Development of a UV-Stabilized Topical Formulation of Nifedipine for the Treatment of Raynaud Phenomenon and Chilblains.

Raynaud's Phenomenon is a vascular affliction resulting in pain and blanching of the skin caused by excessive and prolonged constriction of arterioles, usually due to cold exposure. Nifedipine is a vasodilatory calcium channel antagonist, which is used orally as the first-line pharmacological treatment to reduce the incidence and severity of attacks when other interventions fail to alleviate the condition and there is danger of tissue injury. Oral administration of nifedipine, however, is associated with systemic adverse effects, and thus topical administration with nifedipine locally to the extremities would be advantageous. However, nifedipine is subject to rapid photodegradation, which is problematic for exposed skin such as the hands. The goal of this project was to analyze the photostability of a novel topical nifedipine cream to UVA light. The effect of incorporating the photoprotectants rutin, quercetin, and/or avobenzone (BMDBM) into the nifedipine cream on the stability of nifedipine to UVA light exposure and the appearance of degradation products of nifedipine was determined. Rutin and quercetin are flavonoids with antioxidant activity. Both have the potential to improve the photostability of nifedipine by a number of mechanisms that either quench the intermolecular electron transfer of the singlet excited dihydropyridine to the nitrobenzene group or by preventing photoexcitation of nifedipine. Rutin at either 0.1% or 0.5% (w/w) did not improve the stability of nifedipine 2% (w/w) in the cream after UVA exposure up to 3 h. Incorporation of quercetin at 0.5% (w/w) did improve nifedipine stability from 40% (no quercetin) to 77% (with quercetin) of original drug concentration after 3 h UVA exposure. A combination of BMDBM and quercetin was the most effective photoprotectant for maintaining nifedipine concentration following up to 8 h UVA exposure.

Ficus cunia Buch.-Ham. ex Roxb. (leaves): An experimental evaluation of the cytotoxicity, thrombolytic, analgesic and neuropharmacological activities of its methanol extract.

Background The aim of this experiment was to evaluate the cytotoxic, thrombolytic, analgesic, sedative-hypnotic and anxiolytic activities of the methanolic extract of Ficus cunia leaves. Methods Primary phytochemical screening was accomplished by using established methods. Cytotoxicity was studied by brine shrimp lethality test, and the thrombolytic assay was conducted through clot lysis method with human blood. The in vivo action was done using mice of both sexes. The analgesic activity was evaluated by acetic acid-induced writhing test and formalin-induced paw licking test. Open field, hole cross and thiopental Na-induced sleeping time test were used to examine the sedative-hypnotic activity, and elevated plus maze (EPM) and hole board test were used to identify the anxiolytic activity. Results The results elicited that the extract contained several phytochemicals such as alkaloid, flavonoid, and tannin. The extract was found to have a median lethal concentration (LC50) value of 55.48 µg/mL in the brine shrimp lethality bioassay. It was also assessed for antithrombotic activity when compared with streptokinase; it has significant (p < 0.001) thrombolytic effect (34.72 ± 1.74%) contrasted with standard streptokinase (67 ± 1.56%). The extract at doses of 200 and 400 mg/kg produced inhibition of 32.58% and 46.63% in acetic acid-induced pain and 45.88 and 61.18% in formalin-induced pain. The sedative and hypnotic activities on the central nervous system of the methanol extract of F. cunia (MEFC) leaves were evaluated. The extract delivered critical sedative impact at the doses of 200 and 400 mg/kg (by oral route) treated with reference to the substance diazepam, and the hypnotic impact was also observed in the case of mice. MEFC at its maximum dose (400 mg/kg) significantly (p < 0.01) increased the time spent in the open arms of the EPM. In the hole board test, there was a dose-dependent (at 200 and 400 mg/kg) and a significant (p < 0.05 and p < 0.01) increase in the number of head pokes in comparison to control. Conclusions The results of the present study gave a helpful baseline in progression for the possible use of MEFC as a cytotoxic, thrombolytic, analgesic, sedative-hypnotic and anxiolytic drug.

