A decade of proboscis monkey (Nasalis larvatus) population monitoring in Balikpapan Bay: Confronting predictions with empirical data.

Systematic and well-structured monitoring is essential for taxa with high extinction risk such as primates. Endangered proboscis monkeys Nasalis larvatus are endemic to Borneo, where they are found scattered across lowland habitats of the island, which are under strong anthropogenic pressure. A large population of proboscis monkeys in Balikpapan Bay, Indonesian Borneo, was predicted to decline due to the ongoing habitat loss and degradation, notably because of forest fires. We examined changes in the number and composition of groups of a part of this population from 2007 to 2017, which included a period of forest fires linked to the El Niño-Southern Oscillation events. We conducted a census from a boat; attempting to locate all proboscis monkey groups within the Balikpapan City administrative area in 2007, 2012, and 2017. During the most recent census, we observed a total number of 60 proboscis monkey groups in two subpopulations. The population density was 1.14 group per km2 of suitable habitat. Contrary to previously published predictions, we did not find evidence of a population decline. Contrary to predictions, the 2015 El Niño induced fires impacted mainly forests on ridges and slopes, thus affecting only a small part of the proboscis monkey habitat located close to rivers and mangrove swamps. However, the increasing population density of monkeys, coupled with ongoing habitat degradation and habitat loss in one of the subpopulations, suggests that proboscis monkey population in Balikpapan Bay may be approaching a limit of resilience to habitat changes. In case it proves infeasible to census all individuals in the whole population, we recommend using a group-level census, connected with systematic group counts to obtain a reasonably precise proboscis monkey population size estimate.

Association of stroke risk biomarkers with stroke symptoms: the Reasons for Geographic and Racial Differences in Stroke cohort.

Essentials Stroke symptom history predicts future stroke and may indicate prior unrecognized stroke. We studied associations of stroke symptoms with stroke risk biomarkers. Several stroke risk biomarkers were independently associated with stroke symptom history. Findings support a hypothesis that stroke symptoms may represent unrecognized stroke. SUMMARY: Background History of stroke symptoms in the absence of prior diagnosed stroke or transient ischemic attack (TIA) is associated with future stroke risk, as are biomarkers of inflammation, cardiac function and hemostasis. Objective To better elucidate the pathobiology of stroke symptoms, we studied associations of these biomarkers with history of stroke symptoms. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30 239 black and white Americans age 45 years and older in 2003-7. In cross-sectional analyses in a random sample of 960 participants without prior stroke or TIA, levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), fibrinogen, factor VIII (FVIII), factor XI (FXI), C-reactive protein (CRP) and D-dimer were studied in relation to self-reported history of six sudden onset stroke symptoms. Results There were 190 participants with at least one stroke symptom and 770 without. Adjusting for age, race, sex and stroke risk factors, NT-proBNP, FXI, CRP and D-dimer in the top vs. bottom quartile were associated with prevalent stroke symptoms with odds ratios 2.69 (95% confidence interval [CI], 1.45-4.98), 1.65 (95% CI, 1.00-2.73), 2.21 (95% CI, 1.32-3.71) and 2.14 (95% CI, 1.22-3.75), respectively. Conclusions Strong associations of stroke risk biomarkers with stroke symptoms in persons without a clinical history of cerebrovascular disease support a hypothesis that some of these stroke symptoms represent unrecognized cerebrovascular disease. Future work is needed to determine whether these biomarkers identify persons with stroke symptoms who have a particularly high stroke risk.

Early developmental elevations of brain kynurenic acid impair cognitive flexibility in adults: reversal with galantamine.

