bluuebunny/crossref_metadata_2025_split huggingface dataset:
Muscle Relaxant Activity of Methocarbamol Enantiomers in Mice
Authors: Souri E , Sharifzadeh M , Farsam H , Gharavi N 
Published: July 2003

Abstract
Documented studies support the emerging idea that drug enantiomers could have different pharmacological activity. Our bibliographical data have shown that so far no report has been published on the pharmacological activity of individual enantiomers of methocarbamol.
This study was conducted to characterize the muscle relaxant activity of methocarbamol enantiomers. The rotarod test was used to compare the muscle relaxant activity of racemic methocarbamol and pure enantiomers after intraperitoneal administration of the enantiomers to mice.
The results show that (+)- R-methocarbamol has higher muscle relaxant activity compared with racemic methocarbamol or (-)- S-methocarbamol.
Effects of a Novel Pyridylsulphonyl Thiazole Derivative, FR115092, on Autoimmune and Mitomycin C-induced Thrombycytopenia in Mice
Authors: Nishigaki Fusako , Tsujimoto Susumu , Inami Masamichi , Matsumoto Sanae , Naoe Yoshinori , Kawamura Ikuo , Manda Toshitaka , Shimomura Kyoichi 
Published: July 2003

Abstract
Dapsone (4,4′-diaminodiphenyl sulphone), an antileprotic and antimalarial drug, has been reported to be of therapeutic benefit in idiopathic thrombocytopenic purpura in the clinic. However, adverse reactions such as haemolytic anaemia have often been observed. In this study, we found that dapsone increased the number of platelets and decreased the number of red blood cells in male (NZW × BXSB)F1 (W/BF1) mice, an animal model of idiopathic thrombocytopenic purpura. In studies to prepare derivatives of dapsone with weaker side effects than the parent compound, FR115092 (2-[5-(2-pyridylsulphonyl)thiazolyl]amine) was discovered. The effect of FR115092 on the number of blood cells was studied and compared with dapsone in mice.
FR115092 increased the number of platelets without reducing the number of red blood cells in W/BF1 mice. This drug significantly suppressed the increase in circulating autoantibodies against platelets and increased the number of megakaryocytes. Furthermore, FR115092 inhibited the reduction of the number of platelets in mitomycin C-induced thrombocytopenic mice, as a consequence of its enhancement of growth and maturation of megakaryocytes.
These findings suggest that FR115092 may be effective against various thrombocytopenias, without inducing haemolytic anaemia.
Oral Administration of Sepimostat Mesilate Prevents Acute Alcohol Pancreatic Injury in Rats
Authors: Yuasa Chie , Irimura Kenji , Oda Minoru , Fukui Kiyoshi , Oka Toshinori 
Published: July 2003

Abstract
The preventive effect of a novel synthetic serine protease inhibitor, sepimostat mesilate (sepimostat), on acute alcohol pancreatic injury, induced by exocrine hyperstimulation and ethanol administration, was assessed and compared with that of a similar protease inhibitor, camostat mesilate (camostat).
Conscious rats were infused with 1 μg mL−1 h−1 caerulein intravenously for 6 h and with 0.1g mL−1 h−1 ethanol for 9h, with the latter infusion beginning 3 h after the start of the caerulein infusion. Sepimostat or camostat was administered orally 1 h before the caerulein infusion.
Rats infused with caerulein plus ethanol showed increased plasma amylase and lipase activities, and aggravated pancreatic interstitial oedema when compared with rats given caerulein alone. Sepimostat at 10 and 30mgkg−1 prevented the increase in plasma amylase and lipase activities caused by caerulein plus ethanol infusion. Sepimostat at 30mg kg−1 suppressed the histological change. Camostat did not show any preventive effects at the equivalent dose. When conscious rats were infused with 1 μg mL−1h−1 caerulein alone intravenously for 6 h, plasma amylase and lipase activities were increased compared with rats given saline. Neither drug prevented the increase in these activities at 30mg kg−1.
Our results suggest that sepimostat has superior preventive effects on alcohol-induced acute pancreatic injury compared with camostat. Sepimostat may thus be a useful drug in the therapy of alcohol-induced pancreatitis.
A New HPLC Technique for the Separation of Methocarbamol Enantiomers
Authors: Farsam H , Souri E , Gharavi N 
Published: July 2003