Investigation into spinal anesthetic failure with hyperbaric bupivacaine: the role of cold exposure on bupivacaine degradation.

PURPOSE: Hyperbaric bupivacaine (0.75% in dextrose) is used for spinal obstetric anesthesia. Occasional clusters of anesthetic failures occur in this setting, not readily attributable to clinical factors. We hypothesized that cold temperature exposure is related to bupivacaine instability. METHODS: An electronic survey was distributed to Canadian anesthesiologists to determine consistencies in spinal anesthesia practice, and to invite submission of failed bupivacaine samples for analysis. Another survey for hospital pharmacists focused on bupivacaine logistics. Ultraviolet (UV) spectrometry, differential scanning calorimetry, and high performance liquid chromatography were used to evaluate the effect of temperature on bupivacaine chemical stability. Mass spectrometry (MS) was used to observe bupivacaine and dextrose degradation in laboratory samples of hyperbaric 0.75% bupivacaine in dextrose. Hyperbaric bupivacaine that failed to produce adequate anesthesia in labour and delivery patients was subject to tandem MS/MS analysis on commonly observed ions to look for ion patterns consistent with bupivacaine degradation products and to compare with laboratory samples subjected to cold temperatures. RESULTS: Canadian obstetric anesthesiologists report similar practices and use hyperbaric bupivacaine for spinal anesthesia. Pharmacists surveyed indicated facility storage at room temperature but variable temperatures during shipping. No standard procedure for failure reporting was identified. Analysis of bupivacaine showed a slight decrease in bupivacaine concentration or UV spectral changes after incubation at temperatures ≤ 4°C. Mass spectrometric analysis of hyperbaric bupivacaine from failed spinal anesthesia cases showed complex and inconsistent patterns of ion formation, and different from the ion patterns observed for cooled vs uncooled bupivacaine solutions. Temperature-related changes were noted for dextrose in cooled samples in which dextrose-related ions were formed. CONCLUSIONS: Canadian clinical practice and handling of hyperbaric bupivacaine is consistent. Most respondents indicated an interest in a formal reporting and collection process. Cold exposure did not degrade bupivacaine. A complex and possibly inconsistent reaction involving dextrose was identified that requires further analysis of a larger sample size to elucidate the mechanisms.

RéSUMé: OBJECTIF: La bupivacaïne hyperbare (0,75 % dans du dextrose) est utilisée pour l'anesthésie obstétricale rachidienne. Il arrive parfois que plusieurs anesthésies rapprochées soient inefficaces dans cette situation, et ces échecs ne sont pas nécessairement attribuables à des facteurs cliniques. Nous avons émis l'hypothèse qu'une exposition de la bupivacaïne au froid expliquerait son instabilité. MéTHODE: Un sondage électronique a été distribué aux anesthésiologistes canadiens afin de déterminer les similitudes dans la pratique de la rachianesthésie, et nous avons invité les médecins à nous envoyer des échantillons de bupivacaïne à des fins d'analyse lorsque leur anesthésie était inefficace. Un autre sondage, envoyé aux pharmaciens hospitaliers, mettait l'emphase sur la logistique entourant la manutention de la bupivacaïne. Nous avons utilisé une spectrométrie de rayons ultraviolets (UV), une analyse calorimétrique différentielle et une chromatographie liquide à haute performance afin d'évaluer l'effet de la température sur la stabilité chimique de la bupivacaïne. Une spectrométrie de masse (SM) a été utilisée pour observer la dégradation de la bupivacaïne et du dextrose dans des échantillons de laboratoire de bupivacaïne hyperbare 0,75 % dans le dextrose. La bupivacaïne hyperbare qui n'a pas procuré une anesthésie adéquate chez des patientes en travail ou en accouchement a été sujette à une analyse de SM/SM en tandem sur les ions fréquemment observés afin d'identifier des modèles ioniques correspondant aux produits de dégradation de la bupivacaïne et les comparer à des échantillons de laboratoire soumis au froid. RéSULTATS: Les anesthésiologistes obstétricaux canadiens font état de pratiques semblables et utilisent de la bupivacaïne hyperbare pour réaliser une rachianesthésie. Les pharmaciens interrogés ont indiqué que la bupivacaïne était entreposée à température ambiante au sein de leur établissement mais qu'elle était exposée à des températures variables pendant l'expédition. Aucune procédure standardisée n'a été identifiée pour rapporter les échecs d'anesthésie. L'analyse de la bupivacaïne a montré une légère réduction dans la concentration de bupivacaïne ou des changements spectraux UV après une période d'incubation à des températures ≤ 4°C. L'analyse par spectrométrie de masse des échantillons de bupivacaïne hyperbare utilisés lors d'échecs de la rachianesthésie a révélé des types de formation des ions complexes et incohérents, lesquels différaient des modèles des ions observés dans les solutions de bupivacaïne refroidies vs non refroidies. Les changements liés à la température ont été notés sur le dextrose dans les échantillons refroidis dans lesquels des ions liés au dextrose se sont formés. CONCLUSION: La pratique clinique canadienne et la manutention de la bupivacaïne hyperbare est homogène. La plupart des répondants ont indiqué être intéressés par un processus formel d'enregistrement et de récolte des données. L'exposition au froid n'a pas dégradé la bupivacaïne. Une réaction complexe et possiblement inconstante ayant un rapport avec le dextrose a été identifiée; elle requiert des analyses approfondies sur un échantillonnage plus important afin d'en élucider les mécanismes.

