bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are we underestimating the clinical efficacy of botulinum toxin (type A)? Quantifying changes in spasticity, strength and upper limb function after injections of Botox® to the elbow flexors in a unilateral stroke population
Authors: Pandyan Anand D , Vuadens Philippe , van Wijck Frederike MJ , Stark Sandra , Johnson Garth R , Barnes Michael P 
Published: January 2003

Objective: To quantify the clinical efficacy of botulinum toxin type A in treating elbow flexor spasticity in a unilateral stroke population. Location: A spasticity clinic at a regional neurological rehabilitation centre. Study design: A convenience sample longitudinal study. Fourteen subjects with elbow flexor spasticity secondary to a stroke were recruited. Two repeated measures, one before and another four weeks after treatment, were taken to quantify clinical efficacy. Outcome measures: Elbow flexor spasticity was simultaneously rated with the modified Ashworth scale (MAS) and quantified by measuring the surface EMG from the flexors using a custom-built device. Strength at the elbow (isometric), grip strength and upper limb function (Action Research Arm test) were also assessed. Treatment: Injections of botulinum toxin type A (Botox®) to the m.biceps brachii (mean dose 70 U), m.brachioradialis (mean dose 56.5 U) and m.flexor digitorum longus (mean dose 83.3 U). Results: Following treatment, spasticity (as measured by flexor EMG activity) reduced but the MAS was unable to detect this improvement. In some subjects, isometric flexor strength at the elbow as well as grip strength increased. This was contrary to the expected weakening following treatment with botulinum toxin type A and suggests an optimization of motor control. Conclusion: Treatment with Botox® reduces spasticity but does not necessarily cause a reduction in the force generating capabilities at the joint. The improvement in strength may have contributed to the improvements in upper limb function. The MAS is an inappropriate measure of spasticity.
Physical training for intermittent claudication: a comparison of structured rehabilitation versus home-based training
Authors: Degischer Steve , Labs Karl-Heinz , Hochstrasser Jacques , Aschwanden Markus , Tschoepl Martin , Jaeger Kurt A 
Published: January 2003

In a non-randomized, open-label study results after a structured institution-based peripheral arterial occlusive disease (PAD) rehabilitation program were compared with the results of training at home. Three groups were compared: group 1 (n = 19) PAD rehabilitation; group 2 (n = 19) PAD rehabilitation + clopidogrel 75 mg once daily; group 3 (n = 21) home-based training. The training period was 3 months for all groups, which was followed by a 3-month observation phase (without prescribed training). The rehabilitation program consisted of 3 training hours per week. Background variables, demographics, and baseline claudication distances were comparable between groups. After 3 months of training the absolute claudication distances (ACD) improved by 82.7%, 131.4%, and 5.4% for groups 1, 2 and 3. The initial claudication distances (ICD) changed by 163.8%, 200.6%, and 44.4%, respectively. All changes, except the ACD result for group 3, were statistically significant (p 0.05). Structured training groups (1 and 2) performed significantly better than group 3 (p 0.05). When results from groups 1 and 2 were pooled, ACDs changed from 493.3 218.1 to 1026.0 468.9 m, 546.0 378.8 m [95% CI 417.8 - 674.2 m]; p 0.05. ICDs improved from 175.3 110.8 m to 493.1 326.7 m, 320.8 315.9 m [95% CI 213.9 - 427.7 m]; p 0.05. The difference between the pooled mean results of the structured training groups and the results of group 3 amounted to 474.3 m [95% CI 270.2 - 678.4 m] and 242.4 m [95% CI 99.0 - 385.7 m], for ACD and ICD, respectively. Structured, supervised PAD rehabilitation is a highly efficacious treatment for intermittent claudication and may be regarded as the present gold standard among conservative treatment options.
Poly(L-lysine) as a model drug macromolecule with which to investigate secondary structure and microporous membrane transport, part 2: diffusion studies
Authors: Chittchang Montakarn , Salamat-Miller Nazila , Alur Hemant H , Velde David G Vander , Mitra Ashim K , Johnston Thomas P 
Published: January 2003

