ABSTRACT
To analyse the genetic aetiology of a child with oculocutaneous albinism and to explore the effects of two mutation sites on the function of the OCA2 protein at the mRNA and protein levels via the use of recombinant carriers in vitro. Whole-exome sequencing (WES) and Sanger sequencing were used to analyse the pathogenic genes of the child and validate the mutations in the parents. pEGFP and phage vectors carrying wild-type and mutant OCA2 were constructed using the coding DNA sequence (CDS) of the whole gene-synthesized OCA2 as a template and transfected into HEK293T cells, after which expression analysis was performed. The child in this study was born with white skin, hair, eyelashes, and eyebrows and exhibited nystagmus. Genetic analysis indicated that the child carried two heterozygous mutations: c.1079C > T (p.Ser360Phe) of maternal origin and c.1095_1103delAGCACTGGC (p.Ala366_Ala368del) of paternal origin, conforming to an autosomal recessive inheritance pattern. In vitro analysis showed that the expression of the c.1079C > T (p.Ser360Phe) mutant did not significantly change at the mRNA level but did increase at the protein level, suggesting that the mutation may lead to enhanced protein stability, and the c.1095_1103delAGCACTGGC (p.Ala366_Ala368del) mutation resulted in the loss of three amino acids in exon 10, producing a truncated protein. In vitro expression analysis also revealed that the expression of the mutant gene was significantly downregulated at both the mRNA and protein levels, suggesting that the mutation can simultaneously produce truncated proteins and lead to protein degradation. This case study enriches the phenotypic spectrum of OCA2 gene disease. In vitro expression analysis confirmed that both mutations affect protein expression, providing a theoretical basis for analysing the pathogenicity of these two mutations.
Subject(s)
Albinism, Oculocutaneous , Membrane Transport Proteins , Mutation , Humans , HEK293 Cells , Albinism, Oculocutaneous/genetics , Membrane Transport Proteins/genetics , Exome Sequencing , Female , Male , Pedigree , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Background: Hysterectomy places a considerable physical and mental burden on young female patients with congenital cervical and complete vaginal atresia. Thus, it is necessary to develop a method to detach the obstruction and simultaneously preserve the vagina and uterus in these patients. This study sought to evaluate the efficacy and safety of laparoscopic vaginoplasty using peritoneal flaps and cervicoplasty in patients with congenital cervical and complete vaginal atresia. Methods: Between April 2013 and June 2022, nine patients with congenital cervical and complete vaginal atresia at Henan Provincial People's Hospital were enrolled in this prospective study. All patients were treated with laparoscopic vaginoplasty using peritoneal flaps and cervicoplasty. Baseline clinical data (e.g., age and uterus size) were collected. The surgical success rate and adverse events were assessed. Results: The nine enrolled patients had a median age of 15.0 [interquartile range (IQR), 14.0-18.0] years, and five of these patients had pelvic adhesions. The surgeries were successful in all (9/9) patients, with the vagina, uterus, and a normal menstrual cycle being preserved. After a median follow-up duration of 48 months, the neovaginas had a median length of 7.5 cm. Postoperative complications occurred in three of patients and were cured with the appropriate treatment. The five married patients reported being satisfied with their sex life. Conclusions: The study preliminarily demonstrated the efficacy of laparoscopic vaginoplasty using peritoneal flaps and cervicoplasty in patients with congenital cervical and complete vaginal atresia. However, due to the small sample size, lack of a control group, and relatively high incidence of adverse events, further studies are still needed to verify these results. Regardless, our findings establish an approach for preserving both the vagina and uterus for patients with congenital cervical and complete vaginal atresia.