Development and in vitro characterization of chitosan-coated polymeric nanoparticles for oral delivery and sustained release of the immunosuppressant drug mycophenolate mofetil.

OBJECTIVE: To develop an oral sustained release formulation of mycophenolate mofetil (MMF) for once-daily dosing, using chitosan-coated polylactic acid (PLA) or poly(lactic-co-glycolic) acid (PLGA) nanoparticles. The role of polymer molecular weight (MW) and drug to polymer ratio in encapsulation efficiency (EE) and release from the nanoparticles was explored in vitro. METHODS: Nanoparticles were prepared by a single emulsion solvent evaporation method where MMF was encapsulated with PLGA or PLA at various polymer MW and drug: polymer ratios. Subsequently, chitosan was added to create coated cationic particles, also at several chitosan MW grades and drug: polymer ratios. All the formulations were evaluated for mean diameter and polydispersity, EE as well as in vitro drug release. Differential scanning calorimetry (DSC), surface morphology, and in vitro mucin binding of the nanoparticles were performed for further characterization. RESULTS: Two lead formulations comprise MMF: high MW, PLA: medium MW chitosan 1:7:7 (w/w/w), and MMF: high MW, PLGA: high MW chitosan 1:7:7 (w/w/w), which had high EE (94.34% and 75.44%, respectively) and sustained drug release over 12 h with a minimal burst phase. DSC experiments revealed an amorphous form of MMF in the nanoparticle formulations. The surface morphology of the MMF NP showed spherical nanoparticles with minimal visible porosity. The potential for mucoadhesiveness was assessed by changes in zeta potential after incubation of the nanoparticles in mucin. CONCLUSION: Two chitosan-coated nanoparticles formulations of MMF had high EE and a desirable sustained drug release profile in the effort to design a once-daily dosage form for MMF.

An Overview of Chitosan Nanoparticles and Its Application in Non-Parenteral Drug Delivery.

The focus of this review is to provide an overview of the chitosan based nanoparticles for various non-parenteral applications and also to put a spotlight on current research including sustained release and mucoadhesive chitosan dosage forms. Chitosan is a biodegradable, biocompatible polymer regarded as safe for human dietary use and approved for wound dressing applications. Chitosan has been used as a carrier in polymeric nanoparticles for drug delivery through various routes of administration. Chitosan has chemical functional groups that can be modified to achieve specific goals, making it a polymer with a tremendous range of potential applications. Nanoparticles (NP) prepared with chitosan and chitosan derivatives typically possess a positive surface charge and mucoadhesive properties such that can adhere to mucus membranes and release the drug payload in a sustained release manner. Chitosan-based NP have various applications in non-parenteral drug delivery for the treatment of cancer, gastrointestinal diseases, pulmonary diseases, drug delivery to the brain and ocular infections which will be exemplified in this review. Chitosan shows low toxicity both in vitro and some in vivo models. This review explores recent research on chitosan based NP for non-parenteral drug delivery, chitosan properties, modification, toxicity, pharmacokinetics and preclinical studies.

