HIF-1α induced by hypoxic condition regulates Treg/Th17 axis polarization in chronic immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired immune disorder characterized by increased platelet destruction and reduced platelet (Plt) production. Hypoxia-inducible factor-1α (HIF-1α) have regulatory effects on Treg/Th17 axis balance and may represent relevant factors in the pathogenesis of ITP. Treg/Th17 ratio, serum levels and gene expression were investigated in new diagnosed ITP (NITP) and chronic ITP (CITP). The Treg/Th17 ratio obviously decreased in CITP (P = 0.001). The ratio of Treg/Th17 was correlated with the level of HIF-1α level both in mRNA (r = 0.49, P < 0.0001) and serum level (r = 0.50, P < 0.0001). However, none statistical upregulation of HIF-1α was observed in CITP. In vitro, There was significant polarization difference of Treg/Th17 axis (P = 0.042) and Foxp3-MFI/IL17-MFI (P = 0.0003) in hypoxic condition between NITP and CITP. These findings suggest that HIF-1α induced by hypoxia plays a crucial role in the chronicity of ITP by mediating the imbalance of the Treg/Th17 axis.

Qualitative Exploration of the Experiences of People Who Use Captagon and Therapists in Jordan.

Background: Captagon (Fenethylline) is an amphetamine type stimulant (ATS) and one of the most popular substances of use in the Middle East. This study aims to describe and analyze the trajectory of captagon use, severity of addiction and withdrawal symptoms and its effect on quality of life from the perspectives of people who use captagon, who receive treatment as well as therapists. Methods: This study took a qualitative approach, using semi-structured, audio-recorded interviews, which were transcribed verbatim, translated to English and coded using Nvivo software for thematic analysis. Results: Data saturation was achieved after interviewing a total of 27 participants (7 therapists and 20 patients using captagon either alone or among other illicit drugs), most of which were male (n = 22). Their ages ranged between 18-48 years (median= 27). Four main themes were identified during the interviews: (1) Definition and sought effects of captagon; (2) the downside of captagon use and withdrawal symptoms associated with captagon use; (3) motivations for captagon use and to treatment; and (4) the impact of Covid-19 on captagon's use and on treatment. Conclusion: This qualitative study has illustrated for the first time the several challenges and complicating factors that people who use captagon and therapists face in Jordan. Findings call attention to implementing effective interventions to raise public's awareness of the negative impact of such use, with focus on high-risk groups, address the needs of different users and encourage the use of international treatment guidelines.

Development of a new inhaled swellable microsphere system for the dual delivery of naringenin-loaded solid lipid nanoparticles and doxofylline for the treatment of asthma.

This study developed a new dual delivery system of naringenin (NRG), a polyphenol, and doxofylline (DOX), a xanthine derivative, as an inhaled microsphere system. In this system, NRG has been first loaded into glyceryl tristearate-based solid lipid nanoparticles (NRG SLN), which were further loaded with DOX into swellable chitosan-tripolyphosphate-based microspheres (NRG SLN DOX sMS). The system was characterized based on particle size, PDI, zeta potential, surface morphology (SEM, AFM, and TEM), solid-state and chemical properties (XRD, IR, and NMR), aerodynamic parameters, drug loading, entrapment efficiency and in vitro drug release study. The optimized NRG SLN DOX sMS exhibited particle size, zeta potential, and PDI of 2.1 µm, 31.2 mV, and 0.310, respectively; a drug entrapment efficiency > 79 %; a drug loading efficiency > 13 %; cumulative drug releases of about 78 % for DOX and 72 % for NRG after 6 and 12 h, respectively; good swelling and desirable aerodynamic properties. In addition, in vivo studies conducted in mice, a murine model of asthma showed significant reductions in serum bicarbonate and eosinophil counts and improvement in respiratory flow rate, tidal volume, and bronchial wall lining compared with the asthmatic control group. Overall, this novel inhalable dual-delivery system may represent a good alternative for the effective treatment of asthma.

Simultaneous and trace-level quantification of four benzene sulfonate potential genotoxic impurities in doxofylline active pharmaceutical ingredients and tablets using high-performance liquid chromatography with ultraviolet detection.

