The objective of the present study was to develop new directly compressed, double-layer tablets (DLTs) of lornoxicam, a highly potent nonsteroidal anti-inflammatory drug with short half-life, that are characterized by initial burst drug release in the stomach and comply with the release requirements of sustained-release products. Each of the proposed DLTs is composed of a fast-release layer and a sustained-release layer, anticipating rapid drug release that starts in the stomach to rapidly alleviate the symptoms and continues in the intestine to maintain protracted analgesic effect. An amorphous, freeze-dried inclusion complex of lornoxicam with hydroxypropyl-β-cyclodextrin, present in 1:2 (drug/cyclodextrin) molar ratio, was employed in the fast-release layer to enhance the dissolution of lornoxicam in the stomach and assure rapid onset of its analgesic effect. Xanthan gum (XG), a hydrophilic matrix-forming agent, was integrated in the sustained-release layer to provide appropriate sustainment of drug release. The weight ratios between the sustained-release layer and fast-release layer present in DLTs were adjusted to reach optimal formulations. DLTs composed of sustained-release layer (40% XG) to fast-release layer in 2:1 weight ratio and those composed of sustained-release layer (50% XG) to fast-release layer in 1:1 weight ratio showed the desired release profile. The drug contained in the fast-release layer showed an initial burst drug release of more than 30% of its drug content during the first 30 min of the release study followed by gradual release of the drug for a period of 8 h.
cyclodextrins; double-layer tablets; lornoxicam; sustained release; xanthan gum
A new assay for the precise measurement of microbial killing by leukocytes is presented. The method assumes that release of radioactively labeled DNA from the microbe is direct evidence of cell death. Human peripheral blood leukocytes incubated with [14C]thymidine-labeled Salmonella typhimurium released 32 to 59% of the radioactivity after 4 h and 63 to 75% after 18 h. Inactivated leukocytes released less than 5% of the radioactivity. None of the released radioactivity is retained within the leukocyte, and 60% remains precipitable with trichloroacetic acid. Leukocytes released substantial radioactivity from labeled Escherichia coli but only a slight amount from staphylococci. Mouse peritoneal macrophages were also shown to release radioactivity from Salmonella. The DNA release assay avoids the errors inherent in prior killing methods which measure viability by growth inhibition. It is rapid, reproducible, and highly specific.
In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphoproteins that modulate synaptic transmission and plasticity, and are mutated in epileptic patients. Here we report that inhibitory synapses of the dentate gyrus of Syn II knockout mice display an upregulation of synchronous neurotransmitter release and a concomitant loss of delayed asynchronous release. Syn II promotes γ-aminobutyric acid asynchronous release in a Ca2+-dependent manner by a functional interaction with presynaptic Ca2+ channels, revealing a new role in synaptic transmission for synapsins.
The arrival of action potentials at nerve terminals often leads to synchronous neurotransmitter release. Medrihan and colleagues use electrophysiology on mouse hippocampal neurons to show that the vesicle protein Synapsin II promotes GABAergic asynchronous release by interacting with calcium channels.
New facts have emerged about growth hormone (hgh) secretion in man giving rise to new conceptions and to new questions.
• In well-nourished, lean human beings growth hormone is released in early deep sleep and the pattern of release observed from night to night is fairly constant.
• The release of growth hormone in sleep occurs when plasma glucose is not fluctuating and after insulin has fallen to a very low level. Plasma-free fatty acids may rise about two hours later but insulin does not rise in response to nocturnal hgh release.
• The releases of growth hormone in sleep appear to meet the needs for a physiological test for the study of problems of growth. Correlations of this test with the many pharmacologic maneuvers in current use for diagnosis remain to be made.
• Growth hormone secretion as judged by plasma concentrations relates to protein intake, such that protein depletion initiates compensatory elevation of plasma concentrations of growth hormone. Further elevations may occur with glucose loading—so-called “paradoxical” responses. In contrast, there is compensatory suppression of growth hormone secretion in obesity. Repletion of protein in the malnourished and reduction of weight in obesity cause return toward normal secretion of hgh.