ABSTRACT
Objectives: To explore the influential elements of urinary kidney injury molecule-1 levels in chronic heart failure, and to judge its ability to predict 90-day rehospitalisation. METHODS: The cross-sectional case-control study was conducted from November 2020 to April 2021, at Hanzhong Central Hospital, China, and comprised adult patients having chronic heart failure with normal renal function in group A and healthy subjects in control group B. Patients in group A received anti-heart failure therapy for 1 week in hospital and were followed up for 90 days after discharge. Blood pressure (BP), kidney injury molecule-1, creatinine and serum pro- B-type natriuretic peptide levels were evaluated at baseline and 1 week after treatment in group A, while the samples were collected only at baseline in the control group B. Data was analysed using SPSS 22. RESULTS: Of the 102 subjects, 68(66.6%) were in group A; 44(64.7%) males and 24 (35.3%) females with mean age 62.38±9.51 years. The remaining 34(33.3%) subjects were in group B; 21(61.7%) males and 13(38.2%) females with mean age vs. 58.82±8.11 years. The urinary kidney injury molecule-1 level in group A was essentially on the increase compared to group B (p<0.05). After 1 week of treatment, the kidney injury molecule-1 level decreased compared to the baseline value in group A (p<0.05). Diastolic blood pressure and pro-B-type natriuretic peptide were the determinants of urinary kidney injury molecule-1 level, and urinary kidney injury molecule-1 level before discharge was significantly associated with rehospitalisation within 90 days (p<0.05). CONCLUSIONS: Urinary kidney injury molecule-1 level before discharge was a significant predictor of rehospitalisation within 90 days, and diastolic blood pressure and pro-B-type natriuretic peptide levels were the influencing factors of urinary kidney injury molecule-1. Also, urinary kidney injury molecule-1 levels were significantly raised in chronic heart failure.
Subject(s)
Heart Failure , Natriuretic Peptide, Brain , Male , Adult , Female , Humans , Middle Aged , Aged , Case-Control Studies , Cross-Sectional Studies , Biomarkers/urine , Prognosis , Chronic Disease , KidneyABSTRACT
[This retracts the article DOI: 10.21037/atm-23-217.].
ABSTRACT
Background: Hysterectomy places a huge physical and mental burden on young female patients with congenital cervical and complete vaginal atresia. Thus, it is necessary to develop a method to detach the obstruction and simultaneously preserve the vagina and uterus in these patients. This study sought to evaluate the efficacy and safety of laparoscopic vaginoplasty using the peritoneal flap and cervicoplasty in patients with congenital cervical and complete vaginal atresia. Methods: Between April 2013 and June 2022, 9 patients with congenital cervical and complete vaginal atresia at Henan Provincial People's Hospital were enrolled in this prospective study. All the patients were treated with laparoscopic vaginoplasty using the peritoneal flap and cervicoplasty. Baseline clinical features (such as age, uterus size, etc.) were collected. The surgical success rate and adverse events were assessed. Results: The 9 enrolled patients had a median [interquartile range (IQR)] age of 15.0 (14.0-18.0) years, and 5/9 patients presented with pelvic adhesions. The surgeries were successful in all (9/9) patients, who preserved their vagina and uterus with a normal menstrual cycle. After a median follow-up duration of 48 months, the neovagina had a median length of 7.5 cm. Post-surgical complications occurred in 3/9 patients, which were cured by an appropriate treatment. The 5/9 married patients reported being satisfied with their sexual life. Conclusions: Even though the current study preliminary exhibits the efficiency of laparoscopic vaginoplasty using the peritoneal flap and cervicoplasty in patients with congenital cervical and complete vaginal atresia, due to the small sample size, lack of a control group, and relatively high incidence of the adverse events, further studies are still needed to verify the current findings. The current study put forward a further direction for preserving the vagina and uterus simultaneously for those patients with congenital cervical and complete vaginal atresia.