Antidiarrheal and antinociceptive activities of ethanol extract and its chloroform and pet ether fraction of Phrynium imbricatum (Roxb.) leaves in mice.

BACKGROUND: The objective of the study was to evaluate the antidiarrheal and antinociceptive activities of ethanol extract and its chloroform and pet ether fraction of Phrynium imbricatum (Roxb.) leaves in mice. METHODS: In the present study, the dried leaves of P. imbricatum were subjected to extraction with ethanol, and then it was fractioned by chloroform and pet ether solvent. Antidiarrheal effects were tested by using castor oil-induced diarrhea, castor oil-induced enteropooling, and gastrointestinal transit test. Antinociceptive activity was evaluated by using the acetic acid-induced writhing test and formalin-induced paw licking test. RESULTS: The standard drug loperamide (5 mg/kg) showed significant (p<0.001) inhibitory activity against castor oil-induced diarrhea, in which all the examined treatments decreased the frequency of defecation and were found to possess an anti-castor oil-induced enteropooling effect in mice by reducing both weight and volume of intestinal content significantly, and reducing the propulsive movement in castor oil-induced gastrointestinal transit using charcoal meal in mice. The results showed that the ethanol extract of P. imbricatum leaves has significant dose-dependent antinociceptive activity, and among its two different fractions, the pet ether fraction significantly inhibited the abdominal writhing induced by acetic acid and the licking times in formalin test at both phases. CONCLUSIONS: These findings suggest that the plant may be a potential source for the development of a new antinociceptive drug and slightly suitable for diarrhea, as it exhibited lower activity. Our observations resemble previously published data on P. imbricatum leaves.

Antioxidant, antidiarrheal, hypoglycemic and thrombolytic activities of organic and aqueous extracts of Hopea odorata leaves and in silico PASS prediction of its isolated compounds.

BACKGROUND: Hopea Odorata, locally known as Telsur (Bangladesh), has some traditional uses as folk medicine. This study aims to investigate the antioxidant, antidiarrheal, hypoglycemic and thrombolytic activities of H. odorata leaf extracts as new therapeutic prospects predicting the activity of some of the isolated compounds of this plant. METHODS: Leaves of Hopea odorata was extracted with pure methanol (MEHO), ethanol (EEHO) and water (AEHO). The extract was tested for antioxidant activity by using reducing power and H2O2 scavenging assay. Antidiarrheal effects were assayed by three standard methods of bioassay: Castor oil-induced diarrhea, Castor oil induced enteropooling and gastrointestinal transit test. Hypoglycemic effect was determined by normoglycemic model of mice. Thrombolytic activity was evaluated by clot lyses test for human and mice blood. In silico PASS prediction was applied for phytoconstituents namely Balanocarpol, Hopeaphenol and Ampelopsin H isolated from this plant. RESULT: Among the all extracts, MEHO exhibited strong antioxidant activity in both reducing power and H2O2 scavenging assay. Phenol content of MEHO was 297.22 ± 0.78 mg/g and flavonol content was 91.53 ± 1.82 mg/g. All the experiment of extracts at dose of 200 and 400 mg/kg and the standard drug loperamide (5 mg/kg) showed significant (p < 0.001) inhibition against castor oil induced diarrhea and castor oil induced enteropooling in mice. There were also significant (p < 0.01) reduction in gastrointestinal motility in the charcoal meal test. Leaf extract showed no significant (P < 0.01) decrease of blood glucose compared to Glibenclamide in normoglycemic mice. Using an in vitro thrombolytic model, MEHO showed the highest and significant clot lysis of human and mice blood compared to Streptokinase. PASS predicted the wide range of antioxidant, free radical scavenger, Nitric oxide scavenger, cardioprotectant, hepatoprotectant, thrombolytic, fibrinolytic, antibacterial, antifungal, anticarcinogenic, anthelmintic and anti-inflammatory activity of examined phytoconstituents. CONCLUSION: These findings suggest that the plant may be a potential source of new antidiarrheal, thrombolytic and antioxidative agents but it is found to have no antidiabetic capability. PASS prediction matched with present study for the extracts. Further study needs to identify the PASS predicted biological actions of the phytoconstituents.

