% in comparison to other OAB anticholinergic medications or ß3 agonists. In general, anticholinergic OAB medications may increase the risk of mortality, and a single multicountry study showed that ß3 agonist users had a 20% lower risk of mortality compared to OAB anticholinergic users. PATIENT SUMMARY: Older adults who started using a traditional type of medication for overactive bladder (oxybutynin) had a higher risk of dying compared to people who used newer types of anticholinergic medications and to people who used overactive bladder medications that work in a different way.


Assuntos
Bexiga Urinária Hiperativa , Humanos , Idoso , Bexiga Urinária Hiperativa/tratamento farmacológico , Antagonistas Colinérgicos/efeitos adversos , Ácidos Mandélicos/efeitos adversos
19.
J Cosmet Dermatol ; 22(2): 517-528, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35796684

RESUMO

BACKGROUND: Actually, the use of chemical peels in cosmetics and dermatology continues to grow due to their versatility, clinical endpoint-directed predictability, and favorable risk profile in comparison to lasers. The chemical peel is a generally safe method for treatment of some skin disorders and to refresh and rejuvenate the skin. The major challenge of chemical peels is the tolerability, that is because of sensitive skin which is one of the most common skin disorders. AIM: The aim of this study was to evaluate the effectiveness of the new Miamo Renewal Peel Serum formulated with a pool of new generation acids (ELPA25™) on sensitive skin with respect to mandelic acid serum only and with respect to placebo comparison. MATERIALS AND METHODS: The "in vivo" study following the half-face experimental protocol active versus placebo involved 30 healthy Caucasian female volunteers between 25 and 64 years, with sensitive skin, who were divided into two different groups. ELPA25™ serum was applied in one group three times a week for 8 weeks. The other group, with the same protocol, applied an active serum containing mandelic acid, as control, versus placebo. In particular, skin moisturizing, skin viscoelastic properties, skin surface smoothness, wrinkle reduction, and stratum corneum renewal were evaluated. RESULTS: Renewal Peel Serum was very well tolerated from sensitive skin. A significant decrease in skin roughness and wrinkle breadth, and an improvement in firmness and in skin elasticity, was observed after 2 months of treatment with respect both to mandelic acid serum and to placebo comparison. CONCLUSIONS: Scientific protocol using self-controlled study methodology and noninvasive skin bioengineering techniques with adequate statistical methods were able to evaluate both the safety and the efficacy of the new Miamo Renewal Peel Serum. This study highlighted that the Miamo Renewal Peel Serum formulated with a patent-pending mixture of new generation acids (ELPA25™) exerts many beneficial effects and it can be successfully employed for sensitive skin.


Assuntos
Abrasão Química , Envelhecimento da Pele , Dermatopatias , Feminino , Humanos , Abrasão Química/efeitos adversos , Abrasão Química/métodos , Ácidos Mandélicos/efeitos adversos , Pele , Dermatopatias/induzido quimicamente , Resultado do Tratamento
20.
Chemphyschem ; 24(1): e202200324, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36000956

RESUMO

The photodetachment and stability of R-Mandelate, the deprotonated form of the R-Mandelic acid, was investigated by observing the neutral species issued from either simple photodetachment or dissociative photodetachment in a cold anions set-up. R-Mandalate has the possibility to form an intramolecular ionic hydrogen-bond between adjacent hydroxyl and carboxylate groups. The potential energy surface along the proton transfer (PT) coordinate between both groups (O- …H+ …- OCO) features a single local minima, with the proton localized on the O- group (OH…- OCO). However, the structure with the proton localized on the - OCO group (O- …HOCO) is also observed because it falls within the extremity of the vibrational wavefunction of the OH…- OCO isomer along the PT coordinate. The stability of the corresponding radicals, produced upon photodetachment, is strongly dependent on the position of the proton in the anion: the radicals produced from the OH…- OCO isomer decarboxylate without barrier, while the radicals produced from the O- …HOCO isomer are stable.


Assuntos
Hidrogênio , Prótons , Isomerismo , Ácidos Mandélicos , Ânions/química
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