ABSTRACT
As the human excreta, urine is often used as one of the test materials in medical research due to its composition and content directly reflecting the health status of the body. Considering that the substances in urine may show different effects on its freezing process, solidification characteristics of sessile urine droplets on a horizontal cold plate surface under natural convection were experimentally investigated by comparing with those of water droplets under same conditions. To make the conclusion analysis more reasonable, the urine of a human without any diseases, especially metabolic diseases, was treated and used. The characteristics include nucleation location, dynamic variation of droplet color, and temperatures at different heights inside the droplet, and so forth. It was found that, similar to that of a water droplet, the solidification process of a urine droplet also experiences the following four stages: supercooling, recalescence, freezing, and cooling, in chronological order. Differently, the urine droplet changes from transparent to blur white at the supercooling stage due to the precipitation of inorganic salts. For nucleation locations, 46.67% cases are at the bottom, while others are at the top and middle of urine droplets. For a 10 µL droplet on a surface of -30 °C, urine has a 0.95 s freezing duration shorter than water, and a 5.31 °C lower phase-transition temperature. Results of this study are expected to reflect the content of substances in urine and thus provide references for urinalysis of patients with metabolic diseases.
Subject(s)
Convection , Water , Freezing , Humans , Phase Transition , Transition TemperatureABSTRACT
Heterocycles are often found as the structural nucleus in natural products and biological active compounds. Consequently, research toward the discovery and development of novel and efficient synthetic methodologies is of constant interest to organic chemists. Diels-Alder reactions are powerful at forming multiple bonds simultaneously, often with stereoselectivity, and thus are one of the most widely used synthetic methodologies in organic syntheses. Inverse electron-demand Diels-Alder (IEDDA) reactions, a subclass of Diels-Alder reactions, have been developed for the efficient synthesis of various heterocycles, with 1,3,5-triazines used as azadienes. The initial 1,3,5-triazine IEDDA reactions mostly included nonaromatic, electron-rich species such as vinyl ethers, enamines, ynamines, and amidines as dienophiles, producing in high yields pyrimidine derivatives with excellent regioselectivity. We hypothesized that some electron-rich aromatic heterocycles could be studied as potential dienophiles for 1,3,5-triazine IEDDA reactions; 5-aminopyrazoles proved to be productive dienophiles leading to high yields of pyrazolopyrimidines. Subsequently, many studies were reported to investigate the mechanism and scope of this new type of IEDDA reaction. Mechanistically, this new type of IEDDA reaction is quite interesting since it entails two aromatic compounds proceeding through a perceived high energy nonaromatic transition state, leading to a new aromatic compound, a counterintuitive process. Both theoretical and experimental studies provide key insights to this reaction mechanism, with learnings from these studies possibly stimulating unconventional thinking in other areas. Theoretical calculations of these cascade reactions of amino-substituted heterocycles with 1,3,5-triazines indicate that the reactions occur in a stepwise fashion via a highly polar zwitterionic intermediate; elimination of ammonia from IEDDA adducts and subsequent retro Diels-Alder reaction drive the reaction toward the fully aromatized IEDDA products. This amino substituent is critical in determining the regioselectivity and driving the cascade reactions to completion. With regard to reaction scope, many amino-heterocycles such as pyrroles, imidazoles, furans, thiophenes, and indoles all proved to be productive dienophiles for this new IEDDA reaction, leading to various fused-pyrimidines in a single step with moderate to high yields and high regioselectivity. Application of this new IEDDA reaction with 1,3,5-triazines was reported to lead to interesting heterocyclic compounds such as nucleoside natural product nebularine and analogues, as well as fluorine-containing fused pyrimidines with potential for biological activities.Herein, the scope of various aromatic heterocycles as dienophiles in the 1,3,5-triazine IEDDA reaction is reviewed. Moreover, both experimental and theoretical studies of the mechanisms for this interesting cascade IEDDA reaction are discussed. Finally, applications of this new type (aromatic heterocycles as dienophiles with 1,3,5-triazines as azadienes) of IEDDA reaction are also covered.
Subject(s)
Heterocyclic Compounds/chemistry , Triazines/chemistryABSTRACT
Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 µM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.