In the production of doxofylline, the common occurrence of toxic p-toluene sulfonate generation prompted the development and validation of a method using HPLC with ultraviolet detection (HPLC-UV). This method is designed for detecting four potential genotoxic impurities (PGIs) present in both doxofylline drug substance and tablets, with a focus on the UV-absorbing group p-toluene sulfonate. The four impurities were methyl 4-methylbenzenesulfonate (PGI-1), ethyl 4-methylbenzenesulfonate (PGI-2), 2-hydroxyethyl 4-methylbenzenesulfonate (PGI-3), and 2-(4-methylphenyl)sulfonyloxyethyl 4-methylbenzenesulfonate (PGI-4). In this method, chromatographic separation was achieved using a Waters Symmetry C18 column (250 mm × 4.6 mm, 5 µm). The mobile phases consisted of 20% acetonitrile as mobile phase A and pure acetonitrile as mobile phase B, operating in gradient elution mode at a flow rate of 1.0 mL/min. According to the guidelines of the International Conference on Harmonization, it was determined that this method could quantify four PGIs at 0.0225 µg/mL in samples containing 60 mg/mL. The validated approach demonstrated excellent linearity (R2 > 0.999) across the concentration range of 30%-200% (relative to 0.075 µg/mL doxofylline) for the four PGIs. The accuracy of this method for the four PGIs ranged from 94.8% to 100.4%. The reverse-phase-HPLC-UV analytical method developed in this study is characterized by its speed and precision, making it suitable for the sensitive analysis of benzene sulfonate PGIs in doxofylline drug substances and tablets.

In-vitro cytotoxic evaluation, hemolytic and thrombolytic potential of newly designed acefylline based hydrazones as potent anticancer agents against human lung cancer cell line (A549).

Hydrazones of theophylline-7-acetic acid 5a-g have been synthesized using ultrasonic irradiation as well as conventional heating system and analyzed for their anticancer characteristics against human lung cancer cell line (A549). Compound 5g with cell viability 33.19±0.49% (100 µg/µL) compared to the starting reference drug acefylline having cell viability 86.32±11.75% (100 µg/µL) was found to be the most active anticancer agent among all. The synthesized derivatives were also exposed to hemolytic and thrombolytic studies to determine their cytotoxic profile and results revealed their low toxicity and moderate clot lysis activity.

Biocatalytic hydrogen-transfer to access enantiomerically pure proxyphylline, xanthinol, and diprophylline.

Alcohol dehydrogenases (ADHs; EC 1.1.1.1) have been widely used for the reversible redox reactions of carbonyl compounds (i.e., aldehydes and ketones) and primary or secondary alcohols, often resulting in optically pure hydroxyl products with high added value. In this work, we report a concise chemoenzymatic route toward xanthine-based enantiomerically pure active pharmaceutical ingredients (API) - proxyphylline, xanthinol, and diprophylline employing various recombinant short-chain ADHs with (R)- or (S)-selectivity as key biocatalysts. By choosing the appropriate ADH, the (R)- as well as the (S)-enantiomer of proxyphylline was prepared in excellent enantiomeric excess (99-99.9% ee), >99% conversion, and the isolated yield ranging from 65% to 74%, depending on the used biocatalyst (ADH-A from Rhodococcus ruber or a variant derived from Lactobacillus kefir, Lk-ADH-Lica). In turn, E. coli/ADH-catalyzed bioreduction of the carbonylic precursor of xanthinol and diprophylline furnished the corresponding (S)-chlorohydrin in >99% ee, >99% conversion, and 80% yield (in the case of Lk-ADH-Lica); while the (R)-counterpart was afforded in 94% ee, 64% conversion, and 41% yield (in the case of SyADH from Sphingobium yanoikuyae). After further chemical functionalization of the key (S)-chlorohydrin intermediate, the desired homochiral (R)-xanthinol (>99% ee) was obtained in 97% yield and (S)-diprophylline (>99% ee) in 90% yield. The devised biocatalytic method is straightforward and thus might be considered practical in the manufacturing of title pharmaceuticals.