• Levodopa as a possible specific stimulus to growth hormone release has just been reported and the implications of this finding for the child of short stature cannot yet be assessed.
A new method of optically guided controlled release was experimentally evaluated with liposomes containing a molecular load and gold nanoparticles (NPs). NPs were exposed to short laser pulses to induce transient vapor bubbles around the NPs, plasmonic nanobubbles, in order to disrupt the liposome and eject its molecular contents. The release efficacy was tuned by varying the lifetime and size of the nanobubble with the fluence of the laser pulse. Optical scattering by nanobubbles correlated to the molecular release and was used to guide the release. The release of two fluorescent proteins from individual liposomes has been directly monitored by fluorescence microscopy, while the generation of the plasmonic nanobubbles was imaged and measured with optical scattering techniques. Plasmonic nanobubble-induced release was found to be a mechanical, nonthermal process that requires a single laser pulse and ejects of the liposome contents within a millisecond timescale without damage to the molecular cargo and that can be controlled through the fluence of laser pulse.
liposome; bubble; release; photothermal; gold nanoparticles; pulsed laser
A reservoir-based device constructed of a completely biodegradable elastomer can enable many new implantation and insertion options for localized drug therapy, particularly in the case of urological therapies. We performed an in vitro performance evaluation of an implantable, bioresorbable device that supplies short-term controlled release of ciprofloxacin-HCl (CIP). The proposed device functions through a combination of osmosis and diffusion mechanisms to release CIP for short-term therapies of a few weeks duration. Poly(glycerol-co-sebacic acid) (PGS) was cast in a tubular geometry with solid drug powder packed into its core and a micro-machined release orifice drilled through its wall. Drug release experiments were performed to determine the effective release rate from a single orifice and the range of orifice sizes in which controlled zero-order release was the main form of drug expulsion from the device. It is demonstrated that PGS is sufficiently permeable to water to allow the design of an elementary osmotic pump for drug delivery. Indeed, PGS's water permeability is several orders of magnitude larger than commonly used cellulose acetate for elementary osmotic pumps.
Elementary osmotic pump; Biodegradable polymers; PGS; Ciprofloxacin; Insertable devices
Norepinephrine (NE) released from the nerve terminal of locus coeruleus (LC) neurons contributes to about 70% of the total extracellular NE in primates brain. In addition, LC neurons also release NE from somatodendritic sites. Quantal NE release from soma of LC neurons has the characteristics of long latency, nerve activity-dependency, and autoinhibition by α2-adrenergic autoreceptor. The distinct kinetics of stimulus-secretion coupling in somata is regulated by action potential patterns. The physiological significance of soma and dendritic release is to produce negative-feedback and to down-regulate neuronal hyperactivity, which consequently inhibit NE release from axon terminal of LC projecting to many brain areas. Recent discoveries about the LC somatodendritic release may provide new insights into the pathogenesis of clinic disease involving LC-NE system dysfunction, and may help developing remedy targeted to the LC area.
norepinephrine; somatodendritic; quantal release; locus coeruleus; α2A-adrenoceptor
Primary care is understudied as a re-entry drug and alcohol treatment setting. This study compared treatment retention and opioid misuse among opioid dependent adults seeking buprenorphine/naloxone maintenance in an urban primary care clinic following release from jail vs. community referrals. Post-release patients were either; a) induced to buprenorphine in-jail as part of a clinical trial, or, b) seeking buprenorphine induction post-release. From 2007–2008, N=142 patients were new to primary care buprenorphine: n=32 post-release; n=110 induced after community referral and without recent incarceration. Jail-released patients were more likely African American or Hispanic and uninsured. Treatment retention rates for post-release (37%) vs. community (30%) referrals were similar at 48 weeks. Rates of opioid positive urines and self-reported opioid misuse were also similar between groups. Post-release patients in primary care buprenorphine treatment had equal treatment retention and rates of opioid abstinence vs. community-referred patients.