Levels of kynurenic acid (KYNA), an endogenous α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, are elevated in the brain of patients with schizophrenia (SZ) and might contribute to the pathophysiology and cognitive deficits seen in the disorder. As developmental vulnerabilities contribute to the etiology of SZ, we determined, in rats, the effects of perinatal increases in KYNA on brain chemistry and cognitive flexibility. KYNA's bioprecursor l-kynurenine (100mg/day) was fed to dams from gestational day 15 to postnatal day 21 (PD21). Offspring were then given regular chow until adulthood. Control rats received unadulterated mash. Brain tissue levels of KYNA were measured at PD2 and PD21, and extracellular levels of KYNA and glutamate were determined by microdialysis in the prefrontal cortex in adulthood (PD56-80). In other adult rats, the effects of perinatal l-kynurenine administration on cognitive flexibility were assessed using an attentional set-shifting task. l-Kynurenine treatment raised forebrain KYNA levels ∼3-fold at PD2 and ∼2.5-fold at PD21. At PD56-80, extracellular prefrontal KYNA levels were moderately but significantly elevated (+12%), whereas extracellular glutamate levels were not different from controls. Set-shifting was selectively impaired by perinatal exposure to l-kynurenine, as treated rats acquired the discrimination and intra-dimensional shift at the same rate as controls, yet exhibited marked deficits in the initial reversal and extra-dimensional shift. Acute administration of the α7nAChR-positive modulator galantamine (3.0mg/kg, i.p.) restored performance to control levels. These results validate early developmental exposure to l-kynurenine as a novel, naturalistic animal model for studying cognitive deficits in SZ.

Discussion of the enabling environments for decentralised water systems.

Decentralised water supply systems are becoming increasingly affordable and commonplace in Australia and have the potential to alleviate urban water shortages and reduce pollution into natural receiving marine and freshwater streams. Learning processes are necessary to support the efficient implementation of decentralised systems. These processes reveal the complex socio-technical and institutional factors to be considered when developing an enabling environment supporting decentralised water and wastewater servicing solutions. Critical to the technological transition towards established decentralised systems is the ability to create strategic and adaptive capacity to promote learning and dialogue. Learning processes require institutional mechanisms to ensure the lessons are incorporated into the formulation of policy and regulation, through constructive involvement of key government institutions. Engagement of stakeholders is essential to the enabling environment. Collaborative learning environments using systems analysis with communities (social learning) and adaptive management techniques are useful in refining and applying scientists' and managers' knowledge (knowledge management).

Cortical kynurenic acid bi-directionally modulates prefrontal glutamate levels as assessed by microdialysis and rapid electrochemistry.

Using two in vivo methods, microdialysis and rapid in situ electrochemistry, this study examined the modulation of extracellular glutamate levels by endogenously produced kynurenic acid (KYNA) in the prefrontal cortex (PFC) of awake rats. Measured by microdialysis, i.p. administration of KYNA's bioprecursor L-kynurenine dose-dependently elevated extracellular KYNA and reduced extracellular glutamate (nadir after 50 mg/kg kynurenine: 60% decrease from baseline values). This dose-dependent decrease in glutamate levels was also seen using a glutamate-sensitive microelectrode array (MEA) (31% decrease following 50 mg/kg kynurenine). The kynurenine-induced reduction in glutamate was blocked (microdialysis) or attenuated (MEA) by co-administration of galantamine (3 mg/kg i.p.), a drug that competes with KYNA at an allosteric potentiating site of the alpha 7 nicotinic acetylcholine receptor. In separate experiments, extracellular glutamate levels were measured by MEA following the local perfusion (45 min) of the PFC with kynurenine (2.5 microM) or the selective KYNA biosynthesis inhibitor S-ethylsulfonylbenzoylalanine (S-ESBA; 5 mM). In agreement with previous microdialysis studies, local kynurenine application produced a reversible reduction in glutamate (nadir: -29%), whereas perfusion with S-ESBA increased glutamate levels reversibly (maximum: +38%). Collectively, these results demonstrate that fluctuations in the biosynthesis of KYNA in the PFC bi-directionally modulate extracellular glutamate levels, and that qualitatively very similar data are obtained by microdialysis and MEA. Since KYNA levels are elevated in the PFC of individuals with schizophrenia, and since prefrontal glutamatergic and nicotinic transmission mediate cognitive flexibility, normalization of KYNA levels in the PFC may constitute an effective treatment strategy for alleviating cognitive deficits in schizophrenia.

