- Atypical Amniotic Fluid Embolism Managed with a Novel Therapeutic Regimen. [Journal Article]
- CRCase Rep Obstet Gynecol 2017; 2017:8458375
- Amniotic fluid embolism (AFE) is the second leading cause of maternal mortality in the USA with an incidence of 1 : 15,200 births. The case fatality rate and perinatal mortality associated with AFE a...
Amniotic fluid embolism (AFE) is the second leading cause of maternal mortality in the USA with an incidence of 1 : 15,200 births. The case fatality rate and perinatal mortality associated with AFE are 13-30% and 9-44%, respectively. This rare but devastating complication can be difficult to diagnose as many of the early signs and symptoms are nonspecific. Compounding this diagnostic challenge is a lack of effective treatment regimens which to date are mostly supportive. We present the case of a 26-year-old woman who suffered from suspected AFE and was successfully treated with the novel regimen of Atropine, Ondansetron, and Ketorolac (A-OK). The authors acknowledge that this case does not meet the new criteria proposed, by Clark in 2016, but feel that it is important to share this case report, due to dramatic patient response to the provided supportive therapy presented in this case report. We hope this case report will prompt further research into this novel approach to treating AFE with Atropine, Ondansetron, and Ketorolac.
- Atrial Arrhythmias and Autonomic Dysfunction in Rats Exposed to Chronic Intermittent Hypoxia. [Journal Article]
- AJAm J Physiol Heart Circ Physiol 2018 Feb 09
- Obstructive sleep apnea (OSA), which involves chronic, intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms t...
Obstructive sleep apnea (OSA), which involves chronic, intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms to support AF is unknown. This study investigated the effects of CIH on atrial electrophysiology and arrhythmia vulnerability, and evaluated the role of autonomics in CIH promotion of AF. Adult male Sprague-Dawley rats were exposed to 8h/day of CIH or normoxia for 7 days. Following exposure, rats were anesthetized for intracardiac electrophysiological studies. Atrial effective refractory periods (AERPs) and AF inducibility were determined using programmed electrical stimulation (PES) and burst pacing in the absence and presence of autonomic receptor agonists and antagonists. Western blot analysis measured atrial protein expression of muscarinic M2, M3 and β1-adrenergic receptors. Compared to normoxic controls, CIH rats had enhanced AF vulnerability using both PES and burst pacing, accompanied by greater AERP responses to carbachol and propranolol, lesser responses to isoproterenol and higher atrial M2 receptor protein levels. Enhanced atrial vulnerability was accentuated by carbachol and abolished by atropine, indicating that AF-promoting effects of CIH depended principally on parasympathetic activation. Enhancement of atrial vulnerability and AERP shortening with cholinergic agonists in CIH rats is consistent with sensitivity to parasympathetic activation. Higher responses to adrenergic receptor blockade in CIH rats is consistent with sympathetic potentiation. These findings implicate CIH as an important mediator of enhanced AF susceptibility in OSA and provide novel insights into the underlying mechanisms.
- Low-Dose Atropine for Myopia Control-Reply. [Journal Article]
- JOJAMA Ophthalmol 2018 Feb 08
- Low-Dose Atropine for Myopia Control: Considering All the Data. [Journal Article]
- JOJAMA Ophthalmol 2018 Feb 08
- Relevance of copper transporter 1 and organic cation transporters 1-3 for oxaliplatin uptake and drug resistance in colorectal cancer cells. [Journal Article]
- MMetallomics 2018 Feb 08
- Oxaliplatin is a routinely used drug in the treatment of colorectal cancer. However, development of resistance is a major hurdle of the chemotherapy success. Defects in cellular accumulation represen...
