Biomedical subjects
Publications and source records attributed to W Paul.
A new method for the preparation of porous spherical hydroxyapatite granules is reported. It may be clinically applied towards orthopaedic or maxillofacial surgery as fillers or packing materials, and as biological chromatography supports. Its application towards delivery of macromolecules or protein drugs is discussed utilizing human serum albumin (HSA) as a model protein.
1. New Zealand White (NZW) rabbits were immunized within 24 h of birth with Alternaria tenuis in aluminium hydroxide (Al (OH)3) (i.p.) or sham immunized (saline plus Al (OH)3 i.p.) and subsequently injected with the allergen (i.p.) or sham-immunized for the next 3 months. At 3 months of age, baseline airway responsiveness was assessed using cyclo-pentyl adenosine (CPA). Bronchoalveolar lavage (BAL) was performed in all animals and samples of peripheral blood were collected from some animals for estimation of dexamethasone levels. In some animals, blood was collected at the end of the experiment and cellular function was assessed by measurement of ex vivo proliferation of mononuclear cells in response to phytohaemagglutinin (PHA). 2. Allergen immunization significantly increased baseline airway responsiveness to inhaled CPA (P<0.05) in comparison with sham-immunized animals, at 3 months after immunization. Dexamethasone (0.5 mg kg(-1) day(-1)) treatment for 1 month did not modify this established airway hyper-responsiveness to CPA. Dexamethasone treatment did not affect either total or differential cell numbers in BAL fluid during the 4 week period, although significant plasma levels of dexamethasone were achieved in dexamethasone treated animals. 3. Treatment of rabbits with dexamethasone (0.1 mg kg(-1) i.p.), 6 h prior to each allergen injection from the neonatal stage, significantly reduced baseline airway hyper-responsiveness to CPA measured at 3 months (P<0.05). There was no significant difference in either total or differential cell numbers in BAL fluid, or any difference in mitogen-induced proliferation of mononuclear cells between dexamethasone and vehicle treated rabbits. 4. These results suggest that introduction of glucocorticosteroids in early life can prevent baseline airway hyper-responsiveness to inhaled CPA in allergic rabbits. However, once established, such underlying airway hyper-responsiveness is difficult to resolve, even with prolonged treatment with glucocorticosteroids.
1. 111In-labelled platelets were monitored continuously in the cerebral and pulmonary vascular beds of anaesthetized rabbits. Dopamine can, depending upon the concentration, either potentiate or inhibit thrombin-induced platelet accumulation in the cerebral vasculature of rabbits by unknown mechanisms. The effects of specific adrenergic and dopaminergic receptor antagonists were tested upon dopamine's actions on intracarotid (i.c.) thrombin-induced (80 u kg-1) platelet accumulation in the cerebral vasculature. The effect of adrenaline on the response to thrombin in this vascular bed was also investigated. 2. Thrombin-induced platelet accumulation was significantly (P<0.01) potentiated by dopamine (100 microgkg-1 min-1, i.c.) and this effect was significantly inhibited by infusion of the alpha-adrenoceptor antagonist, phentolamine. 3 A higher dose of dopamine (2 mg kg-1 min-1, i.c.) inhibited thrombin-induced platelet accumulation. The beta-adrenoceptor antagonist, propranolol, did not significantly alter this inhibitory effect whereas it was abolished by the dopamine D1 selective antagonist, SCH23390. 4 Adrenaline (when administered i.c. by bolus injection or infusion) had no significant effect on thrombin-induced accumulation at any of the doses tested. 5 Potentiation of in vivo platelet accumulation by dopamine therefore seems to occur via alpha-adrenergic receptors. However, the inhibitory effect of dopamine appears to be exerted via the activation of dopamine D1 receptors and not via beta-adrenergic receptors. Our findings confirm that dopamine, but not adrenaline, can modify platelet function in the cerebral vasculature and these observations may have implications for current and potential therapeutic uses of dopamine and selective dopaminergic compounds.
In this work we present a Kramers potential study of the orientational dynamics and shear viscosity of short chain alkanes. In this approach the determination of the orientational relaxation time is reduced to the calculation of static moments of single chain conformations. We study a chemically realistic alkane model that asymptotically produces Gaussian chain conformations by means of a Monte Carlo simulation. Our results are applicable to single chain descriptions of polymer melt dynamics and to the intrinsic viscosity of molecules in a Theta solvent. When we map the unknown time unit of our relaxation time result for one particular chain length and temperature to the value obtained for the same parameters from a molecular dynamics simulation of a melt of these chains, we are able to reproduce the experimental data on the chain length dependence of the melt viscosity of alkane chains at this temperature.
Sustained intestinal delivery of drugs such as 5-fluorouracil (choice for colon carcinomas) and insulin (for diabetes mellitus) seems to be a feasible alternative to injection therapy. For successful therapy, the drug should be delivered at proper sites (here, the intestine) for long duration, for producing maximum pharmacological activity. We have attempted to develop a formulation that can bypass the acidity of the stomach and release the loaded drug for long periods into the intestine by using the bioadhesiveness of polyacrylic acid, alginate, and chitosan. Bromothymol blue was taken as a model drug. The formulation exhibited bioadhesive property and released the drug for an eight-day period in vitro.