Jordanian University Students' Lived Experience of Misusing Amphetamine (Captagon): A Qualitative Study.

BACKGROUND: Substance misuse is a growing problem among Jordanian university students. PURPOSE: The aim of this study was to explore the lived experiences of university students who misuse Captagon (amphetamines). METHODS: The interpretative phenomenological analysis methodology was used. In-depth face-to-face interviews were conducted with 10 Jordanian university students, aged 17-22 years, who were using Captagon (amphetamines) for the last 6 months. RESULTS: Three major themes detailed participants' experiences with Captagon: (a) causes for use, (b) effects of taking amphetamines, and (c) seeking help behaviors and support. Participants who experienced academic and personal stress sought help from friends, who provided them with Captagon pills as a way to overcome their life challenges. Initially, taking Captagon provided participants with a sense of control, but it did not solve their problems. Later or as the days passed by, they experienced increased level of stress, felt disorganized in a way that they missed classes, and were being socially isolated. Participants finally sought community help for their problem, but this was difficult because of stigmatizing attitudes in their community toward substance misuse. CONCLUSIONS: Increasing university students' knowledge about the negative consequences of substance misuse and raising awareness of strategies to address the problem will help young people to make more informed choices, because today's young generation are tomorrow's citizens.

Effect of doxofylline on pulmonary inflammatory response and oxidative stress during mechanical ventilation in rats with COPD.

OBJECTIVE: To evaluate the effects of doxofylline on inflammatory responses and oxidative stress during mechanical ventilation in rats with chronic obstructive pulmonary disease (COPD). METHODS: Eight-week-old male Sprague Dawley rats were selected, and the COPD rat model was constructed. The rats were randomly divided into a model group (group M), a model + normal saline group (group N), a doxofylline group (group D), and a control group fed with conventional chow and given normal oxygen supply (group C) (n = 12 in each group). Tracheal intubation and mechanical ventilation were conducted in the rats in each group after anesthesia. A real-time intravenous infusion with 50 mg/kg of doxofylline was conducted in group D, and there was no drug intervention in groups C, N and M. Pathological manifestations of the pulmonary tissues were observed and compared among the groups. And some indicators were evaluated. RESULTS: (1) The pulmonary tissues of the rats in groups M, N, and D exhibited typical pathological histological changes of COPD. (2) Groups M, N, and D showed increased Ppeak, PaCO2, total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue and BALF, and decreased PaO2 and IL-10 and SOD levels, compared with group C. (3). Group D showed decreased Ppeak, PaCO2, total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue, and increased PaO2 and IL-10 and SOD levels, compared with group N or M. CONCLUSION: Doxofylline was shown to improve ventilation and air exchange during mechanical ventilation in rats with COPD, reduce the inflammatory response and oxidative stress, and mitigate the degree of pulmonary tissue injury.

Role of Etophylline and Theophylline Prolonged Release Tablet in COVID-19 Associated Sinus Node Dysfunction.

During COVID-19 pandemic, one of the most common arrythmia reported with this illness is sinus bradycardia. Treatment for COVID-19 and associated cardiac dysfunction is still evolving. Temporary pacemaker insertion is difficult due to pandemic and risk of spread of infection to the additional staff involved. Orciprenaline stimulates the sino-atrial and atrioventricular nodes and accelerates atrioventricular conduction. Theophylline improves sinus node function in subjects with sinus bradycardia and enhances atrioventricular nodal conduction We report a case series of 10 patients admitted in dedicated COVID-19 ICUs and developed sinus node dysfunction. All of these patients were started on etophylline and theophylline prolonged release tablet (150mg) once a day. On subsequent follow up after 72 hours, all patients reported heart rate well within normal range. COVID-19 virus directly involves the myocardium by entering the cardiac myocytes resulting in inflammation and injury. As the sinus bradycardia due to COVID-19 is usually transient and respond well this drug, short course of this drug could be added to treat this arrythmia in future.

Doxofylline Protects Gram-Negative Pathogens against Antibiotic-Mediated Killing.