Oxaliplatin is a routinely used drug in the treatment of colorectal cancer. However, development of resistance is a major hurdle of the chemotherapy success. Defects in cellular accumulation represent a frequently reported feature of cells with acquired resistance to platinum drugs. Nevertheless, the mechanisms of oxaliplatin uptake and their role in oxaliplatin resistance remain poorly elucidated. The aim of this study was to investigate the relevance of copper transporter 1 (CTR1) and organic cation transporters 1-3 (OCT1-3) for oxaliplatin uptake and resistance to the drug in sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cells. Co-incubation with copper(ii) sulfate, a CTR1 substrate, significantly decreased oxaliplatin accumulation but not cytotoxicity in both cell lines. Pre- as well as co-incubation with the OCT1 inhibitor atropine led to a significant reduction in oxaliplatin accumulation in sensitive but not in resistant cells. However, oxaliplatin cytotoxicity was also decreased in the presence of atropine in both cell lines. Cimetidine, an inhibitor of OCT2, induced a significant reduction in the cellular accumulation and potency of oxaliplatin in sensitive and resistant cells. An inhibitor of OCT3, decynium-22, had no influence on oxaliplatin accumulation and cytotoxicity in either cell line. No differences in the transporter expressions were observed between the cell lines, drug-treated or not, either at the mRNA or protein levels. A fluorescent oxaliplatin derivative CFDA-oxPt co-localized with CTR1, OCT1 and OCT2 in sensitive cells, but only with CTR1 and OCT2 in the resistant cell line. Our results suggest that oxaliplatin is transported into the cell by CTR1 in both cell lines. However, contribution of CTR1-mediated uptake to resistance seems unlikely. Uptake of oxaliplatin via OCT1 appears to take place in the sensitive but not in the resistant cell line underscoring the transporter relevance for oxaliplatin resistance. OCT2 is likely to be involved in the uptake of oxaliplatin to a similar extent in both cell lines suggesting no major contribution of this transporter to resistance. In contrast, OCT3 appears to be irrelevant for oxaliplatin transport into the cell and resistance.
- Biotic elicitation for scopolamine production by hairy root cultures of Datura metel. [Journal Article]
- MBMol Biol Res Commun 2017; 6(4):169-179
- The (-)-hyoscyamine, atropine and scopolamine (hyoscine) are three valuable tropane alkaloids while scopolamine is the most important member of this group for the pharmaceutical industry due to its h...
The (-)-hyoscyamine, atropine and scopolamine (hyoscine) are three valuable tropane alkaloids while scopolamine is the most important member of this group for the pharmaceutical industry due to its higher demand compared to hyoscyamine and atropine. Scopolamine is an anticholinergic reagent with several therapeutic applications. In the current study, the hairy roots culture of Daturametel was used as an advantageous method for production of scopolamine. The hairy roots are formed by Agrobacterium rhizogenes and have genetic stability, high growth rate and lateral branching. In this study, the effect of Bacillus cereus and Staphylococcus aureus as biotic elicitors on the production of scopolamine in D.metel hairy roots was investigated. The amount of scopolamine in the hairy roots was detected by HPLC analysis and compared with control samples after 0, 12 and 24 hours. Results showed that, B. cereus and S. aureus enhanced scopolamine production in the culture while the atropine content was decreased. Although in the control samples with no bacterial elicitation no scopolamine was detected, elicitation by B. cereus caused production of scopolamine and about 0.03 gram and 0.017 gram of it was detected in 100 gram dried D.metel hairy roots after 12 and 24 hours respectively. In S. aureus elicited hairy roots, scopolamine was not produced after 12 hours. However, about 0.025 gram of this tropane alkaloid was detected in 100 gram dried hairy roots after 24 hours. In conclusion, S. areus and B. cereus induced the scopolamine production in D. metel hairy roots.
- Cholinergic regulation of proliferation of the urothelium in response to E. coli lipopolysaccharide exposition. [Journal Article]
- IIInt Immunopharmacol 2018 Jan 27; 56:222-229
- How the proliferation of the urothelium is regulated is known to a little degree. E. coli lipopolysaccharide (LPS) activates the innate immune response of the urinary bladder via the Toll-like recept...
How the proliferation of the urothelium is regulated is known to a little degree. E. coli lipopolysaccharide (LPS) activates the innate immune response of the urinary bladder via the Toll-like receptor 4 (TLR4) on the urothelium but induces also urothelial proliferation. We wanted to assess whether muscarinic receptors are involved in the regulation of urothelial proliferation triggered by LPS stimulation. Female Fischer 344 rats were instilled with LPS or saline (control) in the urinary bladder in the absence or presence of muscarinic receptor blockade with atropine and regeneration of the urothelium was assessed 4h and 24h later. In the Fischer 344 bladder, urothelial thinning and urothelial caspase 3 up-regulation occurred at 4h after LPS urinary bladder instillation, which were totally blocked in rats pre-treated with atropine. TLR4 was only expressed in blood vessels in the Fischer 344 bladder, while it was also expressed in umbrella cells in the Sprague-Dawley bladder. Proliferation (Ki67 incorporation) of the human urothelial cell line UROtsa was reduced in the presence of the muscarinic receptor antagonists methoctramine (M2/M4-selective) and pirenzepine (M1/M4-selective), while proliferation instead was enhanced in the presence of atropine. In UROtsa cells exposed to LPS for 24h, 4-DAMP (M3/M1/M5-selective) inhibited instead proliferation. In conclusion, muscarinic receptors regulate urothelial proliferation and LPS may induce urothelial apoptosis via muscarinic receptor-dependent pathways. Our findings also suggest that species differences exist in the expressional pattern of TLR4 in the urothelium.
