Co-solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In vitro–In vivo Evaluation

A number of synthesized chemical molecules suffer from low aqueous solubility problems. Enhancement of aqueous solubility, dissolution rate, and bioavailability of drug is a very challenging task in drug development. In the present study, solubility and dissolution of poorly aqueous soluble drug simvastatin (SIM) was enhanced using hydrophilic, low viscosity grade polymer hydroxypropyl methylcellulose (HPMC K₃LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of HPMC K₃LV. Spray drying and rotaevaporation method were applied for solvent evaporation. Co-solvent-evaporated mixture in solid state was determined by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy, and Fourier-transform infrared spectroscopy. In vitro–in vivo studies were performed on co-solvent-evaporated mixture and compared with SIM. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased in co-solvent-evaporated mixtures compared to SIM. co-solvent-evaporated mixtures showed better reduction in total cholesterol and triglyceride levels than the SIM. The low-viscosity grade HPMC acts as a surfactant, which enhances the wetting of drug and thus improves the solubility of drug. The co-solvent evaporation method provides good encapsulation efficiency and produces amorphous form of SIM, which gave better solubility and dissolution than the crystalline SIM.     

PRIMARY CUTANEOUS COCCIDIOIDOMYCOSIS—The Criteria for Diagnosis and a Report of a Case

Study was made of a case of coccidioidomycosis known to have resulted from primary inoculation of the organisms into the skin. Clinical observations and laboratory data were obtained at the time of clinical illness and for a period of five years thereafter. From the information thus obtained and correlation of it with what already was known of coccidioidomycosis, it was concluded that the disease originates very rarely as the result of primary cutaneous inoculation. In most instances lesions suspected to be of this type have actually resulted by dissemination of the organisms to the skin from a previously unrecognized pulmonary focus.Primary cutaneous coccidioidomycotic lesions closely resemble the primary cutaneous lesions (chancres) in other infectious granulomata, such as syphilis, tuberculosis and sporotrichosis. Spontaneous involution should occur within three months and then there should be immunity to reinfection in all but one or two per thousand instances.From these observations certain criteria were evolved by which to determine in a case of coccidioidomycosis with cutaneous manifestations whether or not the infecting organism entered through the skin.     

Synthesis and Antimicrobial Activity of a New Drug Based on a Retro-Analog of Cathelicidin—Polypeptide SE-33

Russian Journal of Bioorganic Chemistry - Polypeptide SE-33 (SETRPVLNRLFDKIRQVIRKFEKGIKEKSKRFF), which is a retro analog of natural antimicrobial protein cathelicidin LL-37...     

Dissolution Enhancement of a Drug Exhibiting Thermal and Acidic Decomposition Characteristics by Fusion Processing: A Comparative Study of Hot Melt Extrusion and KinetiSol® Dispersing

In this study, hot melt extrusion (HME) and KinetiSol® Dispersing (KSD) were utilized to prepare dissolution-enhanced solid dispersions of Roche Research Compound A (ROA), a BCS class II drug. Preformulation characterization studies showed that ROA was chemically unstable at elevated temperatures and acidic pH values. Eudragit® L100-55 and AQOAT® LF (HPMCAS) were evaluated as carrier polymers. Dispersions were characterized for ROA recovery, crystallinity, homogeneity, and non-sink dissolution. Eudragit® L100-55 dispersions prepared by HME required the use of micronized ROA and reduced residence times in order to become substantially amorphous. Compositions containing HPMCAS were also prepared by HME, but an amorphous dispersion could not be obtained. All HME compositions contained ROA-related impurities. KSD was investigated as a method to reduce the decomposition of ROA while rendering compositions amorphous. Substantially amorphous, plasticizer free compositions were processed successfully by KSD with significantly higher ROA recovery values and amorphous character than those achieved by HME. A near-infrared chemical imaging analysis was conducted on the solid dispersions as a measure of homogeneity. A statistical analysis showed similar levels of homogeneity in compositions containing Eudragit® L100-55, while differences were observed in those containing HMPCAS. Non-sink dissolution analysis of all compositions showed rapid supersaturation after pH adjustment to approximately two to three times the equilibrium solubility of ROA, which was maintained for at least 24 h. The results of the study demonstrated that KSD is an effective method of forming dissolution-enhanced amorphous solid solutions in cases where HME is not a feasible technique.     

