Interannual Dynamics of Ice Cliff Populations on Debris-Covered Glaciers From Remote Sensing Observations and Stochastic Modeling.

Ice cliffs are common on debris-covered glaciers and have relatively high melt rates due to their direct exposure to incoming radiation. Previous studies have shown that their number and relative area can change considerably from year to year, but this variability has not been explored, in part because available cliff observations are irregular. Here, we systematically mapped and tracked ice cliffs across four debris-covered glaciers in High Mountain Asia for every late ablation season from 2009 to 2019 using high-resolution multi-spectral satellite imagery. We then quantified the processes occurring at the feature scale to train a stochastic birth-death model to represent the cliff population dynamics. Our results show that while the cliff relative area can change by up to 20% from year to year, the natural long-term variability is constrained, thus defining a glacier-specific cliff carrying capacity. In a subsequent step, the inclusion of external drivers related to climate, glacier dynamics, and hydrology highlights the influence of these variables on the cliff population dynamics, which is usually not a direct one due to the complexity and interdependence of the processes taking place at the glacier surface. In some extreme cases (here, a glacier surge), these external drivers may lead to a reorganization of the cliffs at the glacier surface and a change in the natural variability. These results have implications for the melt of debris-covered glaciers, in addition to showing the high rate of changes at their surface and highlighting some of the links between cliff population and glacier state.

The expression and impact of antifungal grooming in ants.

Parasites can cause extensive damage to animal societies in which many related individuals frequently interact. In response, social animals have evolved diverse individual and collective defences. Here, we measured the expression and efficiency of self-grooming and allo-grooming when workers of the ant Formica selysi were contaminated with spores of the fungal entomopathogen Metarhizium anisopliae. The amount of self-grooming increased in the presence of fungal spores, which shows that the ants are able to detect the risk of infection. In contrast, the amount of allo-grooming did not depend on fungal contamination. Workers groomed all nestmate workers that were re-introduced into their groups. The amount of allo-grooming towards noncontaminated individuals was higher when the group had been previously exposed to the pathogen. Allo-grooming decreased the number of fungal spores on the surface of contaminated workers, but did not prevent infection in the conditions tested (high dose of spores and late allo-grooming). The rate of disease transmission to groomers and other nestmates was extremely low. The systematic allo-grooming of all individuals returning to the colony, be they contaminated or not, is probably a simple but robust prophylactic defence preventing the spread of fungal diseases in insect societies.

Permeation of a myristoylated dipeptide across the buccal mucosa: topological distribution and evaluation of tissue integrity.

The ex vivo permeation of an acylated model dipeptide, Myristoyl-Tryptophan-Leucine (Myr-Trp-Leu) was studied using pig buccal mucosa. Myr-Trp-Leu, being lipophilic, did not readily penetrate across the membrane. Rather, it accumulated in the epithelial and connective tissue of the mucosal barrier. The topological distribution of Myr-Trp-Leu across the mucosa, following its application in ethanol/phosphate buffer (30/70 pH 7.4), was determinated by thin-sectioning of the tissue, extraction of the peptide, and high performance thin layer chromatography (HPTLC). The concentration profile depended, of course, on the duration of the experiment and appeared to be dependent upon the presence of sufficient ethanol in order that the peptide could be solubilized. This important role for ethanol then raised the question of the solvent's effect on tissue integrity. Light microscopic examination of the mucosa was, therefore, undertaken, under identical conditions to those used in the permeation experiments, to evaluate any perturbation induced by the ethanolic vehicle. No obvious effects were observed.

Factors and strategies for improving buccal absorption of peptides.

Peptides and polypeptides have important pharmacological properties but only a limited number (e.g. insulin, oxytocin, vasopressin) have been exploited as therapeutics because of problems related to their delivery. The buccal mucosa offers an alternative route to conventional, parenteral administration. Peptides are generally not well absorbed through mucosae because of their molecular size, hydrophilicity and the low permeability of the membrane. Peptide transport across buccal mucosa occurs via passive diffusion and is often accompanied by varying degrees of metabolism. This review describes various approaches to improve the buccal absorption of peptides including the use of penetration enhancers to increase membrane permeability and/or the addition of enzyme inhibitors to increase their stability. Other strategies including molecular modification with bioreversible chemical groups or specific formulations such as bioadhesive delivery systems are also discussed.