Given the growing rate of Gram-negative bacterial infections, antibiotics are now frequently prescribed for various respiratory diseases. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities, but its influence on antibiotics remains poorly understood. Here, we first report the discovery of doxofylline-induced high minimum inhibitory concentrations of antibiotics. We also showed that doxofylline blocked antimicrobial-mediated killing for Gram-negative pathogens in vitro and in murine lung infection models in vivo. By combining efflux pump inhibition tests, gene expression analyses, and using the gene tolC knockout strain, we found that doxofylline positively regulated gene expression of the AcrAB-TolC efflux pump and attenuated the effect of doxofylline on antibacterial activities in ΔtolC mutants. Notably, doxofylline-mediated protection correlated with decreased reactive oxygen species (ROS) production. Collectively, our study indicates that doxofylline protects Gram-negative bacteria from antimicrobial lethality by regulating the AcrAB-TolC efflux pump in a TolC-dependent manner and suppressing antibiotic-induced ROS accumulation. These results suggest caution when using antibiotics alongside doxofylline in clinical treatment.

Roles of human cytochrome P450 1A2 in coumarin 3,4-epoxidation mediated by untreated hepatocytes and by those metabolically inactivated with furafylline in previously transplanted chimeric mice.

Coumarin is a naturally occurring component of food products but is of clinical interest for its potential hepatotoxicity in humans. In the current study, the pharmacokinetics of coumarin in humanized-liver mice after oral and intravenous administrations (30 mg/kg) were investigated for its transformations to metabolically active coumarin 3,4-epoxide (as estimated by the levels of o-hydroxyphenylacetic acid) and to excretable 7-hydroxycoumarin. After oral administration, control mice metabolized coumarin to o-hydroxyphenylacetic acid at roughly the same rate as that to 7-hydroxycoumarin (total of unconjugated and conjugated forms). In contrast, the in vivo biotransformation of coumarin to o-hydroxyphenylacetic acid by humanized-liver mice was around two orders of magnitude less than that to conjugated and unconjugated 7-hydroxycoumarin. After intravenous administrations of coumarin, differences were observed in the plasma concentrations of o-hydroxyphenylacetic acid between humanized-liver mice treated with furafylline (daily oral doses of 13 mg/kg for 3 days) and untreated humanized-liver mice. The mean values of the areas under the plasma concentration versus time curves and the maximum concentrations for o-hydroxyphenylacetic acid were significantly lower in the group treated with furafylline (45% and 57% of the untreated values, respectively). These results suggested that the metabolic activation of coumarin in humans was mediated mainly by P450 1A2, which was suppressed by furafylline, and that humanized-liver mice orally treated with furafylline might constitute an in vivo model for metabolically inactivated P450 1A2 in human hepatocytes transplanted into chimeric mice.

Efficacy and safety of combined doxofylline and salbutamol in treatment of acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of combined doxofylline and salbutamol in the treatment of acute exacerbation of chronic obstructive pulmonary disease. METHODS: A total of 68 acute exacerbation of chronic obstructive pulmonary disease patients were randomly divided into control group (34 cases) and experimental group (34 cases), who received the doxofylline treatment and combined doxofylline and salbutamol treatment for 1 week, respectively. During the treatment, the remission time of typical respiratory manifestations was recorded, and the adverse reactions were observed. At the end of treatment, the treatment efficacy was evaluated. Before and after treatment, the pulmonary function indexes and serological indicators were detected. RESULTS: After treatment, compared with control group, in experimental group, the effective rate of treatment was significantly increased (p<0.05), the remission time of typical respiratory manifestations was significantly shortened (p<0.05), the pulmonary function indexes were significantly improved (p<0.05), the serum high-sensitivity C-reactive protein and cystatin C levels were significantly decreased, respectively (p<0.05), and the serum prealbumin level was significantly increased (p<0.05). In addition, the adverse reaction rate had no significant difference between two groups (p>0.05). CONCLUSIONS: In the treatment of acute exacerbation of chronic obstructive pulmonary disease, the combined use of doxofylline and salbutamol can quickly relieve the respiratory symptoms, mitigate the pulmonary dysfunction, and reduce the inflammatory response, thus promoting the outcome of patients.