Antithrombotic and cytotoxic activities of four Bangladeshi plants and PASS prediction of their isolated compounds.

BACKGROUND: This study aims to investigate whether tested organic extracts possess antithrombotic properties with minimal or no toxicity and to predict the activity of some of their isolated compounds. METHODS: An in vitro thrombolytic model was used to check the clot lysis effect of four Bangladeshi herbal extracts viz., roots of Curculigo recurvata W.T. Aiton (Satipata), leaf of Amorphophallus bulbifer Roxb. (Olkachu), leaf of Phyllanthus sikkimensis Muell. Arg., and whole plant of Thunbergia grandiflora Roxb. (Nillata) using streptokinase as a positive control and water as a negative control. Cytotoxicity was screened by brine shrimp lethality bioassay using vincristine sulfate as positive control. In silico prediction of activity spectra for substances (PASS) prediction was applied for phytoconstituents, namely, nyasicoside, glucomannan, grandifloric acid, serine, and alanine. RESULTS: Using an in vitro thrombolytic model, C. recurvata, A. bulbifer, P. sikkimensis, and T. grandiflora showed 28.10±1.64%, 42.47±1.96%, 32.86±1.92%, and 25.51±1.67% of clot lysis, respectively. Reference drug streptokinase exhibited 75.00±3.04% clot lysis. Examined herbs showed significant (p<0.001) percentage (%) of clot lysis compared to negative control. In brine shrimp cytotoxic assay, C. recurvata, A. bulbifer, P. sikkimensis, and T. grandiflora showed LC50 values 210.64±3.44, 98.51±1.47, 187.29±2.01, and 386.43±3.02 µg/mL, respectively, with reference to vincristine sulfate (LC50 0.76±0.04). PASS predicted that examined phytoconstituents have a wide range of biological activity. CONCLUSIONS: Through our study it was found that A. bulbifer and P. sikkimensis could be considered as very promising and beneficial thrombolytic agents.

Guillain-Barré syndrome: clinical profile and management.

INTRODUCTION: Guillain-Barré syndrome (GBS) is a fulminant polyradiculoneuropathy that is acute, frequently severe and autoimmune in nature. Etiology of GBS is incompletely understood, prognosis is usually good with early detection and prompt treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and electrodiagnostic features of patients with GBS and mode of management, complications and prognostic factors. METHODS: Data of 1,166 patients admitted with GBS or presented to outpatient department (previous medical records) with GBS between January 2003 and January 2014 were analyzed. RESULTS: No difference in genders noted. Around 35% of patients are above 50 years of age. Poor control of diabetes with mean HbA1c of 8.1 ± 2.11 is found on analysis. Seasonal occurrence in GBS is prominent in winter 484 (41.50%) and mechanically ventilated were 449 (38.50%) patients. 48 (4.11%) deaths were attributed to GBS. Neurological analysis revealed cranial nerve involvement in 407 (34.90%) patients, facial palsy in 401 (34.39%) and ataxia in 88 (7.54%) patients. Most patients in plasma exchange group belonged to the lower socio-economic status. Mean cerebrospinal fluid (CSF) protein levels was (n=962) 113.8 ± 11.8 mg/dl. Conduction block determined indirectly by absent H-reflex was noted in 891 (90.64%) patients. No difference in complications and outcome is found in treatment regimens of intravenous immunoglobulin (IVIG) and plasma exchange. CONCLUSION: Seasonal occurrence predominantly in winter is noted. Peak flow test may be a predictor of assessing requirement of mechanical ventilation and prognosis. Conduction block is the major abnormality noted in electrophysiological studies and proximal nerve segment assessing with Erb's point stimulation has high predictive value. IVIG treatment is more expensive but is associated with less duration of hospital stay.