Of the established Ca2+ mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations. Recent studies have identified a new class of calcium release channel, the two-pore channels (TPCs), as the likely targets for NAADP. These channels are endolysosomal in localization where they mediate local Ca2+ release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca2+ mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca2+ release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca2+-induced Ca2+ release (CICR) channels at lysosomal-ER junctions. The third is to regulate plasma membrane excitability by the targeting of Ca2+ release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca2+-activated channels. In this review, I discuss the role of NAADP-mediated Ca2+ release from endolysosomal stores as a widespread trigger for intracellular calcium signaling mechanisms, and how studies of TPCs are beginning to enhance our understanding of the central role of lysosomes in Ca2+ signaling.
NAADP is thought to trigger release of calcium from endolysosomes via TPC channels. This regulates vesicle trafficking, triggers global calcium release, and modulates plasma membrane excitability.
The effect of once-daily atenolol, sustained-release oxprenolol (a new formulation of oxprenolol presented as a compressed tablet in a waxed matrix), and long-acting propranolol (a new formulation presented as spheriods in a capsule) was studied in a double-blind crossover trial in 23 carefully selected hypertensive outpatients. After a run-in period with matching placebo each patient received atenolol (100 mg/day), sustained-release oxprenolol (160 mg/day), long-acting propranolol (160 mg/day), and placebo according to a randomised sequence. After four weeks' treatment with sustained-release oxprenolol blood pressure in the two to four hours before the next dose was not significantly lower than after placebo. The effectiveness of atenolol and of the new formulation of propranolol in reducing blood pressure was confirmed. These results suggest that the present formulation of sustained-release oxprenolol should be reconsidered.
To assess the characteristics of medical research that is press released by general medical journals and reported in newspapers.
All original research articles published in Lancet and BMJ during 1999 and 2000.
Main outcome measures
Inclusion of articles in Lancet or BMJ press releases, and reporting of articles in Times or Sun newspapers.
Of 1193 original research articles, 517 (43%) were highlighted in a press release and 81 (7%) were reported in one or both newspapers. All articles covered in newspapers had been press released. The probability of inclusion in press releases was similar for observational studies and randomised controlled trials, but trials were less likely to be covered in the newspapers (odds ratio 0.15 (95% confidence interval 0.06 to 0.37)). Good news and bad news were equally likely to be press released, but bad news was more likely to be reported in newspapers (1.74 (1.07 to 2.83)). Studies of women's health, reproduction, and cancer were more likely to be press released and covered in newspapers. Studies from industrialised countries other than Britain were less likely to be reported in newspapers (0.51 (0.31 to 0.82)), and no studies from developing countries were covered.
Characteristics of articles were more strongly associated with selection for reporting in newspapers than with selection for inclusion in press releases, although each stage influenced the reporting process. Newspapers underreported randomised trials, emphasised bad news from observational studies, and ignored research from developing countries.
What is already known on this topicNewspapers are an important source of information about the results of medical researchThere are two stages on the path to newspaper coverage—selection by medical journal editors of articles to be press released and the selection of newsworthy articles by journalistsWhat this study addsExamination of press releasing by the Lancet and BMJ and reporting by the Times and Sun showed that selection processes acted at both stagesThe net effect meant that newspapers emphasised results from observational studies, in particular studies of women's health, reproduction, and cancerGood news and bad news were equally likely to be press released, but bad news was more likely to be reported in newspaper articles
Madoff, Morton A. (New England Center Hospital, Boston, Mass.), Louis Z. Cooper, and Louis Weinstein. Hemolysis of rabbit erythrocytes by purified staphylococcal alpha-toxin. III. Potassium release. J. Bacteriol. 87:145–149. 1964.—The reaction between staphylococcal alpha-toxin and erythrocytes was characterized by rapid release of K+ from the cells, early in the prelytic period; 50 to 75% of this loss occurred before leakage of hemoglobin was detectable. The addition of specific antitoxin early enough in the reaction to inhibit gross hemolysis also inhibited cation release. The presence of sucrose or polyethylene glycol prevented hemoglobin release, but was without effect on K+ leak. These observations suggest that K+ loss is a more specific indication of the progress of the reaction between alpha-toxin and erythrocytes than is the release of hemoglobin.
Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington’s disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria. Drugs effective at the level of purified mitochondria were evaluated in a cellular model of HD. As proof of principle, one drug was chosen for in depth evaluation in vitro and a transgenic mouse model of HD. Our findings demonstrate the utility of mitochondrial screening to identify inhibitors of cell death and provide further support for the important functional role of cytochrome c release in HD. Given that many of these compounds have been approved by the Food and Drug Administration for clinical usage and cross the blood– brain barrier, these drugs may lead to trials in patients.
drug screen; inhibitors of cytochrome c release; methazolamide; Huntington’s disease; R6/2 mice; mutant-htt ST14A cells
Intercalation of beneficial anion into inorganic host has lead to an opportunity to synthesize various combinations of new organic–inorganic nanohybrids with various potential applications; especially, for the controlled release formulation and storage purposes. Investigation on the release behavior of 2,4-dichlorophenoxyacetate (2,4-D) intercalated into the interlayer of Zn–Al-layered double hydroxide (ZAN) have been carried out using single, binary and ternary aqueous systems of chloride, carbonate and phosphate. The release behavior of the active agent 2,4-D from its double-layered hydroxide nanohybrid ZANDI was found to be of controlled manner governed by pseudo-second order kinetics. It was found that carbonate medium yielded the highest accumulated release of 2,4-D, while phosphate in combination with carbonate and/or nitrate speeds up the release rate of 2,4-D. These results indicate that it is possible to design and develop new delivery system of latex stimulant compound with controlled release property based on 2,4-D that is known as a substance to increase latex production of rubber tree, Hevea brasiliensis.
Layered double hydroxide; 2,4-Dichlorophenoxyacetic acid; Pseudo-second order kinetics; Intercalation; Controlled release
A new solventless photocurable film-coating system was investigated in which nonpareil beads were coated in a minicoating pan with liquid prepolymer (L) and powdered solid pore-forming agents (S) and cured by UV light. Release from the coating could by altered by changing the material, the number of layers, and the coating thickness. Immediate release of a blue dye contained in the nonpareils was obtained with sodium starch glycolate as a pore former that swelled the coating and yielded large pores; through these pores the dye quickly released while leaving behind the scaffold provided by the photocured prepolymer. Simple pore formers (lactose and sodium chloride) dissolved away without swelling and provided a more sustained release. The nature of the scaffold and pore structure of the coating were determined by simultaneously monitoring the release of sodium chloride from the coating and blue dye from the beads. At least 50% of the sodium chloride that was incorporated into the coating released before the dye released through the coating, except at an S/L ratio (ratio of the amount of solid pore-forming agent to the volume of liquid prepolymer) of 2.4, where 40% of the sodium chloride was released before the release of dye. The coupling between dye release and pore formation was found to be dependent on the S/L ratio of the coating. Simulation based on percolation theory showed that the coupling of pore formation and dye release was higher when the variance in tortuosity was lower. The coating was photostable and could withstand normal handling stress.