Influence of Critical Parameters of Nanosuspension Formulation on the Permeability of a Poorly Soluble Drug through the Skin—A Case Study

In transdermal drug delivery systems, it is always a challenge to achieve stable and prolonged high permeation rates across the skin since the concentrations of the drug dissolved in the matrix have to be high in order to maintain zero order release kinetics. Several attempts have been reported to improve the permeability of poorly soluble drug compounds using supersaturated systems. However, due to thermodynamic challenges, there was a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of nanoparticles and influence of different concentrations of solubilizer such as vitamin E TPGS (d-a-tocopheryl polyethylene glycol 1000 succinate) to improve the permeation rate through the skin. Effects of several formulation factors were studied on the nanosuspension systems using ibuprofen as a model drug. The overall permeation enhancement process through the skin was influenced mostly by the solubilizer and also by the size of nanoparticles. The gel formulation developed with vitamin E TPGS + HPMC nanosuspension, consequently represent a promising approach aiming to improve the permeability performance of a poorly water soluble drug candidate.KEY WORDS: dermal drug delivery, human skin, nanosuspension, permeation rate, porcine skin, vitamin E TPGS     

Uses and Conservation of Plant Species in a National Park—A Case Study of Ben En, Vietnam

Uses and Conservation of Plant Species in a National Park—A Case Study of Ben En, Vietnam. This paper surveys the use of wild and cultivated plants by local people in Ben En National Park, Vietnam, and analyzes its impact on the conservation status of some of the utilized species. A total of 208 species used for a range of nonmedicinal purposes are listed. See Hoang et al. (2008a) for 230 medicinal plants used in the park. Most species are used for food. The use of plants contributes very significantly to the livelihood of local people in the park, but the current use patterns are not sustainable and would lead to local extinction of rare and endangered species if no additional conservation measures are introduced. Men collect nonmedicinal plants more often than women. A total of 38 useful plant species are commercialized, and contribute 12% of the average income of individual households. Bamboo shoots of Schizostachyum funghomii (Poaceae) are the most important for income generation. The monetary equivalent of noncommercialized useful plants probably far exceeds the value of the traded plant products. Plant use is independent of the ethnicity of the different populations living in the park. Larger households make use of a greater variety of useful plant species than small families. Abundant species in the forest have a higher use index (UI) than less common species. Out of the 208 useful species, as many as 27 were found to be endangered locally, many more than the 11 or 8 endangered species included in national or global red lists. Currently, useful plants, especially important timber trees, are more abundant in the less disturbed parts of the park, far away from the villages, indicating the pressures of illegal logging and harvesting near villages on the ecosystems.     

Performance of a filter loop reactor using Zymomonas mobilis and validation of the ethanol production model — II

A special loop recycle reactor with capillary crossflow filters was designed to enhance ethanol productivity. The new set-up did not comprise a classical reaction vessel with a stirrer but the working volume consisted only of the void volumes of the filters and the peripheral equipment, however, it behaved as a well mixed CSTR. A circulating pump provided for both mixing and recirculation of the culture fluid. Degassing was accomplished with a cyclone type device. Even if the circulating pump destroyed cells and automated backflushing of the filters could not prevent membrane fouling, maximum biomass concentration reached 98 g l⁻¹ at a dilution rate of 4 h⁻¹ and the maximum ethanol productivity achieved was 224 g l⁻¹ h⁻¹. Using the loop recycle reactor, the ethanol production model proposed in Part I of this study (Nipkow et al. (1986) J. Biotechnol. 3, 35–47) extended with a variable rate accounting for mechanical destruction of cells was verified. It was demonstrated that the predicted productivity of 350 g l⁻¹ h⁻¹ — exploiting the biological potential of Zymomonas mobilis — should be attainable if improved mechanical equipment in a filter recycle system is employed.     

Child Behavior Checklist—Mania Scale (CBCL-MS): Development and Evaluation of a Population-Based Screening Scale for Bipolar Disorder

Context

Early identification of Bipolar Disorder (BD) remains poor despite the high levels of disability associated with the disorder.

Objective

We developed and evaluated a new DSM orientated scale for the identification of young people at risk for BD based on the Child Behavior Checklist (CBCL) and compared its performance against the CBCL-Pediatric Bipolar Disorder (CBCL-PBD) and the CBCL-Externalizing Scale, the two most widely used scales.

Methods

The new scale, CBCL-Mania Scale (CBCL-MS), comprises 19 CBCL items that directly correspond to operational criteria for mania. We tested the reliability, longitudinal stability and diagnostic accuracy of the CBCL-MS on data from the TRacking Adolescents'' Individual Lives Survey (TRAILS), a prospective epidemiological cohort study of 2230 Dutch youths assessed with the CBCL at ages 11, 13 and 16. At age 19 lifetime psychiatric diagnoses were ascertained with the Composite International Diagnostic Interview. We compared the predictive ability of the CBCL-MS against the CBCL-Externalising Scale and the CBCL-PBD in the TRAILS sample.