Effect of Doxofylline on Reducing the Inflammatory Response in Mechanically Ventilated Rats with Chronic Obstructive Pulmonary Disease.

Objective: To evaluate the effect of doxofylline on reducing the inflammatory response in mechanically ventilated rats with chronic obstructive pulmonary disease (COPD). Methods: A total of 40 eight-week-old male Sprague Dawley rats were randomly divided into four groups of 10 rats each: a control group (group C), a model group (group M), a model + natural saline group (group N), and a doxofylline group (group D). Then mechanical ventilation, drug intervention, and the extraction of the experimental material were performed in each group. Pulmonary tissue samples were taken after 120 minutes of mechanical ventilation and the pulmonary histopathological changes and the wet/dry (W/D) weight ratio of the pulmonary tissue were identified. The levels of tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were detected using an enzyme-linked immunosorbent assay, and the expression levels of c-Jun-N-terminal kinase (JNK) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected using immunohistochemistry. Results: Compared with group C, the pulmonary histopathology in groups M, N, and D showed typical changes associated with COPD. Furthermore, the W/D weight ratio and levels of TNF-α, JNK, and p-JNK in the pulmonary tissue increased in groups M, N, and D (P < 0.05), while the levels of IL-10 decreased (P < 0.05). Compared with group M, no statistically significant changes in the above indicators were detected in the pulmonary tissue of group N (P > 0.05). Compared with group N, the W/D weight ratio and levels of TNF-α, JNK, and p-JNK in the pulmonary tissue decreased in group D (P < 0.05), while the levels of IL-10 increased (P < 0.05). Conclusion: Doxofylline might attenuate pulmonary inflammatory responses in mechanically ventilated rats with COPD, and the JNK/stress-activated protein kinase signaling pathway is involved in doxofylline's inhibition of inflammatory responses in the pulmonary tissue of rats with COPD.

Synthesis, Identification, and Biological Study for Some Complexes of Azo Dye Having Theophylline.

This article includes the synthesis of heterocyclic azo dye of theophylline by coupling diazonium salt of 4-chloroaniline with theophylline which is, namely, 8-(1-(4-chlorophenyl)azo)theophylline (CPAT). The complexes of cobalt and nickel were prepared by reacting their ions with CPAT ligand in ethanol under 1 : 2 ratio metal-ligand. The CPAT ligand and its complexes were characterized by elemental analysis, infrared spectrometry, electronic absorption spectroscopy, molar conductivity, and magnetic moment. The cobalt and nickel complexes show octahedral geometry having general formula [M(CPAT)2Cl2]. This article addresses the properties of CPAT dye such as photochromic properties. The CPAT dye exhibited obvious and desired changes under irradiation with visible light (405 nm), high sensitive for pH changes which refer to its ability to be analysis indicator. CPAT dye exhibited solvatochromic properties presenting red shift with polar solvent. The CPAT and its complexes show interesting antibiological activities towards Staph. aureus and E. coli bacteria and Aspergillus fungi.

Deletion of heterogeneous nuclear ribonucleoprotein F in renal tubules downregulates SGLT2 expression and attenuates hyperfiltration and kidney injury in a mouse model of diabetes.