Subject(s)
Adenosine Kinase/metabolism , Adenosine/analogs & derivatives , Drug Design , Mycobacterium tuberculosis/enzymology , Protein Kinase Inhibitors/chemical synthesis , Adenosine/metabolism , Adenosine/pharmacokinetics , Adenosine Kinase/chemistry , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/metabolism , Antitubercular Agents/pharmacokinetics , Catalytic Domain , Female , Mice , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Benzimidazoles/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Administration, Oral , Animals , Benzimidazoles/administration & dosage , Benzimidazoles/therapeutic use , Drug Discovery , Insulin Resistance , Lipid Metabolism/drug effects , MiceABSTRACT
Catalytic inverse electron demand Diels-Alder (IEDDA) reactions of heterocyclic aza-dienes are rarely reported since highly reactive and electron-rich dienophiles are often found not compatible with strong acids such as Lewis acids. Herein, we disclose that TFA-catalyzed reactions of electron-deficient 1,3,5-triazines and electron-deficient aldehydes/ketones can take place. These reactions led to highly functionalized pyrimidines as products in fair to good yields. The reaction mechanism was carefully studied by the combination of experimental and computational studies. The reactions involve a cascade of stepwise inverse electron demand hetero-Diels-Alder (ihDA) reactions, followed by retro-Diels-Alder (rDA) reactions and elimination of water. An acid was required for both ihDA and rDA reactions. This mechanism was further verified by comparing the relative reactivity of aldehydes/ketones and their corresponding vinyl ethers in the current reaction system.
ABSTRACT
Novel 2'-modified guanosine nucleosides were synthesized from inexpensive starting materials in 7-10 steps via hydroazidation or hydrocyanation reactions of the corresponding 2'-olefin. The antiviral effectiveness of the guanosine nucleosides was evaluated by converting them to the corresponding 5'-O-triphosphates (compounds 38-44) and testing their biochemical inhibitory activity against the wild-type NS5B polymerase.
Subject(s)
Antiviral Agents/chemical synthesis , Guanine Nucleotides/chemical synthesis , Nucleic Acid Synthesis Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Alkenes/chemical synthesis , Azides/chemical synthesis , Hepacivirus/enzymology , Viral Nonstructural Proteins/chemistryABSTRACT
BACKGROUND: Placenta accreta is a rare obstetric condition but can lead to life-threatening complications that was mainly diagnosed in the third trimester. We present a case of acute trophoblastic pulmonary embolism (PE) during conservative treatment of placenta accreta. CASE PRESENTATION: A 24-year-old patient who delivered vaginally at 40(+4) weeks gestation. The placenta was retained despite the use of oxytocics and attempts of manual removal. Conservative management including uterine arteria embolism, hysteroscopic resection and mifepristone was used but failed and finally the patient died from acute trophoblastic PE and allergic shock when infusing povidone-iodine into her uterine cavity. CONCLUSION: Although conservative treatment of placenta accreta can retain reproductive potential and trophoblastic PE is rare, clinicians should consider hysterectomy when conservative treatment failed and infusion of povidone-iodine or other liquid into the cavity should be prohibited.
Subject(s)
Placenta Accreta/therapy , Pulmonary Embolism/etiology , Uterine Artery Embolization/methods , Female , Humans , Hysteroscopy/methods , Mifepristone/therapeutic use , Pregnancy , Young AdultABSTRACT
To investigate allelic variation of Myb10-1 genes in Chinese wheat and to examine its association with germination level in wheat, a total of 582 Chinese bread wheat cultivars and 110 Aegilops tauschii accessions were used to identify allelic variations of three Myb10-1 genes. Identification results indicated that there is a novel Tamyb10-B1 allele, designated Tamyb10-B1c, in the five Chinese landraces. The Tamyb10-B1c possibly has a large deletion including Tamyb10-B1 gene. There are three novel Tamyb10-D1 alleles (Aetmyb10-D1c, Aetmyb10-D1d and Aetmyb10-D1e) that were discovered in Aegilops tauschii. Of them, Aetmyb10-D1c allele possessed a 104-bp deletion and this resulted in a frame shift in the open reading frame of the Aetmyb10-D1 gene. AETMYB10-D1d and AETMYB10-D1e proteins possessed three and two different amino acids when compared with TAMYB10-D1b protein, respectively. Association of Tamyb10-1 allelic variation with grain germination level indicated that all five allelic combinations with red grains showed a significantly higher GP (germination percentage) and GI (germination index) values than those of white-grained Tamyb10-A1a/Tamyb10-B1a/Tamyb10-D1a genotype after storing it for one year. Moreover, the Tamyb10-A1b/Tamyb10-B1c/Tamyb10-D1b genotype possesses the significantly highest GP and GI among the six different Tamyb10-1 combinations. This study could provide useful information for wheat breeding programme in terms of grain colour and germination level.