Results

The CBCL-MS had high internal consistency and satisfactory accuracy (area under the curve = 0.64) in this general population sample. Principal Component Analyses, followed by parallel analyses and confirmatory factor analyses, identified four factors corresponding to distractibility/disinhibition, psychosis, increased libido and disrupted sleep. This factor structure remained stable across all assessment ages. Logistic regression analyses showed that the CBCL-MS had significantly higher predictive ability than both the other scales.

Conclusions

Our data demonstrate that the CBCL-MS is a promising screening instrument for BD. The factor structure of the CBCL-MS showed remarkable temporal stability between late childhood and early adulthood suggesting that it maps on to meaningful developmental dimensions of liability to BD.     

The First Example of a Hoogsteen Basepaired DNA Duplex in Dynamic Equilibrium with a Watson-Crick Basepaired Duplex—A Structural (NMR), Kinetic and Thermodynamic Study

Abstract

A single-point substitution of the O4′ oxygen by a CH₂ group at the sugar residue of A ⁶ (i.e. 2′-deoxyaristeromycin moiety) in a self-complementary DNA duplex, 5′- d(C¹G²C³G⁴A⁵A⁶T⁷T⁸C⁹G¹⁰C¹¹G¹²)₂ ^?3, has been shown to steer the fully Watson-Crick basepaired DNA duplex (1A), akin to the native counterpart, to a doubly A ⁶:T⁷ Hoogsteen basepaired (1B) B-type DNA duplex, resulting in a dynamic equilibrium of (1A)→←(1B): K_eq = k₁/k_-1 = 0.56±0.08. The dynamic conversion of the fully Watson-Crick basepaired (1A) to the partly Hoogsteen basepaired (1B) structure is marginally kinetically and thermodynamically disfavoured [k₁ (298K) = 3.9± 0.8 sec^?1; δH°? = 164±14 kJ/mol;-TδS°? (298K) = ?92 kJ/mol giving a δG₂₉₈°? of 72 kJ/mol. Ea (k1) = 167±14 kJ/mol] compared to the reverse conversion of the Hoogsteen (1B) to the Watson-Crick (1A) structure [k-1 (298K) = 7.0±0.6 sec-1, δH°? = 153±13 kJ/mol;-TδS°? (298K) = ?82 kJ/mol giving a δG₂₉₈°? of 71 kJ/mol. Ea (k-1) = 155±13 kJ/mol]. A comparison of δG₂₉₈°? of the forward (k1) and backward (k-1) conversions, (1A)→←(1B), shows that there is ca 1 kJ/mol preference for the Watson-Crick (1A) over the double Hoogsteen basepaired (1B) DNA duplex, thus giving an equilibrium ratio of almost 2:1 in favour of the fully Watson-Crick basepaired duplex. The chemical environments of the two interconverting DNA duplexes are very different as evident from their widely separated sets of chemical shifts connected by temperature-dependent exchange peaks in the NOESY and ROESY spectra. The fully Watson-Crick basepaired structure (1A) is based on a total of 127 intra, 97 inter and 17 cross-strand distance constraints per strand, whereas the double A ⁶:T⁷ Hoogsteen basepaired (1B) structure is based on 114 intra, 92 inter and 15 cross-strand distance constraints, giving an average of 22 and 20 NOE distance constraints per residue and strand, respectively. In addition, 55 NMR-derived backbone dihedral constraints per strand were used for both structures. The main effect of the Hoogsteen basepairs in (1B) on the overall structure is a narrowing of the minor groove and a corresponding widening of the major groove. The Hoogsteen basepairing at the central A ⁶:T⁷ basepairs in (1B) has enforced a syn conformation on the glycosyl torsion of the 2′- deoxyaristeromycin moiety, A ⁶, as a result of substitution of the endocyclic 4′-oxygen in the natural sugar with a methylene group in A ⁶. A comparison of the Watson-Crick basepaired duplex (1A) to the Hoogsteen basepaired duplex (1B) shows that only a few changes, mainly in α, σ and γ torsions, in the sugar-phosphate backbone seem to be necessary to accommodate the Hoogsteen basepair.     

Superposition and scattering of visual fields in a compound,double eye—II. Stimulation sequences for different distances in a stomatopod from a bright habitat

• 1.1. The inputs deriving from a point light moving in front of a column of ommatidia are plotted by a computer.
• 2.2. Overlap of visual fields causes one main, central maximum surrounded by smaller maxima intercalated by minima.
• 3.3. With increasing distance of the point from the eye the central maximum increases.
• 4.4. Ommatidia in each half of the eye are stimulated sequentially in two groups. Stimulation sequences are parallel between the two halves of the eye.
• 5.5. We postulate an integrative mechanism for processing the succession of simultaneous inputs and hypothesize that the animal derives information about speed and distance from that mechanism.