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Biomedical subjects

A Adjei

Publications and source records attributed to A Adjei.

16 recordsLinked to original sources
PubMed2003

A-61C and C-101G Hp gene promoter polymorphisms are, respectively, associated with ahaptoglobinaemia and hypohaptoglobinaemia in Ghana.

We have investigated the genetic basis for the Hp0 phenotype amongst 123 randomly selected Ghanaians. A total of 17 individuals were determined to be Hp0 phenotype, based on the classical method for Hp phenotyping of Hb-supplemented plasma. Out of the 17 Hp0 individuals, nine subjects were further classified as ahaptoglobinaemic and eight as hypohaptoglobinaemic by Western blots and double immunodiffusion. We identified three previously known base substitutions (A-55G, A-61C and T-104A) and three new ones (C-101G, T-191G and C-242T) within the 5' flanking region of the Hp gene. The A-61C base substitution significantly decreased transcriptional activity and was associated strongly with Hp2 allele and ahaptoglobinaemia. The C-101G substitution was similar in transcriptional activity to the wild-type and was associated with Hp1S allele and hypohaptoglobinaemia. The Hpdel allele seen in Asian populations was absent. We conclude that the Hp0 phenotype in Ghana has a genetic basis that differs significantly from that seen in Asia.

Amino Acid Substitution↗
PubMed1998

The effect of soybean protein on bone loss in a rat model of postmenopausal osteoporosis.

This study was designed to investigate the modulatory effect of dietary soybean protein on the skeleton of an ovariectomized rat model with postmenopausal osteoporosis. Thirty-two female Sprague-Dawley rats were weight matched and divided into the following four experimental groups: Soy group, ovariectomized and fed soy protein diet; Estrogen group, ovariectomized, fed casein diet and injected with estrogen; Casein group, ovariectomized and fed casein diet; and Sham group, sham-operated and fed casein diet. The diets and estrogen were started two weeks after surgery, and continued for four weeks. Rats in the Sham, Soy and Estrogen groups had significantly higher (p < 0.05) femur and tibia ash content than those in the Casein group. Accordingly, the calcium content of the tibia and femur were also significantly higher (p < 0.05) in the Soy, Estrogen and Sham groups as compared to the Casein group. Serum total and bone-type alkaline phosphatase levels were both significantly lower (p < 0.05) in the Estrogen and Sham groups in relation to the Soy and Casein groups. This study demonstrated that a 22% soybean protein diet could be just as effective as daily estrogen administration in suppressing bone loss due to ovariectomy. However, unlike estrogen, soy protein diet did not have any uterotrophic effect and did not decrease the markers of bone turnover measured, suggesting a possible difference in the mechanism of action.

Alkaline Phosphatase↗
PubMed1996

Throat microflora in breastfed and formula-fed infants.

Most bacterial infections are caused by organisms that are already colonizing the host, and these infections commonly originate at site of the gastrointestinal and respiratory tracts. However, little attention has been focused on the indigenous microflora of the respiratory tract in the infant. We studied the throat microflora of healthy breastfed and formula-fed infants. The incidence of pathogenic bacterial isolation from breastfed infants (1 out of 23) was lower relative to infants fed formula (5 out 14). The dominant bacteria in the throat flora isolated in both breastfed and formula-fed infants were alpha-haemolytic Streptococcus and gamma Streptococcus. These results suggest that breastmilk may be effcacious in preventing the growth of pathogenic bacteria in the throat.

Bacteria↗
PubMed1994

Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

PURPOSE: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. PATIENTS AND METHODS: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (Css) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT Css values achieved. RESULTS: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT Css values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT Css values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multi-drug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. CONCLUSION: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT Css values are achievable, and that further developmental trials are warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Effect of formulation adjuvants on gastrointestinal absorption of leuprolide acetate.

Leuprolide acetate, [D-Leu6-desGly10]LH-RH ethylamide, a highly potent superagonist of luteinizing hormone-releasing hormone (LH-RH), was administered by intraduodenal (ID) injection to male castrate rats in a saline solution. Absorption was low, approximately 0.01% and 0.08% by oral (PO) and ID administration respectively, compared with intravenous (i.v.) controls. An aqueous formulation and a water in oil emulsion of a lipophilic salt, a decane sulfonic acid derivative of [D-Leu6-desGly10]LH-RH ethylamide gave ID bioavailabilities of approximately 0.2% and 1%, respectively. Evaluation of formulation effects on the oral absorption of leuprolide showed that lipophilicity, surfactant and vehicle properties significantly affected ID absorption of leuprolide. Absolute bioavailability of the drug in typical emulsion systems ranged from approximately 3 to 10% and represent an improvement of about 100 fold in gastrointestinal bioavailability of this peptide. The implications of these findings relative to the effect of formula adjuvants on oral absorption of leuprolide and other peptides following ID administration are discussed.

Adjuvants, Pharmaceutic↗
PubMed1992

Bioavailability of leuprolide acetate following nasal and inhalation delivery to rats and healthy humans.