Subject(s)
Genes, Plant , Germination/genetics , Pigmentation/genetics , Poaceae/genetics , Seeds/genetics , Triticum/genetics , Alleles , Bread , Genetic Markers , Polymorphism, GeneticABSTRACT
An efficient and practical method has been developed for the synthesis of trans-4,5-disubstituted 3-carboxy-4,5-dihydropyrroles via an intramolecular iminium ion cyclization reaction of readily accessible Baylis-Hillman derivatives and aldehydes in moderate to high yield. These new dihydropyrroles could be easily converted to pyrroles or pyrrolidines.
ABSTRACT
OBJECTIVE: To investigate the therapeutic mechanism of bazedoxifene, the third-generation selective ER modulator (SERM), on endometriosis lesions in a rat model. METHODS: Endometriosis was induced by transplanting pieces of endometrium from other syngeneic rats that were as donors onto the subcutaneous of other unmated female rats. The rats with successful ectopic implants were divided into two groups: control group (n=10) and bazedoxifene group (n=10). The macroscopic morphology, volume, histopathology of ectopic implant and rats uterine wet weight were determined before and after the treatment. Expression of proliferation cell nuclear antigen (PCNA), ER and PR in the eutopic endometrium and endometriosis lesions detected by immunohistochemistry in the two groups. RESULTS: (1) The gross morphology and histological changes of endometriosis lesions in rats after treatment: compared with the control group, it was obviously depauperated and had more less glands and blood vessels in the stroma. (2) The change of rats' weight, the volume of endometriosis lesion before and after treatment and rats uterine wet weigh after treatment respectively in the control group and the bazedoxifene group: rats' weight were respectively before treatment: (201±17) g, (202±18) g, that were respectively after treatment: (266±16) g, (261±16) g, which showed no significant difference between two groups before and after treatment (P>0.05). The volume of ectopic implant before treatment were respectively (85±17) mm3, (85±12) mm3, and showed no significant difference between two groups; that were respectively (48±11) mm3, (24±9) mm3 afte rtreatment, which was significantly decreased compared with the control group (P<0.05). Rats uterine wet weight after treatment were respectively: (0.77±0.16) g, (0.45±0.18) g, and was significantly reduced compared with the control group (P<0.05). (3) The protein expression levels of PCNA, ER and PR in the endometriosis lesions after treatment were respectively 0.282±0.044, 0.51±0.06, 0.49±0.05 in the control group, 0.191±0.020, 0.23±0.03, 0.48±0.06 in the bazedoxifene group; that in eutopic endometrium were respectively 0.369±0.081, 0.56±0.08, 0.56±0.10 in the control group, 0.211±0.037, 0.27±0.05, 0.54±0.08 in the bazedoxifene group; the protein expression levels of PCNA and ER in endometriosis lesions and the eutopic endometrium were significantly decreased in the bazedoxifene group compared with the control group (P<0.05), but the protein levels of PR in endometriosis lesionsand and the eutopic endometrium were not significantly altered by treatment (P>0.05). CONCLUSION: Bazedoxifene could obviously reduce the size of endometriosis lesions, the mechanism may be related with suppressing estrogen-induced proliferation, the expression of ER and direct ER antagonism by this SERM.