Physical characterization of polyethylene glycols by thermal analytical technique and the effect of humidity and molecular weight.

Polyethylene glycols (PEGs) are well known as excipients in tablet dosage formulations. PEGs are generally known to be inert and have very few interactions with other components in the solid dosage forms. However, the physical nature of PEGs and how they affect the disintegration of tablets is not very well understood for the different molecular weights of PEGs. The knowledge of the effect of molecular weight of PEGs on their physical properties and the effect of humidity on the physical properties of PEGs are important parameters for the choice of a PEG to be acceptable as an excipient in pharmaceutical formulations. This study was done to determine the precision of the DSC physical properties for a wide range of PEGs with varying molecular weights from 194 to 23000 daltons. Nine different molecular weights of PEGs were examined in a DSC controlled Heat-Cool-Heat-Cool-Heat (HCHCH) cycle and the observed reproducible values of melting temperature, heat of fusion, crystallization temperature and the heat of crystallization were compared with values obtained from the literature and the observed percent crystallinity was again cross-checked by X-ray Diffraction (XRD) studies. The comparison values indicated acceptable precision. This study was also done to check the effect of humidity on the DSC physical properties for the entire range of PEGs. The results indicated that humidity probably has a higher effect on the physical properties of the low molecular weight PEGs as compared to the high molecular weight PEGs.

Evaluation of the drug-polymer interaction in calcium alginate beads containing diflunisal.

Calcium alginate gel beads have been developed in recent years as a unique vehicle for oral drug delivery due to their excellent biocompatibility, biodegradability, simple method of preparation, abundant sources, low cost and minimal processing requirements. The objective of this study was to evaluate the drug-polymer interaction in calcium alginate beads containing diflunisal. Diflunisal loaded calcium alginate beads were successfully prepared by ionotropic gelation from solution of sodium alginate and diflunisal into calcium chloride solution. The weight ratio of drug to polymer was selected as 1:1. The calcium alginate beads were characterized by size, Scanning Electron Microscopy (SEM), weight uniformity and drug entrapment efficiency. The existence of a possible interaction between diflunisal and the calcium alginate was investigated by Differential Scanning Calorimetry (DSC), Powder X-Ray Diffraction (PXRD) and Fourier Transform Infra-Red (FTIR) analysis. Drug loaded beads were spherical to oval in shape with low drug entrapment efficiency. The drug was found to be present inside the beads as crystalline to semicrystalline form with no significant physical or chemical interaction between drug and excipients. The results implied that calcium alginate beads can be used as a suitable controlled release carrier for diflunisal.

Crystal forms of tolbutamide from acetonitrile and 1-octanol: effect of solvent, humidity and compression pressure.

The possibility of obtaining tolbutamide polymorphs was investigated using the solvents acetonitrile and 1-octanol. Tolbutamide is an oral hypoglycemic agent that exists in four polymorphic forms. Characterization of the various polymorphs was carried out by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), infrared spectroscopy (FTIR), optical microscopy and dissolution studies. Form A, crystallized from acetonitrile, resembled the form I polymorph, while form O, crystallized from 1-octanol, resembled the form III polymorph. Tablets of both form A and form O were produced at compression pressures of 2500 lbs and 5000 lbs using cornstarch and talc and were exposed to 40%, 75% and 95% RH conditions. DSC and PXRD studies did not show any significant drug-excipient interaction. Moreover, the change in the crystalline state of either form upon exposure to humidity was not evident. Dissolution studies showed a significantly lower drug release rate from form O tablets compressed at 5000 lbs pressure and exposed to 95% RH. Pressure and humidity had no significant effect on the dissolution profiles on the form A tablets. It was concluded that form A was the robust choice for further formulation development.

A high-performance liquid chromatography assay for yohimbine HCl analysis.