Systemic delivery of leuprolide acetate, a luteinizing hormone releasing hormone (LHRH) agonist, was compared after inhalation (i.h.) and intranasal (i.n.) administration. The i.n. bioavailability in rats was significantly increased by alpha-cyclodextrin (CD), EDTA, and solution volume. Intraanimal variability was 30-60%, and absorption ranged from 8 to 46% compared to i.v. controls. Studies in healthy human males were conducted with leuprolide acetate i.n. by spray, or inhalation aerosol (i.h.), and subcutaneous (s.c.) and intravenous (i.v.) injection. The s.c. injection was 94% bioavailable compared with i.v. The i.n. bioavailability averaged 2.4%, with significant subject-to-subject variability. Plasma peak concentrations (Cmax) with 1- and 3-mg dosages ranged between 0.24-1.6 and 0.10-11.0 ng/ml, respectively. The low human bioavailability may be due to physical loss of drug down the oral cavity and differences between human and rat nasal mucosa. Inhalation delivery gave a slightly lower intersubject variability. Mean Cmax with a 1-mg dose of solution aerosol was 0.97 ng/ml, compared with 4.4 and 11.4 ng/ml for suspension aerosols given at 1- and 2-mg bolus dosages, respectively. The mean bioavailability of the suspension aerosols (28% relative to s.c. administration) was fourfold greater than that of the solution aerosol (6.6%), suggesting that LHRH analogues may be delivered systemically via the lung as aerosol dispersions.

Absorption↗
PubMed1990

Pulmonary delivery of peptide drugs: effect of particle size on bioavailability of leuprolide acetate in healthy male volunteers.

Leuprolide acetate, a nonapeptide with potent luteinizing hormone releasing hormone (LHRH) agonist activity, has low oral bioavailability. Unique aerosols of leuprolide acetate were developed and particle size distribution studies were carried out. A light scattering method (Malvern Model 2600c) was compared to the impaction method (Andersen Sampler) for measuring size distribution. Results showed the Malvern method to be comparable to the impaction method with the Malvern being faster and easier to use. Absolute bioavailability of leuprolide acetate in healthy human male volunteers ranged from 4% to 18% and agreed well with particle size data. Bioavailability corrected for respirable fraction ranged from 35% to 55%, indicating that the pulmonary route may have high potential for systemic delivery of this peptide.

Adult↗
PubMed1984

Membrane solubility parameter and in situ release of theophylline.

The solubility of theophylline in polyethylene glycol 400-water binary mixtures was analyzed in terms of solute-solvent interaction using the solubility parameter principle of Hildebrand. Preliminary in situ (rat gut permeation) studies with the solvent mixtures having varying polarity as expressed by the solubility parameter showed that (a) the more alike the solubility parameter of theophylline (delta 2 = 14, as obtained from solubility studies) and the solubility parameter of the solvent mixture, the greater was the attraction of solvent for the drug (b) sufficient similarity must exist between the solubility parameter of theophylline and that of the intestinal mucosa to promote bioabsorption, and (c) from the above, it follows that there exists a competition between solvent and rat gut membrane for the drug. The solubility parameter of the solvent vehicle must be such that it does not impede absorption of the molecules into the intestinal mucosa.

Animals↗
PubMed1982

Extended Hildebrand solubility approach and the log linear solubility equation.

The log linear solubility equation, log S = log Sw + sigma f, was studied in relationship to the extended Hildebrand solubility approach. It is shown that the log linear form may be derived beginning with the extended Hildebrand approach. The log linear expression gives a good linear fit for semipolar drugs in a number of water-cosolvent mixtures. It is particularly successful when the solubility parameter, delta 1, of the cosolvent is 3 or more solubility parameter units larger than the solubility parameter, delta 2, of the drug. When the cosolvent tends to solvate the drug strongly, the log linear function may even hold where the solubility parameters of the drug and cosolvent are similar. It appears, however, not to be applicable to nonpolar cosolvent systems. An interfacial model for the solubility of drugs in polar mixed solvents is based on sigma, a parameter that also figures prominently in the log linear solubility equation. When used to describe mixed solvent systems, the interfacial model applies in the region of the solubility profile (solubility versus solvent composition) where the log linear relationships hold. The extended Hildebrand solubility approach is applicable over a wide range of cosolvent composition in mixed systems from nonpolar organic solvents to water.

Aminobenzoates↗
PubMed1982

Extended Hildebrand solubility approach: testosterone and testosterone propionate in binary solvents.

Solubilities of testosterone and testosterone propionate in binary solvents composed of the inert solvent, cyclohexane, combined with the active solvents, chloroform, octanol, ethyl oleate, and isopropyl myristate, were investigated with the extended Hildebrand solubility approach. Using multiple linear regression, it was possible to obtain fits of the experimental curves for testosterone and testosterone propionate in the various binary solvents and to express these in the form of regression equations. Certain parameters, mainly K and log alpha 2, were employed to define the regions of self-association, nonspecific solvation, specific solvation, and strong solvation or complexation.