Delivery of antibiotics to the eye using a positively charged polysaccharide as vehicle.

The positively charged polysaccharide chitosan is able to increase precorneal residence time of ophthalmic formulations containing active compounds when compared with simple aqueous solutions. The purpose of the study was to evaluate tear concentration of tobramycin and ofloxacin after topical application of chitosan-based formulations containing 0.3% wt/vol of antibiotic and to compare them with 2 commercial solutions: Tobrex and Floxal, respectively. The influence of the molecular weight, deacetylation degree, and concentration of 4 different samples of chitosan on pharmacokinetic parameters (area under the curve values [AUC(eff)] and time of efficacy [t(eff)]) of tobramycin and ofloxacin in tears was investigated over time. It was demonstrated that the 2 chitosan products of high molecular weight (1350 and 1930 kd) and low deacetylation degree (50%) significantly increased antibiotic availability when compared to the controls, with AUC(eff) showing a 2- to 3-fold improvement. The time of efficacy of ofloxacin was significantly increased from about 25 minutes to 46 minutes by the chitosan of higher Mw (1930 kd) at a concentration of 0.5% wt/vol, whereas a similar performance was achieved by a chitosan of low Mw (580 kd) at a concentration of 1.5% wt/vol in the case of tobramycin.

Chitosan as tear substitute: a wetting agent endowed with antimicrobial efficacy.

A cationic biopolymer, chitosan, is proposed for use in artificial tear formulations. It is endowed with good wetting properties as well as an antibacterial effect that are desirable in cases of dry eye, which is often complicated by secondary infections. Solutions containing 0.5% w/v of a low molecular weight (M(w)) chitosan (160 kDa) were assessed for antibacterial efficacy against E. coli and S. aureus by using the usual broth-dilution technique. The in vitro evaluation showed that concentrations of chitosan as low as 0.0375% still exert a bacteriostatic effect against E. coli. Minimal inhibitory concentration (MIC) values of chitosan were calculated to be as low as 0.375 mg/ml for E. coli and 0.15 mg/ml for S. aureus. Gamma scintigraphic studies demonstrated that chitosan formulations remain on the precorneal surface as long as commonly used commercial artificial tears (Protagent collyrium and Protagent-SE unit-dose) having a 5-fold higher viscosity.

Synthesis and characterization of an acylated di-peptide (Myr-Trp-Leu) with modified transmucosal transport properties.

In order to improve the buccal absorption of a dipeptide model compound, Tryptophan-Leucine (Trp-Leu), we have synthesised a lipophilic derivative by myristoylation of the N- terminal amino group of Trp-Leu. The acylated peptide (Myr-Trp-Leu) was characterized by HPTLC, purified and isolated by chromatography on a silica gel column. Its structure was confirmed by (13)C and (1)H NMR and mass spectroscopy. The increased lipophilicity of the Myr-Trp-Leu was compared to that of the native peptide by chromatography and by its partition coefficient between n-octanol and saline phosphate buffer. In addition, the sensitivity towards hydrolytic enzymes was studied. The interaction of Trp-Leu with liposomes as model membranes was also studied. The phase transition temperature of dipalmitoylphosphatidylcholine (DPPC) was lowered in the presence of Myr-Trp-Leu, while it was increased in the presence of native parent peptide. Permeation experiments performed in vitro with pig buccal mucosa showed that the Myr-Trp-Leu accumulated in the tissue at the various concentrations tested. In contrast, the native peptide was able to pass through the membrane at all concentrations used. Lipophilic modification of the peptide by acylation drastically changes its behaviour towards tissue systems.

Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention.

The mucoadhesive polysaccharide chitosan was evaluated as a potential component in ophthalmic gels for enabling increased precorneal drug residence times. This cationic vehicle was expected to slow down drug elimination by the lacrymal flow both by increasing solution viscosity and by interacting with the negative charges of the mucus. The molecular weight (Mw) and concentration of polysaccharide were studied in four types of chitosan as parameters that might influence ocular tolerability and precorneal residence time of formulations containing tobramycin as therapeutic agent. An ocular irritation test, using confocal laser scanning ophthalmoscopy (CLSO) combined with corneal fluorescein staining, clearly demonstrated the excellent tolerance of chitosan after topical administration onto the corneal surface. Gamma scintigraphic data showed that the clearance of the formulations labelled with 99mTc-DTPA was significantly delayed in the presence of chitosan with respect to the commercial collyrium (Tobrex(R)), regardless of the concentration and of the molecular weight of chitosan in solution. At least a 3-fold increase of the corneal residence time was achieved in the presence of chitosan when compared to Tobrex(R).