Coating; photocurable; solventless; photoinitiator; process and formulation parameters; functional release; photostability
Pramipexole, the most commonly prescribed dopamine agonist worldwide, meanwhile serves as a reference substance for evaluation of new drugs. Based on numerous clinical data and vast experiences, efficacy and safety profiles of this non-ergoline dopamine agonist are well characterized. Since October 2009, an extended-release formulation of pramipexole has been available for symptomatic treatment of Parkinson's disease. Pramipexole administration can be cut down from three times to once a day due to the newly developed extended-release formulation. This is considerable progress in regard to minimizing pill burden and enhancing compliance. Moreover, the 24 h continuous drug release of the once-daily extended-release formulation results in fewer fluctuations in plasma concentrations over time compared to immediate-release pramipexole, given three times daily. The present study summarizes pharmacokinetics and all essential pharmacological and clinical characteristics of the extended-release formulation. In addition, it provides all study data, available so far, with regard to transition and de-novo administration of extended-release formulation for patients with Parkinson's disease. It further compares efficacy and safety data of immediate-release pramipexole with the extended-release formulation of pramipexole.
The purpose of this study was to evaluate the release of chlorhexidine as an antifungal drug from doped self-cured poly (methyl methacrylate) (PMMA) acrylic resin and the effect of the drug released on the growth of Candida albicans.
Release of chlorhexidine was evaluated using liquid chromatography, and the effect of the drug on the growth of C. albicans was investigated microbiologically using a “well” technique on Saboraud culture medium inoculated with a resistant strain of C. albicans.
Chlorhexidine leached steadily out of the acrylic resin into distilled water at mouth temperature, and the sustained drug release continued throughout the 28-day test period. The drug released also demonstrated antifungal activity against the resistant strain of C. albicans.
The findings of this study support the use of chlorhexidine-impregnated self-cured PMMA chair-side resin as a new dosage form for the treatment of denture-induced stomatitis.
chlorhexidine; poly (methyl methacrylate); eluates; antifungal drug; denture stomatitis; Candida albicans
Intercalation of beneficial anion into inorganic host has lead to an opportunity to synthesize various combinations of new organic–inorganic nanohybrids with various potential applications; especially, for the controlled release formulation and storage purposes. Investigation on the release behavior of 2,4-dichlorophenoxyacetate (2,4-D) intercalated into the interlayer of Zn–Al-layered double hydroxide (ZAN) have been carried out using single, binary and ternary aqueous systems of chloride, carbonate and phosphate. The release behavior of the active agent 2,4-D from its double-layered hydroxide nanohybrid ZANDI was found to be of controlled manner governed by pseudo-second order kinetics. It was found that carbonate medium yielded the highest accumulated release of 2,4-D, while phosphate in combination with carbonate and/or nitrate speeds up the release rate of 2,4-D. These results indicate that it is possible to design and develop new delivery system of latex stimulant compound with controlled release property based on 2,4-D that is known as a substance to increase latex production of rubber tree,Hevea brasiliensis.
Layered double hydroxide; 2,4-Dichlorophenoxyacetic acid; Pseudo-second order kinetics; Intercalation; Controlled release
We report a new approach to selectively delivering antimicrobials to the sites of bacterial infections by utilizing bacterial toxins to activate drug release from gold nanoparticle-stabilized phospholipid liposomes. The binding of chitosan modified gold nanoparticles to the surface of liposomes can effectively prevent them from fusing with one another and from undesirable payload release in regular storage or physiological environments. However, once these protected liposomes “see” bacteria that secrete toxins, the toxins will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. Using methicillin-resistant Staphycoccus aureus (MRSA) as a model bacterium and vacomycin as a model anti-MRSA antibiotic, we demonstrate that the synthesized gold nanoparticle-stabilized liposomes can completely release the encapsulated vacomycin within 24 h in the presence of MRSA bacteria and lead to inhibition of MRSA growth as effective as an equal amount of vacomycin loaded liposomes (without nanoparticle stabilizers) and free vacomycin. This bacterial toxin enabled drug release from nanoparticle-stabilized liposomes provides a new, safe and effective approach for the treatment of bacterial infections. This technique can be broadly applied to treat a variety of infections caused by bacteria that secrete pore-forming toxins.