Chemistry, Pharmaceutical↗
PubMed1981

Extended Hildebrand Solubility Approach: methylxanthines in mixed solvents.

The solubility profiles of theobromine, theophylline, and caffeine at 25 degrees were examined in binary solvent systems including dioxane-formamide, water-polyethylene glycol 400, and glycerin-propylene glycol. Theobromine solubility was studied in dioxane-water mixtures, a solvent system that was investigated earlier for the solubility of theophylline and caffeine. Solubilities were calculated in these polar systems by a regression method, based on an extension of the Hildebrand-Scatchard equation of regular solution theory. A linear relationship between the mixed solvent solubility parameter, and dielectric constant, epsilon, was introduced earlier and was confirmed in the present study. In addition, it was observed that a regression of log (activity coefficient) on epsilon in a second or higher degree polynomial provides reasonable solubility values for the methylxanthines in mixed solvents. A direct regression of molal or mole fraction (but not molar) solubility against delta 1, epsilon, or against volume percent of one or the other solvent in a binary solvent mixture provided a suitable measure of solubility for these crystalline drugs in mixed polar solvents. The drug's solubility parameter as determined from peak solubility in mixed polar solvents varied somewhat, depending on the specific solvent system employed. It is suggested that a drug may exhibit one (or more) solubility parameters in nonpolar solutions and multiple solubility parameters in polar systems. The extended solubility approach serves for the back-calculation of solubilities in mixed solvent systems, even though the solubility parameter of the solute may vary from one solvent system to the next.

Caffeine↗
PubMed1981

Extended Hansen solubility approach: naphthalene in individual solvents.

A multiple regression method using Hansen partial solubility parameters, delta D, delta p, and delta H, was used to reproduce the solubilities of naphthalene in pure polar and nonpolar solvents and to predict its solubility in untested solvents. The method, called the extended Hansen approach, was compared with the extended Hildebrand solubility approach and the universal-functional-group-activity-coefficient (UNIFAC) method. The Hildebrand regular solution theory was also used to calculate naphthalene solubility. Naphthalene, an aromatic molecule having no side chains or functional groups, is "well-behaved', i.e., its solubility in active solvents known to interact with drug molecules is fairly regular. Because of its simplicity, naphthalene is a suitable solute with which to initiate the difficult study of solubility phenomena. The three methods tested (Hildebrand regular solution theory was introduced only for comparison of solubilities in regular solution) yielded similar results, reproducing naphthalene solubilities within approximately 30% of literature values. In some cases, however, the error was considerably greater. The UNIFAC calculation is superior in that it requires only the solute's heat of fusion, the melting point, and a knowledge of chemical structures of solute and solvent. The extended Hansen and extended Hildebrand methods need experimental solubility data on which to carry out regression analysis. The extended Hansen approach was the method of second choice because of its adaptability to solutes and solvents from various classes. Sample calculations are included to illustrate methods of predicting solubilities in untested solvents at various temperatures. The UNIFAC method was successful in this regard.

Chemical Phenomena↗
PubMed1980

Extended Hildebrand solubility approach: solubility of theophylline in polar binary solvents.

A quantitative approach is presented for predicting solubilities of crystalline compounds in binary solvent systems. The solubility of theophylline in mixed solvents consisting of dioxane and water was determined at 25 +/- 0.1 degrees. The solubilities across this range of polar solvents were back-calculated using a technique involving an interaction energy term, W. This parameter is regressed against a polynomial expression in delta 1, the solubility parameter for the mixed solvents. Except for the end-points, solubilities were predicted within less than 12% and with considerably better accuracy in most cases. The new approach modifies the well-known Hildebrand solubility equation to make it applicable to polar systems. Although the method may be used with solutes in pure solvents, its greatest application appears to be the prediction of drug solubility in binary solvent mixtures.

Mathematics↗
PubMed1980

Extended Hildebrand approach: solubility of caffeine in dioxane-water mixtures.

The solubility of caffeine in various dioxane-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of the Hildebrand treatment for regular solutions. The solubility equation employs a term (W) to replace the geometric mean (c1c2)1/2, where c1 and c2 are the cohesive energy densities for the solvent and solute, respectively. The new equation provides an accurate prediction of solubility once the interaction energy, W, is obtained. In this case, the energy term is regressed against a polynomial in delta 1 of the binary mixture. A quartic expression of W in terms of the solvent solubility parameter was found for predicting the solubility of caffeine in dioxane-water mixtures. The expression yields an error in mole fraction solubility of less than 3%, a value approximating that of the experimentally determined solubility. The one exception to a good fit is near the maximum solubility, where a depression or valley occurs between the two peaks in solubility data; at this point, the theoretical equation predicts the solubility within approximately 9%. The new model also may be used to estimate the solubility of drug molecules employing the volume fraction of water in the solvent mixture instead of the composite solubility parameter, delta 1. The method has potential usefulness in preformulation and formulation studies during which solubility determination is important for drug design.

Caffeine↗