Nitric oxide (NO) is a powerful vasodilator and an inhibitor of platelet aggregation in vitro. While the ability of NO to modulate vascular tone in vivo has been proven, only a few studies have assessed its platelet inhibitory activity in vivo. We have employed two complementary animal models of pulmonary platelet thromboembolism to assess the antithrombotic activity of endogenous NO in vivo. The inhibition of nitric oxide synthase (NOS) by L-NAME significantly potentiated while the administration of the NOS substrate L-arginine significantly reduced the accumulation of 111In-labelled platelets in the pulmonary vasculature of rabbits induced by intravenous collagen plus epinephrine. L-NAME or L-arginine did not, however, modify 111In-labelled erythrocyte distribution in lungs and phenylephrine had no effect on platelet accumulation following collagen + adrenaline, suggesting that the effects of L-NAME were not due to vasoconstriction but rather to a direct modification of platelet function. In mice, L-NAME significantly reduced the dose of collagen + adrenaline required to induce thromboembolic mortality, increased the fall in circulating platelets and increased the % of pulmonary vessels occluded by platelet thrombi. The effects of L-NAME were reversed by L-arginine but not by a dose of nicardipine exerting maximal vasodilatation. Phenylephrine did not potentiate collagen + adrenaline-induced mortality. In the pulmonary vasculature in vivo, endogenous NO inhibits collagen + adrenaline-induced aggregation and enhances platelet disaggregation. This natural modulator function of NO is exerted via a direct effect on platelets and not as a result of haemodynamic changes.
The rate of decline of plasma HIV RNA in patients treated with anti-retroviral drugs has been postulated to reflect the half-lives of previously HIV-infected cells. Here, Zvi Grossman and colleagues argue that the observed decline is explained by the kinetics of ongoing infection cycles. Residual cell-to-cell infection that becomes increasingly difficult to block could stabilize cellular provirus reservoirs.
Bioprosthetic heart valves made from glutaraldehyde (GA)-fixed porcine aortic valves or bovine pericardium (BP) are having some advantages over mechanical valves. However, their durability is low due to the calcification and immunological rejection. Study on immunogenicity is an important part in understanding the biocompatibility of materials. Polyethylene glycol (PEG) on pericardium can control biodegradation and calcification. Also, PEG exhibits low immunogenicity. We have studied the complement activation potential and the contribution of complement factors (biologic factors) on the calcification of PEG grafted pericardium samples and compared with standard (control) glutaraldehyde-treated pericardium samples. PEG-grafted BP activated using GA and carbodiimide (EDC) could be selected for further studies since complement activation and calcification observed on these samples has been relatively low.
Many drugs exist as asymmetric three-dimensional (chiral) molecules and will therefore have several stereoisomers. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between enantiomers. The choice between developing a racemate or single enantiomers depends on therapeutic advances and developmental costs involved. Regarding the target environment for drug intervention, even if natural physiological mediators are achiral, their receptors may demonstrate a preference for the (-)- or (+)-enantiomer of agonists or antagonists. It is also obvious that the majority of enzymes and channels are stereospecific, at least to a variable extent. From a pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. With a few exceptions, toxicological differences between isomers of known drugs are less dramatic than thought to be and only seldom substantiate the necessity of a racemic switch. The pharmaceutical industry is currently very interested in the so-called "racemic switch." Before proceeding to a racemic switch it is necessary to determine if 1) it is chemically feasible to produce a single enantiomer; 2) a clinical advantage is obtainable through a racemic switch; and 3) a marketing advantage is obtainable. The real goal of a racemic switch should be the rational development of compounds that are profitable for the company and--first of all--beneficial for the patient.
We have investigated the effects of L-arginine, D-arginine and L-lysine on airway smooth muscle responsiveness to spasmogens in vitro. Both L-arginine and D-arginine (100 mM) significantly reduced the contractile potency and maximal contractile response to histamine but not to methacholine or potassium chloride in guinea-pig epithelium-denuded isolated trachea. Similarly, the contractile response to histamine was significantly reduced by L-arginine (100 mM) in rabbit epithelium-denuded isolated bronchus. The amino acid L-lysine (100 mM) failed to significantly alter the contractile potency of histamine in guinea-pig isolated trachea (P > 0.05). In guinea-pig isolated trachea precontracted with histamine, both L-arginine and D-arginine produced a concentration-dependent relaxation which was not significantly altered by epithelium removal or by the presence of the nitric oxide synthase inhibitor, NG-nitro L-arginine methyl ester (L-NAME; 50 microM). Thus, at very high concentrations, arginine exhibit a non-competitive antagonism of histamine-induced contraction of isolated airway preparations that was independent of the generation of nitric oxide and was not dependent on charge. These observations confirm previous studies of cutaneous permeability responses and of contractile responses of guinea-pig isolated ileal smooth muscle. Taken together, the data suggest that high concentrations of arginine can exert an anti-histamine effect.
