A novel polymorphism (471C-->T) in alpha-1-antitrypsin in a patient with asthma.
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Asthma↗
Biomedical subjects
V Pillay
Publications and source records attributed to V Pillay.
Characterization of a new variant of alpha(1)-antitrypsin E(Johannesburg) (H15N) in association with asthma.
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Amino Acid Substitution↗
In situ electrolyte interactions in a disk-compressed configuration system for up-curving and constant drug delivery.
A new approach in drug delivery system design for meeting the needs that are associated with certain circadian variations is presented. The system is comprised of a pure compressed drug disk, which is encased by a polymeric coat using hydroxypropylmethylcellulose or polyethylene oxide. Within the polymeric coat, a physiologically acceptable binary electrolyte combination such as sodium deoxycholate and adipic acid is disposed. Through this process and upon exposure to dissolution media, ionic interactions occur and a texturally variable matrix is manifested in the form of peripheral stiffening' with self-correcting boundaries as demonstrated by texture analysis studies. The peripheral boundaries erode and progressively shift toward the disk-core, thus constantly reducing the diffusional pathlength with the resultant up-curving kinetics. Utilizing these mechanisms, a lag time is induced and drug is delivered over a 24-h period in one of two ways namely, in an up-curving or constant manner for drug models theophylline and diltiazem hydrochloride with water solubilities of 0.85% and > 50% at 25 degrees C, respectively. It appears that for both sparingly and highly soluble drugs, sum of the dissolution/diffusion rates, dynamics of diffusional pathlength and system erosion rate control the release process. The heterogeneous nature of changes in coat thickness, stiffening dynamics and erosion rate in relation to disk geometry is discussed. The developed technology has potential to provide release patterns, compatible with specific chronophysiological conditions, and overcome the absorption-limited capacity of the distal gastrointestinal tract
Diltiazem↗
A novel approach for constant rate delivery of highly soluble bioactives from a simple monolithic system.
A novel monolithic drug delivery system for highly water-soluble bioactive agents to follow pH-independent zero-order kinetics is described. The system utilizes a hydrophilic gel-based swellable polymeric material (polyethylene oxide), a model drug (metoprolol tartrate, 100% water soluble at 25 degrees C) and different electrolytes, such as sodium carbonate and/or pentasodium tripolyphosphate. Based on the induction of in situ intra-gel chemical reactions between different ionic species, drug and polymer, a heterogeneous structure manifested as 'peripheral boundary stiffening,' is accomplished. The consequence of these interactions essentially include the development of gradient-controlled matrix swelling as elucidated through textural profiling, which may contribute to inhibition of drug solubility and its outward diffusion. Analysis of textural profiles and photomicroscopy distinctly provides information on the disposition of peripheral boundary densification for the electrolyte-containing matrices. Electrolytic conductivity measurements performed with the simultaneous analysis of matrix swelling showed that sodium carbonate forms a highly reactive matrix within the first 3 h of medium penetration. On the other hand, larger molecules such as pentasodium tripolyphosphate maintain a constant conductivity level, which may be related to its lower solubility and diffusion in comparison to sodium carbonate. Based on model fitting and statistical analysis, it is shown that drug release kinetics were adequately described by M(t)/M(infinity)=k(0)t, with zero-order release rate constant k(0) of 0.054 h(-1). This novel approach in formulation development could potentially be used for constant rate delivery of highly soluble bioactive agents over an extended period for specific biopharmaceutical needs.
Calcium Carbonate↗
Differences in the genotypes and plasma concentrations of the INTERLEUKIN-1 receptor antagonist in black and white South African asthmatics and control subjects.
The allelic frequency of a variable tandem repeat (VNTR) polymorphism in intron 2 of the IL-1 Ra gene was studied in black and white patients with asthma as well as control individuals. The plasma IL-1 Ra concentration was also determined in asthmatics and compared to control individuals. The 410-bp allele of the IL-1 Ra was significantly increased in all black subjects (90%) as compared to all white subjects (74%, P<0.0001), while the 240-bp allele was significantly reduced in all black subjects (11%) as compared to all white subjects (27%, P<0.0001). There was no difference in the frequency of the VNTR of the IL-1 Ra between black asthmatics and black controls and between white asthmatics and white controls. The IL-1 Ra levels were significantly increased in black and white patients with severe or moderate asthma as compared to patients with mild asthma. Increased plasma concentrations of the IL-1 Ra was found to be associated with disease severity in all asthmatic patients.