The analysis used yohimbine HCl solution prepared from commercially available yohimbine HCl powder. Stability-indicating high-performance liquid chromatographic (HPLC) assay procedures were established and utilized to analyze the concentration of the drug. The method proved to be a simple model since it does not contain a buffer system. The mobile phase used, a methanol:water 70:30 ratio, was similar to that suggested by the manufacturer for the storage of the column. Therefore, the solvent system saves analytical processing time since it does not require a change in the mobile phase before and after the analysis. The analytical method has been shown to be stability indicating. The assay method showed a retention time for yohimbine of 4.2 min; for caffeine, the internal standard, it was 2.3 min. The standard deviation and the coefficient of variation were under acceptable limits of 2% and were specifically 1.51% and 1.35% for within-day and between-day samples, respectively. The results showed that the degradation products obtained from stressing yohimbine HCl by heat and extremes in pH did not interfere with the yohimbine HCl peak, although the internal standard, caffeine, did show some interference due to having a retention time similar to the degradation products.

Analysis of extemporaneous alprostadil formulaions.

Twenty-two extemporaneous alprostadil (PGE1) injection solutions samples from five different suppliers and three Caverject (Pharmacia and Upjohn, Inc., Bridgewater, NJ) samples from three different lots, all intended for the clinical treatment of erectile dysfunction, were analyzed to determine PGE1 concentration, assess formation of the PGE1 aqueous breakdown product (PGA1), define pH and assess active microbial contamination. High-pressure liquid chromatography (HPLC), pH meter and cell culture techniques were used to conduct the analyses. Of the 22 extemporaneously formulated samples, six showed PGE1 concentrations 10% greater than their listed amounts and seven showed PGA1 weight fractions corresponding to at least 1.5% of the total prostaglandidn content. It should be noted that no standard has been published in the United States Pharmacopeia/National Formulary for this preparation as of this date. All samples were within the pH range 4.5 to 6.0. Four samples tested positive for active microbial contamination. In adition, nearly all the extemporaneously formulated samples contained what appeared to be benzyl alcohol, and about one half had at least two other undefined peaks within their HPLC chromatograms. In contrast, all three Caverject samples were within +/- 7.5% of their listed PGE1 concentrations while showing PGA1 prostaglandins weight fractions of less 0.6%, all were within the pH range 4.0 to 4.5 and all tested negative for active microbial contamination. Chromatograms of the Caverject samples also diplayed peaks consistent with the presence of benzyl alcohol but did not exhibit addtional undefined peaks. The results suggest that significant variations in PGE1 concentration and in PGA1 formation, accompanied by the possibility of microbial contamination, can occur as a result of the extemporaneous formulation and subsequent transfer of this type of product as a premixed solution intended for treating erectile dysfunction.

Stability of Magnesium Sulfate in 0.9% Sodium Chloride and Lactated Ringers solutions.

Storage stability test were peformed on two extemporaneous formulation alternatives to the commercially available magnesium sulfate injection solutions that are in 5% dextrose or in water. Preparations of the commercial water for injection formulation and two alternative formulations in lactated Ringers and in 0.9% sodium chloride were stored at room temperature in glass bottles and in polyvinyl chloride bags over a three-month period. Solutions were monitored for gross precipitation and for changes in magnesium, sulfur and calcium levels as measured by elemental analysis using atomic absorption spectroscopy and inductively coupled plasma atomic emission spectroscopy. The results demonstrate no consistent decreases in measured elemental concentrations or gross signs of precipitation for any formulation tested.

An improved high-performance liquid chromatography assay for spironolactone analysis.

This study prepared an extemporaneously formulated liquid suspension dosage form (5 mg/ml) from commercially available 25 mg tablets. Stability-indicating HPLC assay procedures were established and utilized to analyze the concentration of the drug. The method proved to be a simple model since it does not contain a buffer system. The mobile phase used was the same as that suggested by the manufacturer for the storage of the column. Therefore, the solvent system saves analytical processing time, since it does not require a change in the mobile phase before or after the analysis. The analytical method has been shown to be stability-indicating. The results have shown that there is no interference from any of the degradation products obtained from stressing spironolactone by heat and extremes in pH or with the internal standard, hydrocortisone 21-acetate.