Plasma protein extravasation has been measured in guinea pig skin using 125I-albumin and blood flow using 133Xenon (133Xe) clearance. The nitric oxide (NO) synthase inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME), N(G)-monomethyl-L-arginine (l-NMMA) and N(G)-nitro-L-arginine (L-NOArg) and the alpha-adrenoceptor agonist, phenylephrine, inhibited bradykinin induced plasma protein extravasation when co-injected with the peptide. The inhibitory effects of L-NAME and L-NOArg lasted for up to 8 and 4 h, respectively, whereas phenylephrine and L-NMMA had no persistent inhibitory effects. When co-injected with 133Xe, L-NAME, L-NMMA, L-NOArg and phenylephrine, but not D-NAME, produced significant reductions in skin blood flow. When injected prior to 133Xe, L-NAME and L-NOArg, but not phenylephrine or L-NMMA, significantly reduced flow. The effect of L-NAME on flow was not significant at 8 h. Thus, although the inhibitory effects of the NO synthase inhibitors on mediator induced plasma protein extravasation show correlations with their effects on blood flow, the persistent effect of L-NAME on exudation appears to extend beyond its effect on flow.
1. A selection of novel compounds were shown to exhibit dopaminergic activity in vitro. 2. 111Indium-labelled platelets were continuously monitored in the cerebral and pulmonary vasculature of anaesthetized rabbits. The effects of dopamine and selective dopamine receptor agonists on ADP and thrombin induced platelet accumulation were recorded. 3. Pretreatment with dopamine (2 mg kg(-1) min(-1), i.v.) significantly reduced ADP (20 microg kg(-1), i.v.) induced platelet accumulation in the pulmonary vasculature whereas lower doses had no effect. 4. Dopamine (100 microg kg(-1) min(-1) intra-carotid, i.c.) potentiated thrombin (90 u kg(-1), i.c.) induced platelet accumulation in the cerebral vasculature whereas higher doses (1-2 mg kg(-1) min[-1]) inhibited accumulation. 5. The selective dopamine receptor agonists tested did not significantly inhibit platelet accumulation induced by ADP or thrombin. Two of these selective agonists, at doses higher than the intended therapeutic doses, induced thrombocytopaenia and an associated increase in platelet accumulation in the lung in response to thrombin. 6. These results extend previous in vitro studies regarding the dual actions of dopamine upon platelets and show for the first time the effects of selective dopamine receptor agonists upon platelet aggregation in vivo.
Membranes developed from poly(vinyl alcohol) (PVA) have superior permeability because of the highly hydrophilic character of PVA. However, its blood compatibility needs to be further improved. For this we have developed acetylsalicylic acid (ASA, aspirin) loaded PVA membranes. It seems that the slow release of aspirin from the membrane provides a surface concentration of aspirin sufficient for partially inhibiting platelet adhesion. PVA membrane with 531 micrograms cm-2 of ASA loaded, may be selected for hemodialysis applications. This may help to reduce the amount of heparin infused during hemodialysis, thereby reducing the side-effects associated with the systemic administration of heparin.
The study reported here originates from a county in California between Los Angeles and San Francisco. 658 mothers were tested over a 1-mo. period in June 1991 to ascertain the prevalence of drug misuse among pregnant women. 11% of the mothers tested positive for some type of substance. Of those substances found in the urine of the mothers who tested positive, the most prevalent were barbiturates, marijuana, methamphetamines, and amphetamines. When the multivariate analysis of logistic regression was performed with test results as the dependent variable, history of drug use was the most important factor related to mothers testing positive for drugs.
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Eosinophils are known to be present in the airways of allergic asthmatics, and have been suggested to contribute to the pathophysiological changes accompanying this condition, particularly hyperresponsiveness to airway spasmogens. However, a causal relationship between pulmonary eosinophil accumulation and bronchial hyperresponsiveness in asthma is not proven. In the present study, the time course of pulmonary cell influx was investigated in an immunized guinea-pig model. Eosinophil activation status was also determined together with the bronchial responsiveness to histamine. Guinea-pigs were sensitized [20 micrograms ovalbumin (OVA) per animal in A1(OH)3 (0.5 ml) i.p.] and subsequently challenged with aerosolized OVA (100 micrograms/ml) for 1 h 18-21 days later. At different time points (1 h to 72 h) after OVA challenge, bronchial responses to i.v. histamine were measured and bronchoalveolar lavage (BAL) was performed to assess pulmonary cell influx. Eosinophil peroxidase (EPO) and total protein levels were measured in BAL fluid supernatants. Exposure of sensitized animals to aerosolized OVA produced a significant increase (P < 0.05 vs. sham immunized) in eosinophil infiltration 24 h later which was sustained up to 72 h. Despite this, OVA challenge did not cause either eosinophil activation, as measured by EPO release, or bronchial hyperresponsiveness to histamine at any of the time points examined. These data show that allergen challenge of sensitized guinea-pigs can elicit airway eosinophil accumulation without accompanying airways hyperresponsiveness or eosinophil activation.
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