Abstract
Peptide drugs are hydrophilic in nature and so their preferred pathway of membrane transport is by the paracellular route, which primarily involves passive diffusion across intercellular pores. The objective of the present study was to investigate the effect of secondary structure on the aqueous diffusion of a model polypeptide, poly(l-lysine), through a microporous membrane. The primary aim was to systematically evaluate the variables (e.g. viscosity and/or hydrodynamic radius) that may contribute to the difference, if any, in the calculated values of the aqueous diffusion coefficient (Daq) for each conformer of poly(l-lysine). Variations in pH and temperature of the medium were used to induce secondary structural changes in poly(l-lysine). Transport studies were conducted for 3 h at 25 or 37°C using side-by-side diffusion cells. Hydrophilic microporous polyester membranes with a 1-μm pore diameter were used to measure the free diffusion of each conformer. The values for the apparent permeability (Papp) and Daq were calculated using standard equations. The viscosity of each conformer solution was determined and the hydrodynamic radius of each conformer was then estimated. At 25°C, both Papp and Daq of the α-helix conformer were approximately the same as those of the random coil conformer. In contrast, at 37°C, the Papp and the Daq of the β-sheet conformer were significantly (P &lt; 0.05) less than those of the random coil conformer. At 25°C, the solutions containing primarily either the random coil or the α-helix conformers had approximately the same viscosity. On the other hand, at 37°C, the solutions containing the β-sheet conformer had a significantly (P &lt; 0.05) higher viscosity than when this conformer was absent. The random coil and the α-helix conformers appeared to have comparable sizes, whereas the hydrodynamic radius estimated for the β-sheet conformer was significantly (P &lt; 0.05) larger than those for the other two conformers. In summary, changing the secondary structure of poly(l-lysine) from the random coil to the α-helix did not affect its Papp and intrinsic Daq. On the other hand, appearance of the β-sheet conformer significantly decreased the values of Papp and Daq. The differences appeared to result from the significantly higher solution viscosity as well as the extended structure associated with the β-sheet conformer of poly(l-lysine). This strategy may represent a potential mechanism to sustain the delivery of therapeutic peptide drugs from a controlled drug delivery device.
Effects of histamine H2-receptor antagonists on human plasma levels of calcitonin gene-related peptide, substance P and vasoactive intestinal peptide
Authors: Itoh Hiroki , Naito Takafumi , Takeyama Masaharu 
Published: January 2003

Abstract
The effects of the histamine H2-receptor antagonists (H2-antagonists), ranitidine, nizatidine, cimetidine and famotidine, on plasma levels of gastrointestinal peptides, calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP) was investigated with respect to regulation of gastric mucosal blood flow, in healthy volunteers. H2-Antagonists or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after drug administration. The levels of plasma gastrointestinal peptides were determined by enzyme immunoassay. The administration of ranitidine and nizatidine caused significant increases in plasma CGRP and SP levels at 30 to 120 min compared with the placebo group. Peak plasma CGRP levels (39.8 ± 3.1 and 40.6 ± 3.6 pg mL−1) were achieved 60 min after administration of ranitidine and nizatidine, respectively. Maximum plasma SP levels (21.3 ± 5.2 and 22.8 ± 4.2 pg mL−1) were reached 60 min after administration of ranitidine and nizatidine, respectively. However, all H2-antagonists did not alter the levels of VIP. The released CGRP and SP by ranitidine and nizatidine administration may produce a gastroprotective effect, increase mucosal blood flow, and inhibit acid secretion in the gastrointestinal tract.
Antihypertensive, vasodilator and antioxidant effects of a vinifera grape skin extract
Authors: de Moura R Soares , Viana F S Costa , Souza M A V , Kovary K , Guedes D C , Oliveira E P B , Rubenich L M S , Carvalho L C R M , Oliveira R M , Tano T , Correia M L Gusmão 
Published: January 2003