Nanoparticle-stabilized liposome; Pore-forming protein; Passive targeting; Drug delivery; Controlled release; Methicillin-resistant Staphycoccus aureus
The design and fabrication of sustained/controlled release dosage forms, employing new excipients capable of extending/controlling the release of drugs from the dosage forms over prolonged periods, has worked well in achieving optimally enhanced therapeutic levels of the drugs. In this sense, the objective of this study was to investigate the suitability of selected cellulose ether derivatives for use in direct compression (DC) and as efficient drug release controlling agents. Controlled release matrix tablets of ciprofloxacin were prepared at different drug-to-polymer (D : P) ratios by direct compression using a fine particle sized ethylcellulose ether derivative (ETHOCEL Standard Premium 7FP) as rate controlling polymer. The tablets obtained were evaluated for various physico-chemical characteristics and in-vitro drug release studies were conducted in phosphate buffer (pH 7.4) using PharmaTest dissolution apparatus at constant temperature of 37°C ± 0.1. Similarity factor f2 was employed to the release profiles of test formulations and were compared with marketed ciprofloxacin conventional tablets. Drug release mechanism and the kinetics involved were investigated by fitting the release profile data to various kinetic models. It was found that with increasing the proportion of ethylcellulose ether derivative in the matrix, the drug release was significantly extended up to 24 hours. The tablets exhibited zero order or nearly zero order drug transport mechanism. In vivo drug release performance of the developed controlled release tablets and reference conventional tablets containing ciprofloxacin were determined in rabbit serum according to randomized two-way crossover study design using High Performance Liquid Chromatography. Several bioavailability parameters of both the test tablets and conventional tablets including Cmax, Tmax and AUC0-t were compared which showed an optimized Cmax and Tmax (P < 0.05). A good correlation was obtained between in vitro drug release and in vivo drug absorption with correlation value (R2 = 0.934). Relative bioavailability was found to be 93%. Reproducibility of manufacturing process and accelerated stability of the developed tablets were performed in stability chamber at 40 ± 2°C and 75 ± 5% relative humidity for a period of 6 months and were found to be stable throughout the stability period.
Anionic polymer sodium carboxymethylcellulose (CELLOGEN® HP-HS and/or HP-12HS) was investigated for its ability to influence the release of three model drugs propranolol hydrochloride, theophylline and ibuprofen from polyethylene oxide (POLYOX™ WSR 1105 and/or Coagulant) hydrophilic matrices. For anionic ibuprofen and non-ionic theophylline, no unusual/unexpected release profiles were obtained from tablets containing a mixture of two polymers. However, for cationic propranolol HCl, a combination of polyethylene oxide (PEO) with sodium carboxymethylcellulose (NaCMC) produced a significantly slower drug release compared to the matrices with single polymers. The potential use of this synergistic interaction can be a design of new extended release pharmaceutical dosage forms with a more prolonged release (beyond 12 h) using lower polymer amount, which could be particularly beneficial for freely water-soluble drugs, preferably for once daily oral administration. In order to explain changes in the obtained drug release profiles, Fourier transform infrared absorption spectroscopy was performed. A possible explanation for the more prolonged propranolol HCl release from matrices based on both PEO and NaCMC may be due to a chemical bond (i.e. ionic/electrostatic intermolecular interaction) between amine group of the cationic drug and carboxyl group of the anionic polymer, leading to a formation of a new type/form of the active (i.e. salt) with sustained release pattern.