Failure of a 1-day high-dose quadruple therapy for cure of Helicobacter pylori infection.

BACKGROUND: The optimal duration of treatment for eradication of Helicobacter pylori has still to be defined. A 1-day high-dose quadruple therapy with a combination of amoxycillin (or tetracycline), metronidazole, a bismuth salt and a proton pump inhibitor has led to eradication rates of 57-77%. In view of the high frequency of metronidazole-resistant strains of H. pylori in Europe, we hypothesized that by using clarithromycin in place of metronidazole and by increasing the dose of proton pump inhibitor, the efficacy of a 1-day high-dose quadruple therapy could be improved. METHODS: Patients were randomized to receive either amoxycillin 1000 mg b.d., clarithromycin 500 mg b.d. and lansoprazole 30 mg b.d. for 7 days, or amoxycillin 2000 mg q.d.s., clarithromycin 500 mg q.d.s., lansoprazole 30 mg t.d.s. and bismuth subcitrate 240 mg q.d.s. for 1 day. RESULTS: It was originally intended to include 100 patients. The first planned interim analysis performed after follow-up was completed for 30 patients revealed H. pylori eradication rates of 80% (12/15) in the 7-day triple therapy group and 20% (3/15) in the 1-day quadruple therapy group, the difference being highly significant (P = 0.003). Because the efficacy of the 1-day treatment was so low, the study was stopped for ethical reasons. Eleven patients who failed with the 1-day treatment were re-treated with the 7-day triple therapy: the eradication rate was 91% (10/11). CONCLUSIONS: One-day high-dose quadruple therapy with amoxycillin, clarithromycin, lansoprazole and bismuth subcitrate is dramatically less effective than the classic 7-day triple therapy with the same antibiotics.

Comparative pharmacokinetic study of a floating multiple-unit capsule, a high-density multiple-unit capsule and an immediate-release tablet containing 25 mg atenolol.

The purpose of this study was to evaluate the possible advantages of floating and high-density dosage forms and their influence on pharmacokinetic parameters. Atenolol was chosen as a model drug because of its poor absorption in the lower gastrointestinal tract. Three formulations containing 25 mg atenolol, a floating multiple-unit capsule, a high-density multiple-unit capsule, and an immediate-release tablet were compared with respect to estimated pharmacokinetic parameters. The two multiple-unit dosage forms were composed of compressed minitablets and had sustained release properties. The bioavailability of the two gastroretentive preparations with sustained release characteristics was significantly decreased when compared to the immediate-release tablet. The floating minitablets seemed to be retained longer in the stomach than the high-density dosage form. The first atenolol concentration detectable in the plasma and the time to peak Tmax were delayed for the floating dosage form. For the parameters Cmax and AUC 0-infinity, the lower limit of the 90% confidence interval was outside the bioequivalence range (0.80-1.25). This study showed that it was not possible to increase the bioavailability of a poorly absorbed drug such as atenolol using gastroretentive formulations. Atenolol absorption was delayed and the maximum plasma concentration was diminished.

Buoyancy and drug release patterns of floating minitablets containing piretanide and atenolol as model drugs.

The purpose of this study was to evaluate factors for improving the in vitro buoyancy and the drug release characteristics of floating minitablets containing either piretanide or atenolol as model drugs. The buoyancy of the minitablets was achieved either by the swelling of the excipient or by incorporation of the gas-generating agent sodium bicarbonate. Resultant-weight kinetics were performed in order to evaluate the buoyancy. The release rate of the poorly soluble drug piretanide was enhanced by increasing its solubility or by promoting the erosion of the minitablets. For the sparingly soluble drug atenolol, the minitablets were coated with different ratio of insoluble polymer in order to diminish the release rate of this drug. The swelling of a hydrophilic excipient was not sufficient to obtain floating minitablets. The buoyancy of the minitablets containing either piretanide or atenolol was greatly improved by adding sodium bicarbonate as well as by a wet granulation. The most satisfactory improvement in the release rate of piretanide was achieved using a solid dispersion with povidone, thus increasing the drug solubility concomitantly with the increase of the minitablets' erosion. Regarding atenolol, minitablets containing 7% sodium bicarbonate and coated with Eudragit NE30D:RS 70:30 gave satisfactory results concerning buoyancy and drug release rate. This study showed that it was possible to produce minitablets containing either piretanide or atenolol, which have a positive resultant-weight during more than 6 hr and satisfactory release profiles.