Abstract
Cumulative evidence suggests that moderate wine consumption exerts a cardioprotective effect. We investigated the occurrence of an antihypertensive effect of an alcohol-free hydroalcoholic grape skin extract (GSE) obtained from skins of a vinifera grape (Vitis labrusca) in experimental rodent hypertension models. The vasodilator effect of GSE (polyphenols concentration 55.5 mg g−1) was also assessed in the isolated mesenteric vascular bed of Wistar rats and the antioxidant effect was studied on lipid peroxidation of hepatic microsomes. Oral administration of GSE significantly reduced systolic, mean and diastolic arterial pressure in Wistar rats with desoxycorticosterone acetate-salt and NG- nitro-L-arginine methyl ester (L-NAME) induced experimental hypertension. In the rat isolated mesenteric vascular bed pre-contracted with norepinephrine, bolus injections of GSE induced endothelium-dependent vasodilatation that was substantially inhibited by L-NAME, but not by indometacin, tetraethylammonium or glibenclamide. Lipid peroxidation of hepatic microsomes estimated as malondialdehyde production was concentration-dependently inhibited by GSE. In conclusion, the antihypertensive effect of GSE might be owing to a combination of vasodilator and antioxidant actions of GSE. These findings also suggest that the beneficial effect of moderate red wine consumption could be owing to an antihypertensive action induced by compounds occurring in the skin of vinifera grapes.
Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants
Authors: Daniel Wladysława A , Haduch A , Wójcikowski J 
Published: January 2003

Abstract
The aim of this study was to investigate the influence of tricyclic antidepressants (imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2D, measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg−1 i.p.; desipramine, fluoxetine, sertraline 5 mg kg−1 i.p.; mirtazapine 3 mg kg−1 i.p.), in the absence of the antidepressants in-vitro. Antidepressants decreased the activity of the rat CYP2D by competitive inhibition of the enzyme, the potency of their inhibitory effect being as follows: clomipramine (Ki = 14 μM) &gt; sertraline ≈ fluoxetine (Ki = 17 and 16 μM, respectively) &gt; imipramine ≈ amitriptyline (Ki = 26 and 25 μM, respectively) &gt; desipramine (Ki = 44 μM) &gt; nefazodone (Ki = 55 μM) &gt; mirtazapine (Ki = 107 μM). A one-day treatment with antidepressants caused a significant decrease in the CYP2D activity after imipramine, fluoxetine and sertraline. After prolonged administration of antidepressants, the decreased CYP2D activity produced by imipramine, fluoxetine and sertraline was still maintained. Moreover, amitriptyline and nefazodone significantly decreased, while mirtazapine increased the activity of the enzyme. Desipramine and clomipramine did not produce any effect when administered in-vivo. The obtained results indicate three different mechanisms of the antidepressants-CYP2D interaction: firstly, competitive inhibition of CYP2D shown in-vitro, the inhibitory effects of tricyclic antidepressants and SSRIs being stronger than those of novel drugs; secondly, in-vivo inhibition of CYP2D produced by both one-day and chronic treatment with tricyclic antidepressants (except for desipramine and clomipramine) and SSRIs, which suggests inactivation of the enzyme apoprotein by reactive metabolites; and thirdly, in-vivo inhibition by nefazodone and induction by mirtazapine of CYP2D produced only by chronic treatment with the drugs, which suggests their influence on the enzyme regulation.
Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations
Authors: Kressmann S , Biber A , Wonnemann M , Schug B , Blume H H , Müller W E 
Published: January 2003

Abstract
To be effective, herbal medicinal products are expected to meet comparable standards concerning the assessment of efficacy, safety and biopharmaceutical quality as chemically defined synthetic drugs as food supplements. However, these requirements are often not fulfilled, particularly regarding the characterization of biopharmaceutical properties such as in-vitro dissolution and in-vivo bioavailability. With respect to the relevance of biopharmaceutical quality of herbal medicinal products, two different Ginkgo biloba brands (test product: Ginkgo biloba capsules; reference product: Ginkgold) were analysed for dissolution rates and bioavailability of the most relevant active ingredients. Dissolution rates at pH 1 and 4.5 were determined according to the USP 23. The relative bioavailability of ginkgolide A, ginkgolide B and bilobalide was investigated after single oral administration of 120 mg Ginkgo biloba extract as tablets or capsules. Bioavailability data (area under the curve and peak concentration in plasma) were clearly different and did not show bioequivalence of test and reference products. The slow in-vitro dissolution of the test product resulted in a large decrease in bioavailability. These results indicate for the first time that the pharmaceutical properties of a herbal medicinal product have a significant impact on the rate and extent of drug absorption, and very likely on efficacy in humans.
Influence of hydroxypropyl-β-cyclodextrin on photo-induced free radical production by the sunscreen agent, butyl-methoxydibenzoylmethane
Authors: Scalia Santo , Simeoni Silvia , Barbieri Andrea , Sostero Silvana 
Published: January 2003