Subject(s)
Endometriosis/drug therapy , Endometrium/drug effects , Indoles/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Animals , Disease Models, Animal , Endometrium/pathology , Female , Humans , Immunohistochemistry , Proliferating Cell Nuclear Antigen/analysis , Rats , Receptors, Estrogen/analysis , Uterus/pathologyABSTRACT
Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethylâ (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.
Subject(s)
HIV Integrase Inhibitors/chemistry , Oxadiazoles/chemistry , Prodrugs/chemistry , Pyrimidinones/chemistry , Pyrrolidinones/chemistry , Acetals/chemistry , Animals , Area Under Curve , Carbonates/chemistry , Dogs , Drug Evaluation, Preclinical , HIV Integrase/chemistry , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacokinetics , HIV-1/enzymology , Half-Life , Hepatocytes/metabolism , Humans , Intestinal Mucosa/metabolism , Male , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , ROC Curve , Raltegravir Potassium , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
A sequence of C-O bond cleavage and redox reactions in oxa-bridged azepines was realized under acid promoted conditions. This protocol provides an atom-economical and straightforward approach to access benzo[b]azepin-5(2H)-ones in high yields. The formal synthesis of tolvaptan was achieved by exploiting this new transformation.
Subject(s)
Azepines/chemical synthesis , Benzazepines/chemistry , Azepines/chemistry , Benzazepines/chemical synthesis , Catalysis , Molecular Structure , Oxidation-Reduction , Oxytocin/analogs & derivatives , TolvaptanABSTRACT
OBJECTIVES: Both diabetes mellitus (DM) and coronary artery spasm (CAS) are associated with endothelial dysfunction. Thus, a higher incidence of CAS is expected in diabetic patients (pts). We evaluated the impacts of DM and the status of blood sugar control on CAS with intracoronary acetylcholine (ACh) provocation test. METHODS: A total of 986 pts (106 DM vs 880 non-DM pts) with angiographically normal coronary artery received ACh provocation test. Significant CAS was defined as a transient >90% luminal narrowing with concurrent chest pain and/ or ST-segment changes. HbA1c <7% was considered a controlled blood sugar level. RESULTS: The incidence of CAS was similar between patients with versus without DM (30.2% vs 23.5%; P=.13). Multivariable analysis showed that DM was not an independent risk factor for significant CAS (odds ratio [OR], 1.29; 95% confidence interval [CI], 0.81-2.07; P=.28). The angiographic characteristics of CAS were also similar between these two groups. Subgroup analysis regarding the impact of the status of blood sugar control on CAS showed that the incidence of CAS was similar between diabetic pts with versus without controlled blood sugar levels (35.4% vs 25.9%; P=.29). Multivariable analysis showed that the uncontrolled blood sugar level was not an independent risk factor for CAS (OR, 0.79; 95% CI, 0.29-2.13; P=.64). CONCLUSIONS: Despite the expected endothelial dysfunction, DM and the status of blood sugar control are not associated with CAS, suggesting the existence of different mechanisms for CAS and coronary artery disease.
Subject(s)
Acetylcholine , Coronary Vasospasm/chemically induced , Coronary Vasospasm/epidemiology , Coronary Vessels/physiopathology , Diabetes Complications/complications , Vasodilator Agents , Acetylcholine/administration & dosage , Acetylcholine/pharmacology , Adult , Aged , Blood Glucose/metabolism , Coronary Angiography , Coronary Vasospasm/diagnostic imaging , Coronary Vessels/diagnostic imaging , Coronary Vessels/drug effects , Diagnostic Tests, Routine , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Female , Humans , Incidence , Injections, Intra-Arterial , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Risk Factors , Vasodilator Agents/administration & dosage , Vasodilator Agents/pharmacologyABSTRACT
Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption.
ABSTRACT
A one-pot three-component reaction, involving condensation of 2-aminopyridines, aldehydes, and ketones/aldehydes under trifluoromethanesulfonic acid catalysis, provides rapid access to highly substituted novel 4H-pyrido[1,2-a]pyrimidines.