The effect of keratolytic agents on the permeability of three imidazole antimycotic drugs through the human nail.

The permeability of three imidazole antimycotics (miconazole nitrate, ketoconazole, and itraconazole) through the free edge of healthy human nail was evaluated in vitro using side-by-side diffusion cells. The influence of keratolytic substances (papain, urea, and salicylic acid) on the permeability of the antimycotics was also studied. The results suggested that the nail constituted an impermeable barrier for these antimycotics; it could be considered that the nail behaved as a hydrophilic gel membrane, through which drugs of low solubility could not permeate. The use of ethanol did not promote the passage of any of the antimycotic drugs. Although scanning electron microscopy indicated that the keratolytic substances had a significant effect on the nail surface (papain > salicylic acid > urea), the passage of the three antimycotics was not improved by pretreatment with salicylic acid alone (20% for 10 days), or by the application of the drug in a 40% urea solution. It was found that only the combined effects of papain (15% for 1 day) and salicylic acid (20% for 10 days) were capable of enhancing the permeability of the antimycotic.

Chitosan: a unique polysaccharide for drug delivery.

The aim of this review is to give an insight into the many potential applications of chitosan as a pharmaceutical drug carrier. The first part of this review concerns the principal uses of chitosan as an excipient in oral formulations (particularly as a direct tableting agent) and as a vehicle for parenteral drug delivery devices. The use of chitosan to manufacture sustained-release systems deliverable by other routes (nasal, ophthalmic, transdermal, and implantable devices) is discussed in the second part.

An investigation of the physical behaviour of moisture-activated mucoadhesive hydrogels upon contact with biological and non-biological substrates.

The physical behaviour of moisture-activated mucoadhesive hydrogels in contact with a Plexiglas plate or artificial mucin gels was investigated using an adapted tensile tester fitted with force and displacement transducers. Our study of the 'Plexiglas-hydrogel' interface showed that the intrinsic mechanical response of most poly(acrylic acid) polymers is quite different from that exhibited by cellulose derivatives. The former exert an attractive interaction towards the substrate in contrast to the latter where the interaction is essentially repulsive. The interfacial forces developed by pure mucin were closely related to those of poly(acrylic acid) polymers. Similar results were observed when the Plexiglas was replaced by artificial mucin gels. A correlation was found between the attractive force developed by poly(acrylic acid) hydrogels towards the inert substrate and their in vitro mucoadhesive joint strength. Therefore, a non-specific physical interaction occurs during the initial adhesive process, whatever the nature of the substrate. Besides the water absorption capacity and swelling properties of the candidate materials, it seems that their initial mucoadhesiveness depends more on their mechanical response to hydration and less on the extent of molecular interactions at the adhesive interface.

Gamma scintigraphic comparison of eyedrops containing pilocarpine in healthy volunteers.

The aim of the present study was to compare, in healthy human volunteers (male and female), the corneal contact time of various formulations, each containing one viscosity enhancer from the following list: a phase-transition system (gellan gum, Gelrite), a heteropolysaccharide (xanthan gum) and currently used polymers hydroxyethylcellulose, hydroxypropylmethylcellulose, or poly(vinyl alcohol). These different solutions were compared to a reference solution containing no viscosity enhancers. The corneal contact time of the formulations was evaluated over more than 20 minutes by gamma scintigraphy using Technetium-99m (Tc-99m DTPA) as a radioactive label. An eyedrop containing pilocarpine salts (25 microliters) was instilled in one eye only. Each volunteer received 4 formulations, the interval between the instillations being one week. The protocol has been approved by the relevant institutional human experimentation committee. One minute after instillation, only 23% of the reference solution remained on the ocular surface, whereas the novel formulations maintained, respectively, 77% (xanthan gum) or 82% (Gelrite) of the tracer on the ocular surface. Twenty-one min after instillation, 12% (reference solution), 25% (xanthan gum solution), and 39% (gelrite solution) of the tracer remained on the ocular surface. The results confirm that an increase in viscosity of the formulation (xanthan) delays the clearance of the instilled solution by the tear flow. The effect of the gelation mechanism is superior, especially at the later time points. In this respect, xanthan gum and, particularly, Gelrite are suitable vehicles for ophthalmic drugs.

