- ABILITY OF GELATIN AND BSA TO STABILIZE THE SUPERSATURATED STATE OF POORLY SOLUBLE DRUGS. [Journal Article]
- EJEur J Pharm Biopharm 2018 Aug 16
- Gelatin and bovine serum albumin (BSA), two readily available biopolymers, were examined for their effect on solubility and supersaturation of drugs because of their capacity to interact with drugs (...
Gelatin and bovine serum albumin (BSA), two readily available biopolymers, were examined for their effect on solubility and supersaturation of drugs because of their capacity to interact with drugs (e.g. via hydrogen bonding, van der Waals or electrostatic interactions, etc.). Carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen were selected accordingly as twelve structurally different model BCS Class II drugs. All selected drugs were evaluated for solubility and supersaturation in presence and absence of these two biopolymers in four media (purified water, FaSSIF, FaSSGF and FeSSIF) by means of the shake flask method for 48h and solvent shift induced supersaturation, respectively. In ca. 75% of the supersaturation experiments with these two biopolymers, drug concentrations significantly different (p > 0.05) from solubility were observed with supersaturation factors (SF) varying between 1.28 and 7.89 (p ≤ 0.05) and between 1.16 and 20.51 (p ≤ 0.01). In order to make an estimation on the relevance of these results, a comparison with three commonly used (semi-) synthetic polymers (HPMC, PVP and PVPVA) was included in purified water. This showed that both biopolymers were at least as efficient as the (semi-) synthetic polymers in sustaining induced supersaturation as in ten out of twelve API comparable results were obtained.
- Smooth muscle gap-junctions allow propagation of intercellular Ca2+ waves and vasoconstriction due to Ca2+ based action potentials in rat mesenteric resistance arteries. [Journal Article]
- CCCell Calcium 2018 Aug 07; 75:21-29
- The role of vascular gap junctions in the conduction of intercellular Ca2+ and vasoconstriction along small resistance arteries is not entirely understood. Some depolarizing agents trigger conducted ...
The role of vascular gap junctions in the conduction of intercellular Ca2+ and vasoconstriction along small resistance arteries is not entirely understood. Some depolarizing agents trigger conducted vasoconstriction while others only evoke a local depolarization. Here we use a novel technique to investigate the temporal and spatial relationship between intercellular Ca2+ signals generated by smooth muscle action potentials (APs) and vasoconstriction in mesenteric resistance arteries (MA). Pulses of exogenous KCl to depolarize the downstream end (T1) of a 3 mm long artery increased intracellular Ca2+ associated with vasoconstriction. The spatial spread and amplitude of both depended on the duration of the pulse, with only a restricted non-conducting vasoconstriction to a 1 s pulse. While blocking smooth muscle cell (SMC) K+ channels with TEA and activating L-type voltage-gated Ca2+ channels (VGCCs) with BayK 8644 spread was dramatically facilitated, so the 1 s pulse evoked intercellular Ca2+ waves and vasoconstriction that spread along an entire artery segment 3000 μm long. Ca2+ waves spread as nifedipine-sensitive Ca2+ spikes due to SMC action potentials, and evoked vasoconstriction. Both intercellular Ca2+ and vasoconstriction spread at circa 3 mm s-1 and were independent of the endothelium. The spread but not the generation of Ca2+ spikes was reversibly blocked by the gap junction inhibitor 18β-GA. Thus, smooth muscle gap junctions enable depolarization to spread along resistance arteries, and once regenerative Ca2+-based APs occur, spread along the entire length of an artery followed by widespread vasoconstriction.
- Extreme and Cyclical Blood Pressure Elevation in a Pheochromocytoma Hypertensive Crisis. [Journal Article]
- CRCase Rep Endocrinol 2018; 2018:4073536
- Pheochromocytomas are rare adrenal neoplasms characterized by excess secretion of catecholamines. We describe the case of a 65-year-old man, known for hypertension, with no family history of heredita...
Pheochromocytomas are rare adrenal neoplasms characterized by excess secretion of catecholamines. We describe the case of a 65-year-old man, known for hypertension, with no family history of hereditary pheochromocytoma syndromes. He reported a two-year history of flushing, systolic blood pressure surges to 200 mmHg, headaches, tremors, and syncope. His initial workup revealed elevated 24h urine catecholamines and metanephrines. An adrenal MRI in March 2017 showed a large 7.6 cm heterogeneous right adrenal lesion. Given orthostatic hypotension, his final preoperative dose was limited to a low dose of terazosin and metoprolol. In the operating room, shortly after intubation and Foley insertion, his blood pressure rose to 350 mmHg. Surgery was cancelled and he was admitted to the intensive care unit, where intravenous phentolamine, nitroprusside, and nicardipine were started. His systolic blood pressure would oscillate between 60 mmHg and 350 mmHg at 2-3 minutes' intervals. After 3 days, he was weaned off intravenous medications. His oral medications were uptitrated to high doses of phenoxybenzamine, metoprolol, and nifedipine. Three weeks later, he underwent successful open right adrenalectomy. This case outlines the importance of preoperative preparation of pheochromocytomas and raises the question if phenoxybenzamine is the alpha-blocker of choice for larger tumours with significant hormonal secretion.
- Impact of presence of excipients in drug analysis in fed-state gastric biorelevant media. [Journal Article]
- EJEur J Pharm Biopharm 2018 Aug 12
- In this study, the influence of the presence of excipients in sample preparation and clean-up steps required prior to drug analysis in milk-based media which simulate the in vivo properties of the fe...