The formulatiion development and stability of spironolactone suspension.

The purpose of this study was to extemporaneously formulate a liquid dosage form from commercially available tablets and establish the chemical stability of the drug. A suspension of spironolactone (5mg/mL) was formulated from 25-mg spironolactone tablets. Stability-indicating, high perfpromance liquid chromatography assay procedures were used to analyze the concentration of the drug. Chemical stability was predicted using accelerated stability studies. The stability studies were conducted at four temperatures, namely 5*, 30*, and 50*, and 60*C. The spironolactone suspension showed less than 10% degradation at all four temperatures for a period of three months. It appears that the formulation may be stable for longer periods of time; however, the investigation did not extend past this timeline and no recommendation should be implied.

The formulation development and stability of metronidazole suspension.

The purpose of this study was to extemporaneously formulate a liquid dosage form from commercially available tablets and establish the chemical stability of the drug. A suspension of metronidazole (15 mg/mL) was formulated from 500-mg metronidazole tablets. Stability-indicating, high-performance liquid chromatography assay procedures were utilized to analyze the concentration of the drug. Chemical stability was predicted using accelerated stability studies conducted at four temperatures, namely, 40 deg, 50 deg, 60 deg, and 70 deg C for metronidazole. The Arrhenius plot was used to predict the shelf-life of the metronidazole suspension at room temperature. The shelf-life was calculated from the initial concentration and k0 was found to be 73 years. Howwever, it would be more reasonable to expect that a quantity lasting no more than 90 days should be prepared and dispensed.

Stability of an extemporaneously formulated levothyroxine sodium syrup compounded from commercial tablets.

The stability of 40 micrograms/mL extemporaneously formulated syrup from commercially available levothyroxine sodium tablets, using sorbitol 70% as the diluting vehicle, was studied. The concentration of levothyroxine sodium in the formulation was 40 micrograms/mL. The protocol included accelerated stability testing at temperatures of 40 deg, 50 deg, 60 deg, and 70 deg C and a high-performance liquid chromatography assay procedure using testosterone propionate as the internal standard. The data were analyzed using an Arrhenius plot to determine the shelf-life of formulation. The shelf-life was found to be approximately 15 days at 25 deg C and 47 days at 5 deg C.

Stability of allopurinol suspension compounded from tablets.

The stability of allopurinol as an extemporaneous suspension compounded form tablets was studied. The allopurinol suspension (20 mg/mL) was prepared by incorporating pulverized 300-mg allopurinol tablets into the suspending vehicle containing sodium carboxymethylcellulose and magnesium aluminum silicate (Veegum). Lycasin (a syrup vehicle that is 75% maltilol was added to this mixture. Appropriate antioxidants, preservatives, sweeteners and flavoring agents also were used. Samples of the suspension were stored in amber-colored glass bottles at 50 deg, 60 deg, 70 deg, and 80 deg C. At various times during the 97-day study period, the concentration of allopurinol in each sample was determined by a stability-indicating high performance liquid chromatography assay procedure. At the same time, samples were inspected visually for signs of caking or settling and evaluated for redispersibility and pourability. The aqueous solubility of allopurinol as a function of temperature also was studied. It was found that the aqueous solubility of allopurinol increased with an increase in the temperature. A zero-order reaction was assumed for the suspension. The kinetics of degradation were determined and the energy of activation and shelf-life were calculated using the Arrhenius plot. During the study period all samples remained homogenous and showed no signs of caking or settling. The allopurinol suspension compounded from tablets was found to be pharmaceutically acceptable and easily pourable and redispersible. The energy of activation for the suspension was found to be 21.92 kcal/mol. The shelf-life (t90) of the suspension was found to be 8.3 years at room temperature.