Abstract
The aim of the study was to investigate the effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) on the photo-induced production of free radicals by the sunscreen agent, butyl-methoxydibenzoylmethane (BMDBM). Spin-trapping/electron paramagnetic resonance spectroscopy was used to evaluate the formation of radicals and the extent of BMDBM photodegradation was measured by high-performance liquid chromatography. The stable 2,2,6,6-tetramethylpiperidine-1-oxyl, nitroxide radical (TEMPO) was used as spin-trap. Any free radicals generated during irradiation of the sunscreen agent will couple with the TEMPO radicals giving diamagnetic species and thus a decrease of the signal intensity in the electron paramagnetic resonance spectrum. Following 2-h illumination with simulated sunlight, the solution containing free BMDBM exhibited a 93.9% decrease of the intensity of the TEMPO signal. Under the same irradiation conditions, only a 12.2% reduction of the TEMPO concentration was measured in the sample containing BMDBM complexed with HP-β-CD. Moreover, the decrease of the spin-trap level observed for the HP-β-CD/BMDBM complex was not significantly different from that produced when solutions containing TEMPO only or TEMPO in the presence of HP- β-CD alone were subjected to irradiation. In addition, the photodegradation of the sunscreen agent was reduced by complexation with HP-β-CD (the extent of degradation was 27.6% for the complex compared with 63.1% for free BMDBM). The results obtained indicate that the free radicals generated by BMDBM when exposed to simulated sunlight are effectively scavenged by inclusion complexation of the sunscreen agent with HP-β-CD.
Solubilization of the lichen metabolite (+)-usnic acid for testing in tissue culture
Authors: Kristmundsdóttir Thórdís , Aradóttir Halldóra Aesa , Ingólfsdóttir Kristín , Ögmundsdóttir Helga M 
Published: January 2003

Abstract
The pharmacological testing of natural products can often be hampered by the poor solubility of such compounds in non-toxic solvents. There is thus a need for a suitable agent for solubilization of natural substances to allow testing on a variety of cell lines in-vitro. Such an agent should ideally have no direct effects on any of the commonly used cell lines from a variety of tissues and mammalian species to allow proper comparison. In this study, the lichen metabolite (+)-usnic acid, a dibenzofuran derivative, was used as a prototype for an insoluble natural product with the aim of finding a solvent that was both capable of solubilizing usnic acid and was free of direct activity against a test cell line. Solubilization was measured at different pH values in various concentrations of co-solvents (glycofurol 75, propylene glycol, polyethylene glycol 400), surfactants (polysorbate 20 and Cremophor RH40), and the complexing agent 2-hydroxypropyl-β-cyclodextrin. The solubility achieved in a 20% aqueous solution was 0.11 mg mL−1 for propylene glycol, 0.19 for PEG 400, 0.27 for glycofurol 75, 0.57 for Cremophor RH40, 0.68 for 2-hydroxypropyl-β-cyclodextrin and 0.84 for polysorbate 20. The direct effects of the various solvent systems were tested on the human leukaemia cell line K-562 in a standard proliferation assay. Most of the solvents proved toxic with the exception of propylene glycol, PEG 400 and 2-hydroxypropyl-β-cyclodextrin. Anti-proliferative activity of usnic acid could be demonstrated with an ED50 (amount of substance required to reduce thymidine uptake to 50% of uptake by untreated control culture) of 4.7μg mL−1 using PEG 400 and 2-hydroxypropyl-β-cyclodextrin but only the latter gave satisfactory solubility. 2-Hydroxypropyl-β-cyclodextrin was thus identified as a solubilizing agent that fulfilled both set criteria of solubility and lack of toxicity against the test cells.
Radioprotection: the non-steroidal anti-inflammatory drugs (NSAIDs) and prostaglandins
Authors: Lee Tat Khuen , Stupans Ieva 
Published: January 2003