extended release; FT-IR; ibuprofen; matrix tablet; polyethylene oxide; polymer combination; propranolol hydrochloride; sodium carboxymethylcellulose; theophylline
This study presents the results of a pilot study of mandatory pre-release testing for sexually transmitted disease (STD) and a behavioral risk survey for male inmates at an Ohio prison. Approximately 4–6 weeks prior to scheduled release, inmates took part in a mandatory blood test and optional genital swab and physical examination to test for STDs. At the time of testing, a voluntary behavioral and knowledge survey was administered to inmates. Pre-release testing identified 53 new cases of STDs among the 916 inmates (5.5%) scheduled for release during the pilot study period. Trichomoniasis and hepatitis C were the most common infections identified through pre-release testing. Nearly all inmates participated in the required blood test. Participation rates for the other testing methods averaged less than 45%. Inmates reported engaging in various risky behaviors during incarceration such as having sex (12.1%), tattooing (36.5%), and drug use (19.5%). Pre-release testing identified several new cases of STDs not identified through existing intake and for-cause testing procedures. Substantial useful information about the prevalence of STD risk behaviors can be obtained through a pre-release survey.
HIV testing; Inmates; Behavioral risk; Pre-release testing
Gonadotropin releasing hormone (GnRH) plays a key role in reproduction. This decapeptide is synthesized and released by hypothalamus and induces the pituitary gonadotrop cells to release pituitary gonadotropin hormones. In some extrapituitary compartments GnRH and its receptor act as part of the autocrine regulatory system of cell proliferation. The anticancer activity of GnRH and its analogues has been observed by many researchers. In this study the anticancer activity of a new analogue of GnRH and triptorelin was investigated by cell proliferation assay. Results indicate that proliferation of human breast and ovarian cancer cell lines are dose-dependently inhibited. The inhibitory efficiency of the new analogue is proved to be higher than the original triptorelin. In addition to its antimitogenic activity, evidence was found for the involvement of the apoptotic mechanism in the action of the new analogue and triptorelin. In conclusion, the new analogue can be considered as a good pharmaceutical candidate.
Anticancer activity; Breast cancer; LHRH analogue; Ovarian cancer; Peptidomimetics; Triptorelin
This report describes the immune release of a new mediator from human peripheral leukocytes, a basophil kallikrein-like activity (BK-A). The release process is initiated by the interaction of antigen on anti-IgE with cell-bound IgE, and appears to be similar in mechanism to the relase of histamine and other mediators of the immediate hypersensitivity reaction. The dose-response relationships and kinetics of histamine and BK-A release from antigen-challenged peripheral leukocytes are similar. The relase of the BK-A is calcium and temperature dependent, requires metabolic energy, and is controlled by hormone-receptor interactions that influence the cellular level of cyclic AMP, as has been described for other mediators of immediate hypersensitivity reactions. The data indicate that the interaction of BK-A with human plasma kininogen, generates immunoreactive kinin. We conclude that the antigen-IgE interation leads to the release from human basophils of a new mediator, a basophil kallikrein-like activity which may well be a link between reactions of immediate hypersenstivitity and the plasma and/or tissue kinin-generating systems.
An exciting new direction in responsive liposome research is endogenous triggering of liposomal payload release by overexpressed enzyme activity in affected tissues and offers the unique possibility of active and site-specific release. Bringing to fruition the fully expected capabilities of this new class of triggered liposomal delivery system requires a collection of liposome systems that respond to different upregulated enzymes; however, a relatively small number currently exist. Here we show that stable, ~100 nm diameter liposomes can be made from previously unreported quinone-dioleoyl phosphatidylethanolamine (Q-DOPE) lipids, and complete payload release (quenched fluorescent dye) from Q-DOPE liposomes occurs upon their redox activation when the quinone headgroup possesses specific substituents. The key component of the triggerable, contents-releasing Q-DOPE liposomes is a “trimethyl-locked” quinone redox switch attached to the N-terminus of DOPE lipids that undergoes a cleavage event upon two-electron reduction. Payload release by aggregation and leakage of “uncapped” Q-DOPE liposomes is supported by results from liposomes wherein deliberate alteration of the “trimethyl-locked” switch completely deactivates the redox-destructible phenomena (liposome opening). We expect that Q-DOPE liposomes and their variants will be important in treatment of diseases with associated tissues that overexpress quinone reductases, such as cancers and inflammatory diseases, because the quinone redox switch is a known substrate for this group of reductases.