Adolescent↗
In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract. I. Comparison of pH-responsive drug release and associated kinetics.
Multiple unit dosage forms for oral delivery of bioactive agents offer many advantages over single unit products (e.g., site-specific delivery, predictable gastrointestinal transit time and less localized adverse effects). In view of such benefits, this paper investigates the crosslinking of sodium alginate, low methoxylated pectin and their novel binary mixture with calcium ions through ionotropic gelation to pelletize the model drug, diclofenac sodium, using "environmentally benign" solvents and processing techniques. Crosslinked pellets of the above polymers in 2% (w/v) aqueous calcium chloride solution were prepared and evaluated for their structural and release behavior. The average size of the different pellets was 1.3 mm and drug entrapment capacity was optimized by reducing the calcium chloride solution pH to 1.6. Three types of pellet formulations were subjected to dissolution studies using the USP 23 Apparatus 2 and 3 over a pH range simulating the human gastrointestinal tract. Negligible drug release occurred in pH 1-4. However, rate of drug release in pH 6.6 ranged from rapid to slow (i. e., 100% drug release in 4 to 10 h, respectively) but always in a controlled manner. Weight change/erosion studies and swelling measurements were used to provide experimental correlation of kinetic model analysis for each of the three pellet systems. From model fitting studies and statistical treatment, the modified Hopfenberg equation {Mt/M infinity =1-[1-k1(t-tL,min)]n} best described the release kinetics for calcium-pectinate pellets. The model assumes heterogeneous erosion with kinetic constant k1=k0/C0r0, in which k0 is the erosion rate constant, C0 is the uniform initial concentration of drug in the matrix, r0 is the initial radius and tL, min is the lag time. The n values of 1, 2 and 3 apply to a slab, cylinder and sphere, respectively. In addition, the exponential models, namely the Power Law (Mt/M infinity =k1tn) and its derivative containing the lag time [Mt/M infinity =k1(t-tL,min)n], employed in the statistical treatment of data provided n values of approximately 0.8-1 in the case of the calcium-alginate and calcium-alginate-pectinate release kinetics. It is concluded that the proper selection of rate-controlling polymers and their interactive potential for crosslinking is important, and will determine the overall size and shape of pellets, the duration and pattern of dissolution profiles, pH sensitivity, drug loading capacity and mechanism of drug release.
Administration, Oral↗
In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract. II. Physicochemical characterization of calcium-alginate, calcium-pectinate and calcium-alginate-pectinate pellets.
Pellets of calcium-alginate, calcium-pectinate and calcium-alginate-pectinate were produced via crosslinking in an aqueous medium for site-specific drug delivery in the gastrointestinal tract. A comparative study of their physicochemical characteristics by means of texture analysis, modulated temperature differential scanning calorimetry (MTDSC), scanning electron microscopy and swelling dynamics under different pH conditions was undertaken. It was found that the incorporation of low methoxylated pectin (i.e., degree of methoxylation approximately 35%) together with alginate appears to influence the degree of crosslinking and subsequently the physical, mechanical and resilience behavior. In general, texture analysis of various pellets indicated that both strength and resilience profiles were in the order of calcium-alginate>/=calcium-alginate-pectinate>calcium-pectinate. Calcium-alginate pellets were found to be viscoelastic, while calcium-pectinate was highly brittle. Through the application of MTDSC, depolymerization transitions, reversing and non-reversing heat flow were determined and interpreted for each formulation. Scanning electron microscopy and micro-thermal analysis revealed distinct morphological differences in each case. The influence of and nature of crosslinking, and textural properties of such pellets on drug release rate modulation is discussed.
Administration, Oral↗
Electrolyte-induced compositional heterogeneity: a novel approach for rate-controlled oral drug delivery.