In vivo evaluation of an indomethacin monolithic, extended zero-order release hard-gelatin capsule formulation based on saturated polyglycolysed glycerides.

The sustained release properties of an indomethacin hard-gelatin capsule formulated with saturated polyglycolysed glycerides (Gelucire) were demonstrated in vivo. Indomethacin was selected as a model drug with very poor solubility in water and acidic media. It is known to exhibit high intersubject variability because of enterohepatic circulation. The formulation, which in vitro showed an erosion-controlled release, was compared in six human volunteers in the fed state by using a randomized cross-over design, to a standard multiple-unit diffusion-controlled pellet capsule. Close action period values (time duration with plasma levels higher than 0.5 micrograms/ml) were found for the test and the reference formulation (5.2 and 5.7 h). The time to reach peak t(max) appeared slightly shorter for the test preparation (1.75 h) than for the reference formulation (2.67 h), but the difference was not statistically significant because of the high intersubject variability (non-parametric Wilcoxon matched pair test). Again, due to the small number of subjects entered in the study (insufficient for a real bioequivalence study) equivalence could not be accepted in terms of extent and rate of absorption based on the decision procedures involving the 90% confidence interval and the two one-sided t-tests. The mean maximum plasma concentrations Cmax were 3.35 and 2.82 micrograms/ml for the test and the reference formulation respectively, with the corresponding values of the area under the plasma concentration-time curve AUC amounting to 10.14 and 11.38 micrograms h/ml. However, a simulation on 24 subjects (3 repetitions of the same data) would lead to bioequivalence of the two preparations. As for other corrosion-controlled forms, drug release from the proposed Gelucire formulation was very sensitive to hydrodynamic conditions, leading to poor in vitro-in vivo correlation, when comparison is made with a reference formulation characterized by a diffusion-controlled release. Finally, it was concluded that erosion-controlled release formulations are especially suitable for drugs, such as indomethacin, that have low solubility in water or acidic media. More generally, sustained release hard gelatin capsules with thermosetting excipients is very versatile and their preparation is very straightforward.

Effect of formulation additives upon the intranasal bioavailability of a peptide drug: tetracosactide (ACTH1-24).

Nasal absorption of tetracosactide (ACTH1-24; Synacthen) was evaluated in anesthetized rats and compared to intravenous and intramuscular (i.m.) administration. The effect of formulation additives on tetracosactide bioavailability was studied following modification of nasal saline solution. Poloxamer 407 (Pluronic F-127) was used as a vehicle for drug sustained release, whereas sodium glycocholate and bacitracin were used as enhancers. Tetracosactide plasma levels were monitored with radioimmunoassay. Nasal bioavailability was low (4.4%) compared to i.m. (24%). Poloxamer 407 addition did not improve drug kinetics profiles and showed a non-significant decrease in bioavailability (4%). On the other hand, both enhancers effectively increased tetracosactide nasal absorption. The sodium glycocholate effect was very fast (Tmax = 5 min), but did not last long. Moreover, absorption was increased threefold compared to the simple formulation. On the other hand, maximum tetracosactide levels in plasma were reached after 15 min for the formulation containing bacitracin as enhancer, and tetracosactide bioavailability was strongly increased, to 24%, i.e., as much as after an i.m. injection.

In vivo evaluation of dosage forms: application of gamma scintigraphy to non-enteral routes of administration.

The trend to deliver drugs to defined areas of the body involves sophisticated carriers systems. In addition to the in vitro drug release profile one must be aware of the in vivo behaviour of the dosage form and the drug. Gamma scintigraphy is an elegant way to gain insights of the actual in vivo distribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables the in vivo determination of the targeting of the formulation administered through a large number of routes. The present paper reviews applications of gamma scintigraphy for the evaluation of dosage forms administered by the parenteral, rectal, buccal, nasal, pulmonary, and ophthalmic routes.