- Bilateral Pathways from the Basal Forebrain to Sensory Cortices May Contribute to Synchronous Sensory Processing. [Journal Article]
- FNFront Neuroanat 2018; 12:5
- Sensory processing in the cortex should integrate inputs arriving from receptive fields located on both sides of the body. This role could be played by the corpus callosum through precise projections...
Sensory processing in the cortex should integrate inputs arriving from receptive fields located on both sides of the body. This role could be played by the corpus callosum through precise projections between both hemispheres. However, different studies suggest that cholinergic projections from the basal forebrain (BF) could also contribute to the synchronization and integration of cortical activities. Using tracer injections and optogenetic techniques in transgenic mice, we investigated whether the BF cells project bilaterally to sensory cortical areas, and have provided anatomical evidence to support a modulatory role for the cholinergic projections in sensory integration. Application of the retrograde tracer Fluor-Gold or Fast Blue in both hemispheres of the primary somatosensory (S1), auditory or visual cortical areas showed labeled neurons in the ipsi- and contralateral areas of the diagonal band of Broca and substantia innominata. The nucleus basalis magnocellularis only showed ipsilateral projections to the cortex. Optogenetic stimulation of the horizontal limb of the diagonal band of Broca facilitated whisker responses in the S1 cortex of both hemispheres through activation of muscarinic cholinergic receptors and this effect was diminished by atropine injection. In conclusion, our findings have revealed that specific areas of the BF project bilaterally to sensory cortices and may contribute to the coordination of neuronal activity on both hemispheres.
- The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption. [Journal Article]
- EJEur J Pharm Sci 2018 Feb 02; 117:21-26
- Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to ev...
Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (VFMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro VFMSwas examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, kmc, was determined from the disappearance profiles of FMS. kmcwas decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between kmcand VFMS(r2 = 0.9745, p < 0.001). These results indicate that in vivo kmccan be estimated from the in vitro parameter, VFMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC.
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- Comparison of two hyoscyamine 6β-hydroxylases in engineering scopolamine biosynthesis in root cultures of Scopolia lurida. [Journal Article]
- BBBiochem Biophys Res Commun 2018 Jan 31
- Scopolia lurida, a medicinal plant native to the Tibetan Plateau, is among the most effective producers of pharmaceutical tropane alkaloids (TAs). The hyoscyamine 6β-hydroxylase genes of Hyoscyamus n...
Scopolia lurida, a medicinal plant native to the Tibetan Plateau, is among the most effective producers of pharmaceutical tropane alkaloids (TAs). The hyoscyamine 6β-hydroxylase genes of Hyoscyamus niger (HnH6H) and S. lurida (SlH6H) were cloned and respectively overexpressed in hairy root cultures of S. lurida, to compare their effects on promoting the production of TAs, especially the high-value scopolamine. Root cultures with SlH6H/HnH6H overexpression were confirmed by PCR and real-time quantitative PCR, suggesting that the enzymatic steps defined by H6H were strongly elevated at the transcriptional level. Tropane alkaloids, including hyoscyamine, anisodamine and scopolamine, were analyzed by HPLC. Scopolamine and anisodamine contents were remarkably elevated in the root cultures overexpressing SlH6H/HnH6H, whereas that of hyoscyamine was more or less reduced, when compared with those of the control. These results also indicated that SlH6H and HnH6H promoted anisodamine production at similar levels in S. lurida root cultures. More importantly, HnH6H-overexpressing root cultures had more scopolamine in them that did SlH6H-overexpressing root cultures. This study not only provides a feasible way of overexpressing H6H to produce high-value scopolamine in engineered root cultures of S. lurida but also found that HnH6H was better than SlH6H for engineering scopolamine production.