In this work a new approach for in situ interactions between drug and electrolyte(s) is devised to control the release of highly water soluble drugs from oral hydrophilic monolithic systems. The model drug diltiazem hydrochloride (water solubility in excess of 50% at 25 degrees C), in conjunction with specific electrolytes, was principally employed in the design of swellable tablet formulations comprised of hydrophilic polymers such as hydroxypropylmethlcellulose (HPMC) or poly(ethylene oxide) (PEO). Electrolytes such as sodium bicarbonate or pentasodium tripolyphosphate were used to modulate intragel pH dynamics, swelling kinetics, and gel properties. Through in situ ionic interactions (an intragel matrix system composed of different chemical species that promote competition for water of hydration), a compositionally heterogeneous structure referred to as a "metamorphic scaffold" was established. It is shown that this latter structure results in the inhibition of drug dissolution, induction of a differential swelling rate, and attainment of "matrix stiffening" and axially provides a uniform gel layer. Presence of such phases in matrix structure and its influence on swelling dynamics enabled control of diltiazem hydrochloride release in a zero-order manner in different pH environments over a 24-h period. From kinetic analysis using the power law expressions [M(t)/M(infinity) = k(1)t(n), M(t)/M(infinity) = k(1)t(n) + k(2)t(2)(n)] and Hopfenberg model [M(t)/M(infinity) = 1 - (1 - k(1)t)(n)], it became apparent that the dynamics of matrix relaxation and controlled erosion were major factors involved in the release mechanism, while the composite rate constant k(1) (in Hopfenberg model) decreased by approximately 2-fold in the presence of electrolyte(s). These findings indicated that the dynamics of swelling and gel formation in the presence of ionizable species within hydrophilic matrices provide an attractive alternative for zero-order drug delivery from a simple monolithic system.
Administration, Oral↗
Unconventional dissolution methodologies.
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Algorithms↗
A new method for dissolution studies of lipid-filled capsules employing nifedipine as a model drug.
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1-Octanol↗
Evaluation and comparison of dissolution data derived from different modified release dosage forms: an alternative method.
Dissolution testing is an essential requirement for the development, establishment of in vitro dissolution and in vivo performance (IVIVR), registration and quality control of solid oral dosage forms. The objective of the present study was to investigate the effect of delivery system positioning in accordance with the USP 23-recommended dissolution methods and the proposed modification on drug release from controlled release systems having different operating release mechanisms, namely, swellable floatable, swellable sticking and osmotic pump. The delivery systems were evaluated by placing each dosage form either in the dissolution vessel in accordance with the USP 23 methods or over/below a designed ring/mesh device for achieving full surface exposure to the dissolution medium for sticking or floatable systems respectively. Results indicate that the overall release profiles from the sticking and floatable systems of theophylline are sensitive to their positioning in the dissolution vessel (P<0.05). Furthermore, release of diltiazem hydrochloride from the sticking system also demonstrated sensitivity (P<0.05). In contrast, the floatable dosage form of this latter drug with the application of a helical wire sinker, or when it was placed below the ring/mesh assembly, or by allowing the dosage form to float, did not show sensitivity (P>0.05) for the overall release behavior. This was attributed to the greater solubility of diltiazem hydrochloride (50% solubility in water at 25 degreesC) in comparison to theophylline which is a sparingly soluble drug (0.85% solubility in water at 25 degreesC). Drug release from the osmotic pump appeared to be identical under the given experimental conditions (P>0.05). Statistical analysis of data was performed by comparing the t50%, t70%, t90%; mean dissolution times (MDT50%, MDT70%, MDT90%); the "difference factor, f1" and "similarity factor, f2". It is concluded that the results derived from the application of the "similarity factor, f2" are superior to the individual time points (e.g. tx%) and MDTx% values in differentiating between overall release patterns or the border line release profile differences. It also became apparent that in the case of the swellable sticking systems full surface exposure to the dissolution medium results in greater release rate. For the osmotic pump the required osmotic pressure threshold necessary for constant rate drug delivery appears to have reached independent of the hydrodynamic conditions. A successful and more accurate evaluation of dissolution data can be derived when full surface exposure is considered and this can be accomplished by dissolution method modification with the aid of the designed ring/mesh assembly.
Algorithms↗
Upregulation of P-glycoprotein in rat hepatoma rho(o) cells: implications for drug-DNA interactions.
Rat hepatoma cells lacking mitochondrial DNA (rho(o) cells) were used as a model system to examine the possible roles of mitochondrial DNA as a target for the DNA-acting anticancer drug Adriamycin (doxorubicin). The rho(o) cells were 45-fold less sensitive to Adriamycin than the parental rho+ cells containing mitochondrial DNA. Other non-DNA-acting drugs also exhibited similar behaviour, and this was shown to be due to a multidrug resistance (MDR) phenotype in the rho(o) cells. This was indicated by confocal microscopy where rho+ cells exhibited thirteenfold higher cellular levels of Adriamycin than rho(o) cells. Upregulation (tenfold) of P-glycoprotein in rho(o) cells was also confirmed by Northern dot blot analysis. Since the MDR phenotype is present in rho(o) cells and upregulation of P-glycoprotein is maintained in these cells, rho(o) cells are not a good model system for drug-DNA studies (where the drug is susceptible to extrusion by P-glycoprotein), and any such results obtained with this system must be treated with considerable caution.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Circulating cytokine concentrations and cytokine production by monocytes from newborn babies and adults.