AIMS/HYPOTHESIS: We previously reported that renal tubule-specific deletion of heterogeneous nuclear ribonucleoprotein F (Hnrnpf) results in upregulation of renal angiotensinogen (Agt) and downregulation of sodium-glucose co-transporter 2 (Sglt2) in HnrnpfRT knockout (KO) mice. Non-diabetic HnrnpfRT KO mice develop hypertension, renal interstitial fibrosis and glycosuria with no renoprotective effect from downregulated Sglt2 expression. Here, we investigated the effect of renal tubular Hnrnpf deletion on hyperfiltration and kidney injury in Akita mice, a model of type 1 diabetes. METHODS: Akita HnrnpfRT KO mice were generated through crossbreeding tubule-specific (Pax8)-Cre mice with Akita floxed-Hnrnpf mice on a C57BL/6 background. Male non-diabetic control (Ctrl), Akita, and Akita HnrnpfRT KO mice were studied up to the age of 24 weeks (n = 8/group). RESULTS: Akita mice exhibited elevated systolic blood pressure as compared with Ctrl mice, which was significantly higher in Akita HnrnpfRT KO mice than Akita mice. Compared with Akita mice, Akita HnrnpfRT KO mice had lower blood glucose levels with increased urinary glucose excretion. Akita mice developed kidney hypertrophy, glomerular hyperfiltration (increased glomerular filtration rate), glomerulomegaly, mesangial expansion, podocyte foot process effacement, thickened glomerular basement membranes, renal interstitial fibrosis and increased albuminuria. These abnormalities were attenuated in Akita HnrnpfRT KO mice. Treatment of Akita HnrnpfRT KO mice with a selective A1 adenosine receptor inhibitor resulted in an increase in glomerular filtration rate. Renal Agt expression was elevated in Akita mice and further increased in Akita HnrnpfRT KO mice. In contrast, Sglt2 expression was increased in Akita and decreased in Akita HnrnpfRT KO mice. CONCLUSIONS/INTERPRETATION: The renoprotective effect of Sglt2 downregulation overcomes the renal injurious effect of Agt when these opposing factors coexist under diabetic conditions, at least partly via the activation of tubuloglomerular feedback.

Effects of Doxofylline Combined with Ceftazidime on Clinical Efficacy, Drug Safety, and Prognosis in Patients with Chronic Obstructive Pulmonary Disease Complicated with Infection.

BACKGROUND The aim of this study was to investigate the effects of doxofylline combined with ceftazidime on clinical efficacy, drug safety, and prognosis in patients with COPD complicated with infection. MATERIAL AND METHODS A total of 450 patients admitted to the Inner Mongolia BaoGang Hospital for treatment of COPD from January 2017 to December 2019 were selected to participate. All patients were randomly divided into control and observation groups, with 225 patients in each group. In addition, patients with COPD in the remission stage were matched by sex and age for a blank control group. The control group was treated with doxofylline, and the observation group was treated with ceftazidime and doxofylline. No drug intervention was given to the blank control group. Short-term efficacy, pulmonary ventilation function, patient quality of life, peripheral blood TNF-alpha and PGDF-B levels, and adverse drug reactions were observed. RESULTS The effective treatment rate in the observation group was 96.89%, which was significantly higher than that in the control group (84.00%). Measures of pulmonary ventilation function and patient quality of life in the observation group were significantly higher than those in the control group. Levels of TNF-alpha and PDGF-B in the observation group were significantly lower than those in the control group. There were no significant differences in the above indicators between the blank control group and the observation group. CONCLUSIONS Doxofylline combined with ceftazidime effectively treated patients with COPD complicated with infection. These results provide a reference for clinical treatment.

Adenosine 5'-monophosphate induces hypothermia and alters gene expressions in the brain and liver of chicks.

The adenosine A1 receptor is important for body temperature regulation in mammals; however, little is known about its function in avian species. In this study, we investigated the effects of the adenosine A1 receptor agonist and antagonist (adenosine 5'-monophosphate [5'-AMP] and 8 p-sulfophenyl theophylline [8-SPT], respectively) on thermoregulation in chickens. Male chicks were used in this study. After administration of 5'-AMP and 8-SPT, the rectal temperature, plasma metabolites, and gene expressions in the hypothalamus and liver were measured. The rectal temperature was reduced by peripheral administration of 5'-AMP, and the hypothermic effect of 5'-AMP was attenuated by central injection of 8-SPT in chicks. In the hypothalamus, the mRNA level of the agouti-related protein (AgRP) was increased by 5'-AMP administration, whereas it was suppressed by 8-SPT. The plasma levels of free fatty acid were elevated in 5'-AMP-treated chicks and that elevation was suppressed by the 8-SPT treatment. The gene expression of proopiomelanocortin in the hypothalamus was affected by 8-SPT. Nevertheless, the gene expressions of the thermoregulation-related genes, such as the thyrotropin-releasing hormone, were not affected by 5'-AMP and 8-SPT. Hepatic gene expressions related to lipid intake and metabolism were suppressed by 5'-AMP. However, the gene expression of the uncoupling protein was upregulated by 5'-AMP. Based on these results, birds, like mammals, will undergo adenosine A1 receptor-induced hypothermia. In conclusion, it is suggested that 5'-AMP-mediated hypothermia via the adenosine A1 receptor may affect the central melanocortin system and suppress hepatic lipid metabolism in chickens.