In this study, the influence of the presence of excipients in sample preparation and clean-up steps required prior to drug analysis in milk-based media which simulate the in vivo properties of the fed state stomach was investigated. 15 excipients, normally present in solid dosage forms of five APIs tested (atenolol, paracetamol, furosemide, nifedipine and propafenone hydrochloride) were mixed (one at a time) with the active pharmaceutical ingredient of interest either via vortexing, co-grinding or shaking of the physical mixture and dissolved in Fed State Simulated Gastric Fluid (FeSSGF). The objective of the study was the assessment of the extraction efficiency of three protein precipitation protocols (using MeOH, ΑCN and 10% w/v TCA), typically used in drug analysis, in milk-based biorelevant media in the presence of the excipients. The mixing technique, fat content of the medium and excipient and solvent effects were investigated. The efficiency of three different protein precipitation reagents in drug extraction when dissolved as API:excipient mixtures in the fed-state medium was compared against the equivalent drug amount recovered in the absence of the excipient in FeSSGF. Most excipients had a significant negative effect (p < 0.05) on drug recovery in the milk-based medium as indicated by the multiple linear regression (MLR) analysis performed. For magnesium stearate and HPMC, the % recovery values were the lowest in four out of the five drugs studied, with a range of 10-100% depending on the API, mixing technique and protein precipitation protocol selected. The negative excipient-dependent effect was more profound in nifedipine and propafenone hydrochloride, the most lipophilic compounds of the study. Acetonitrile was the most effective extraction reagent for most drugs in the presence of excipients, followed by methanol and 10% w/v trichloroacetic acid. Data analysis also revealed a dependence of the extraction method efficiency on the medium lipid content. Application of the above extraction protocols in commercially available formulations highlighted the need for assessment of the effect of excipients in extraction efficiency, before transferring the method directly to dissolution studies of formulations in milk-based fed gastric media. In conclusion, the presence of excipients and the selection of protein precipitation protocol are parameters which can affect significantly the efficiency of protein precipitation when FeSSGF is used as dissolution medium and need to be taken into consideration when developing a quantitative method based on the above sample clean-up technique.
- Access to medicines for hypertension: a survey in rural Yogyakarta province, Indonesia. [Journal Article]
- RRRural Remote Health 2018; 18(3):4393
- CONCLUSIONS: These Indonesian participants obtained their anti-hypertensive medications from various sources; however, the inadequate supplies found in this study could compromise both short- and long-term management of hypertension. Direct dispensing, non-doctor prescribing, and self-medication with anti-hypertensive medications indicate the current complex healthcare system in Indonesia. This study also shows some challenges involved in managing patients with chronic diseases such as hypertension in resource-poor settings. It provides important findings for quality improvement practices that should be considered to improve the health lifespan in populous countries such as Indonesia.
- Determination of precipitation inhibitory potential of polymers from amorphous solid dispersions. [Journal Article]
- DDDrug Dev Ind Pharm 2018 Aug 13; :1-31
- CONCLUSIONS: The outcome of the study concluded that SHC can be a promising parameter in screening of polymers for the development of the ASDs.
- Chemistry And Pharmacological Activities Of Biginelli Product- A Brief Overview. [Journal Article]
- CDCurr Drug Discov Technol 2018 Aug 07
- Dihydropyrimidinones are extremely advantageous small sized molecules owning adaptable pharmaceutical properties. With a molecular formula C4H6N2O, they hold a wide range of biological activities. It...
Dihydropyrimidinones are extremely advantageous small sized molecules owning adaptable pharmaceutical properties. With a molecular formula C4H6N2O, they hold a wide range of biological activities. It is a heterocyclic moiety having two N-atoms at positions 1 and 3. They are derivatives of pyrimidine containing an additional ketone group. They have inspired development of a wide range of synthetic methods for preparation and chemical transformations. Taking into consideration their structural similarity and involvement with DNA and RNA, they have become very imperative in the world of synthetic organic chemistry. Aryl substituted moieties and their derivatives are significant class of substances in medicinal and organic chemistry. Many alkaloids from natural marine sources comprising dihydropyrimidinones core have been isolated which possess fascinating biological properties. Intensive explorations have been carried out on these compounds because they possess close similitude to clinically used nifedipine, nicardipine etc. which are also Biginelli product analogues. Due to the interesting pharmacological properties associated with the privileged DHPM structures, the Biginelli reaction and related procedures have received increasing attention in recent years.
- STIM1 deficiency is linked to Alzheimer's disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry. [Journal Article]
- JMJ Mol Med (Berl) 2018 Aug 07
- STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry...
STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer's disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer's disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death.
- A functional KATP channel is required in high carbohydrate diet-induced increase in β-cell mass. [Journal Article]
- JDJ Diabetes Investig 2018 Aug 07
- CONCLUSIONS: These results indicate that high starch diet increases β-cell mass in a KATP channel-dependent manner, which is mediated through up-regulation of cyclinD2 expression. This article is protected by copyright. All rights reserved.
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- Preparation of Nanoparticles Including Antisolvent Drugs by the Combination of Roll Milling and High-pressure Homogenization. [Journal Article]
- CNCurr Nanosci 2018; 14(2):143-147
- CONCLUSIONS: These findings demonstrate that most IB and GF nanoparticles exist as crystals in phospholipids.