As a possible factor responsible for reduced fever responses in the newborn, we measured plasma cytokine concentrations and cytokine production by neonatal monocytes after lipopolysaccharide or IL (interleukin)-1 alpha stimulation in vitro and compared these data with those obtained from adult plasma and monocytes. Whole blood was collected from afebrile adults (n = 12) and the umbilical cord of normal term infants (n = 12). Plasma and peripheral blood monocytes were prepared by conventional techniques. Significantly lower concentrations of IL-1 alpha, IL-1 beta (P < 0.05, t-test) and IL-6 (P < 0.01, t-test) were found in the plasma of newborn babies compared with that of adults. There was no significant difference in plasma tumour necrosis factor (TNF) concentrations between the adults and newborn babies. Monocytes from newborn babies had the capacity to produce IL-1 alpha and IL-1 beta as readily as adult cells after stimulation with lipopolysaccharide or IL-1 alpha, and produced significantly lower concentrations of TNF and IL-6 than those produced by stimulated adult monocytes (P < 0.01, ANOVA). Our results suggest that the reduced production of IL-6 by monocytes of the newborn during infection could be partly responsible for attenuated fever responses observed in the neonate.
Adult↗
Interleukin-1 receptor antagonist in newborn babies and pregnant women.
We have investigated the possible role of the interleukin-1 receptor antagonist (IL-1ra) in the attenuated fever response in the newborn. Umbilical cord blood was collected from normal full-term infants (n = 12), and venous blood was obtained from afebrile, non-pregnant adults, of both genders (n = 12) and women in late pregnancy (n = 12). Plasma IL-1ra, and IL-1ra produced in vitro by peripheral blood monocytes stimulated with IL-1 alpha or LPS, were assayed by ELISA. Significantly higher concentrations of IL-1ra (P < 0.01, t test) were found in umbilical cord plasma than in plasma of non-pregnant adults. Furthermore concentrations of IL-1ra in the plasma of women in late pregnancy were significantly higher than in the plasma of neonates and non-pregnant adults (P < 0.01, Mann-Whitney rank-sum test). Neonatal monocytes failed to produce significant amounts of IL-1ra upon stimulation in vitro. The monocytes of pregnant women produced much higher concentrations of IL-1ra than the monocytes of non-pregnant adults (P < 0.01 Mann-Whitney rank-sum test). We speculate that IL-1ra may attenuate the febrile response to Gram-negative pyrogens in women in late pregnancy, and by crossing the placenta, also in the newborn.
Enzyme-Linked Immunosorbent Assay↗
Ionotropic gelation: encapsulation of indomethacin in calcium alginate gel discs.
Ionotropic gelation by divalent metal interaction was employed as an approach to design a modified release multiple-unit oral drug-delivery system. This process was achieved by crosslinking an indomethacin-sodium alginate dispersion with calcium ions to induce the spontaneous formation of indomethacin-calcium alginate gel discs. A significant part in the validation of the integrity of the system, involved a preformulatory stage for the optimization of the curing conditions and potency determination of the gel discs. A three-phase approach was developed to establish the critical curing parameters. Since curing involved crosslinking of the sodium alginate with calcium ions, an optimal concentration of calcium chloride (phase one) and crosslinking reaction-time (phase two) had to be determined. Furthermore, the third phase involved the optimization of the air-drying time of the gel discs. In phases one and two, stabilization of in vitro drug-release characteristics was used as the marker of optimal crosslinking efficiency. Phase three was based on achieving fully dried gel discs by drying to constant weight at 21 degrees C under an extractor. The study revealed that optimal crosslinking efficiency was achieved in 1%w/v calcium chloride solution for 24 h and air-dried at 21 degrees C under an extractor for 48 h. The three solvent/solution systems investigated for their ability to liberate completely the drug from the matrix system were methanol, sodium citrate (1%w/v) and phosphate buffer pH 6.2. Phosphate buffer provided optimal drug removal, in addition to its ability to induce swelling of the calcium alginate gel discs. Furthermore, drug loading also increased with the use of increasing concentrations of sodium alginate in the formulations.
Administration, Oral↗