Treatment of spinal anaesthesia-induced hypotension with cafedrine/theodrenaline versus ephedrine during caesarean section: Results from HYPOTENS, a national, multicentre, prospective, noninterventional study.

BACKGROUND: In Germany, hypotension induced by spinal anaesthesia is commonly treated with a combination of cafedrine hydrochloride (C, 200 mg) and theodrenaline hydrochloride (T, 10 mg) in 2 ml. We compared the effectiveness of C/T with ephedrine. OBJECTIVES: The primary objectives were to assess the speed of onset and the ability to restore blood pressure without an increase in heart rate. Secondary objectives were to evaluate maternal/foetal outcomes and the number of required additional boluses or other additional measures. DESIGN: HYPOTENS was a national, multicentre, prospective, open-label, two-armed, noninterventional study comparing C/T with ephedrine in two prospectively defined cohorts. This study relates to the cohort of patients receiving spinal anaesthesia for caesarean section. SETTING: German hospitals using either C/T or ephedrine in their routine clinical practice. PATIENTS: Women aged at least 18 years receiving spinal anaesthesia for caesarean section. INTERVENTIONS: Bolus administration of C/T or ephedrine at the discretion of the attending anaesthesiologist. MAIN OUTCOME MEASURES: Endpoints within 15 min after initial administration of C/T or ephedrine were area under the curve between the observed SBP and the minimum target SBP; and incidence of newly occurring heart rate of at least 100 beats min-1. RESULTS: Although effective blood pressure stabilisation was achieved with both treatments, this effect was faster and more pronounced with C/T (P < 0.0001). The incidence of tachycardia and changes in heart rate were higher with ephedrine (P < 0.01). Fewer additional boluses (P < 0.01) were required with C/T. Although favourable neonatal outcomes were reported in both groups, base deficit and lactate values were greater with ephedrine (P < 0.01). Physician satisfaction was higher with C/T. CONCLUSIONS: After C/T, tachycardia was not a problem, providing an advantage over ephedrine. Fewer additional boluses were required with C/T, suggesting greater effectiveness. An increased base deficit with ephedrine suggests reduced oxygen supply or increased demands in foetal circulation. TRIALS REGISTRATION: Clinicaltrials.gov: NCT02893241, German Clinical Trials Register: DRKS00010740.

Biophysical insight into the binding mechanism of doxofylline to bovine serum albumin: An in vitro and in silico approach.

Insight into the mechanistic binding of bovine serum albumin (BSA) with doxofylline can layout pivotal enlightenment with relevance to pharmacokinetics and pharmacodynamics properties. Herein, many spectroscopic techniques and computational methods had been employed to interpret the structural and binding dynamics of BSA-doxofylline interaction. Doxofylline quenched the intrinsic fluorescence of BSA by static quenching. The stoichiometry and the binding constant of the BSA-doxofylline complex were 1:1 and in the order of 103 M-1. It was also concluded that the binding process was spontaneous and exothermic, primarily based on the thermodynamic study. Circular dichroism and three-dimensional excitation-emission matrix fluorescence results concluded pronounced conformational and microenvironmental changes in BSA structure on binding with doxofylline. The influence of metal ions and vitamins on the binding affinity of the BSA-doxofylline system were also explored. The in vitro findings were further supported by in silico analysis. With a score value of -6.25 kcal/mol, molecular docking showed strong interactions. Molecular dynamics simulation interpretation also suggested the stable binding with lower deviation in the values of RMSD and RMSF obtained by uninterrupted long simulation run. These studies will propose the optimum potency of distribution of the doxofylline into the bloodstream for asthma treatment.