Abstract
Clinical and experimental studies of the acute and late effects of radiation on cells have enhanced our knowledge of radiotherapy and have led to the optimisation of radiation treatment schedules and to more precise modes of radiation delivery. However, as both normal and cancerous tissues have similar response to radiation exposure, radiation-induced injury on normal tissues may present either during, or after the completion of, the radiotherapy treatment. Studies on both NSAIDs and prostaglandins have indeed shown some evidence of radioprotection. Both have the potential to increase the survival of cells but by entirely different mechanisms. Studies of cell kinetics reveal that cells in the mitotic (M) and late G2 phases of the cell cycle are generally most sensitive to radiation compared with cells in the early S and G1/G0 phases. Furthermore, radiation leads to a mitotic delay in the cell cycle. Thus, chemical agents that either limit the proportion of cells in the M and G2 phases of the cell cycle or enhance rapid cell growth could in principle be exploited for their potential use as radioprotectors to normal tissue during irradiation. NSAIDs have been shown to exert anti-cancer effects by causing cell-cycle arrest, shifting cells towards a quiescence state (G0/G1). The same mechanism of action was observed in radioprotection of normal tissues. An increase in arachidonic acid concentrations after exposure to NSAIDs also leads to the production of an apoptosis-inducer ceramide. NSAIDs also elevate the level of superoxide dismutase in cells. Activation of heat shock proteins by NSAIDs increases cell survival by alteration of cytokine expression. A role for NSAIDs with respect to inhibition of cellular proliferation possibly by an anti-angiogenesis mechanism has also been suggested. Several in-vivo studies have provided evidence suggesting that NSAIDs may protect normal tissues from radiation injury. Prostaglandins do not regulate the cell cycle, but they do have a variety of effects on cell growth and differentiation. PGE2 mediates angiogenesis, increasing the supply of oxygen and nutrients, essential for cellular survival and growth. Accordingly, PGE2 at sufficiently high plasma concentrations enhances cellular survival by inhibiting pro-inflammatory cytokines such as TNF-α and IL-1β. Thus, PGE2 acts as a modulator, rather than a mediator, of inflammation. Prospective studies have suggested the potential use of misoprostol, a PGE1 analogue, before irradiation, in prevention of radiation-induced side effects. The current understanding of the pharmacology of NSAIDs and prostaglandins shows great potential to minimise the adverse effects of radiotherapy on normal tissue.
Effect of gentamicin on pharmacokinetics of lysozyme in rats: interaction between megalin substrates in the kidney
Authors: Nagai Junya , Katsube Takayuki , Murakami Teruo , Takano Mikihisa 
Published: January 2003

Abstract
To investigate the pharmacokinetic interaction between substrates of megalin, a 600-kDa endocytic receptor abundantly expressed in the renal proximal tubules, we examined the effect of gentamicin infusion on the pharmacokinetics of fluorescein isothiocyanate (FITC)-lysozyme in rats. Infusion of gentamicin did not affect the plasma concentration-time profile of FITC-lysozyme. On the other hand, gentamicin significantly decreased the accumulation of FITC-lysozyme in the renal cortex and medulla, whereas the accumulation in the renal papilla, liver, brain and lung was not changed. Urinary excretion of FITC-lysozyme was increased by gentamicin, whereas there was no change in the biliary excretion of FITC-lysozyme or its degradation products. Gentamicin infusion had little influence on the ATP content in the renal cortex and urinary excretion of glucose, indicating that nephrotoxicity is not induced by short-term infusion of gentamicin. These findings suggest that lysozyme and gentamicin interact with each other in their reabsorption processes in the renal proximal tubules, probably by competing for their binding to megalin expressed in the apical membrane of the renal proximal tubules.
Physically cross-linked chitosan hydrogels as topical vehicles for hydrophilic drugs
Authors: Cerchiara T , Luppi B , Bigucci F , Orienti I , Zecchi V 
Published: January 2003

Abstract
Physically cross-linked chitosan hydrogels with lauric, myristic, palmitic or stearic acid were prepared by freeze-drying and have been studied for topical use. This study selected propranolol hydrochloride as a hydrophilic model drug to design a transdermal delivery system. We evaluated the effect of the nature of the cross-linker on drug permeation through porcine skin and the main permeation parameters (diffusion coefficient, flux and lag time) were calculated. All the chitosan hydrogels analysed provided more transcutaneous permeation of propranolol hydrochloride than the corresponding solution of the commercial drug. Among the different chitosan vehicles, chitosan-laurate and chitosan-myristate hydrogels enhanced lyophilised drug diffusion through the skin with respect to chitosan-palmitate and chitosan-stearate hydrogels. This can been explained by the interaction of the hydrogels with the stratum corneum, increasing the solubility of the drug in the skin.