Abstract
We have developed a stereoselective high-performance liquid chromatography technique for analytical separation of methocarbamol enantiomers.
Precolumn derivatization was performed at room temperature using (-)-menthylchloroformate as a chiral reagent in the presence of pyridine as catalyst. The resulting diastereomers were separated on two Resolve C18 columns connected in series. The mobile phase was phosphate buffer (pH 7.5)-acetonitrile (50: 50, v/v) at a flow rate of 1 mL min−1. UV detection was set at 274 nm.
The optimum amount of reagent and the maximum peak intensity of the diastereomers were determined. The resolution of the diastereomers was satisfactory (α = 1.04) under the conditions used.
Preparation, Relative Toxicity and Therapeutic Efficacy in Mice and Rats of Liposomal HA-1–92, a New Oxohexaene Polyene Macrolide Antibiotic
Authors: Harindran Jyoti , Chakraborty Kishor K , Naik Suresh R 
Published: July 2003

Abstract
HA-1–92, a new polyene oxohexaene macrolide antibiotic isolated from Streptomyces CDRIL-312, was incorporated into liposomes containing phosphotidyl choline and cholesterol.
The liposomal incorporated HA-1–92 considerably decreased toxicity when compared with free HA-1–92 in mice. Liposomal HA-1–92 showed improved pharmacokinetic profiles in rats. When administered to aspergillosis- and cryptococcosis-infected Balb/c mice, liposomal HA-1–92 showed increased antifungal activity, compared with free HA-1–92, with improved survival rate and decreased colony-forming units in lung, liver, spleen and kidney.
These results suggest that liposomal HA-1–92 is more effective than free HA-1–92 in controlling experimental aspergillosis and cryptococcosis in Balb/c mice.
Pharmacokinetics and Pharmacological Effect of Recombinant Human Granulocyte Colony-stimulating Factor Conjugated to Poly(styrene-co-maleic acid) in Rats
Authors: Kunimasa Jun-Ichi , Itoga Yoshie , Yasuhara Masato , Hori Ryohei , Inui Ken-Ichi 
Published: July 2003

Abstract
A new derivative of recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been synthesized by conjugating rhG-CSF to poly(styrene-co-maleic acid) (poly(styrene-co-maleic acid)-rhG-CSF) to try to avoid glomerular filtration and thus potentiate the neutrophil-proliferating activity of rhG-CSF.
Poly(styrene-co-maleic acid)-rhG-CSF was highly bound to bovine serum albumin (BSA) and the molecular weight of the poly(styrene-co-maleic acid)-rhG-CSF-BSA complex was estimated to be about 90 000 by gel filtration.
Intravenous administration of poly(styrene-co-maleic acid)-rhG-CSF to normal rats resulted in a dose-dependent increase in neutrophil count. The neutrophil-proliferating activity of poly(styrene-co-maleic acid)-rhG-CSF was about 10 times greater than that of rhG-CSF. After intravenous injection at a dose of 5 protein kg−1, the total clearance of rhG-CSF fell from 71.0 to 32.1mL h−1kg−1 following poly(styrene-co-maleic acid) modification. An isolated perfusion study in rat kidney showed that the filtered fraction of rhG-CSF was reduced by conjugation with poly(styrene-co-maleic acid).
These results suggest that poly(styrene-co-maleic acid)-conjugation can potentiate the neutrophil-proliferating activity of rhG-CSF by reducing, at least in part, its renal clearance.
Effect of Fatty acids on the Permeation of Melatonin across Rat and Pig Skin In-vitro and on the Transepidermal Water Loss in Rats In-vivo
Authors: Kandimalla K , Kanikkannan N , Andega S , Singh M 
Published: July 2003

Abstract
Transdermal delivery of melatonin would be advantageous in the treatment of sleep disorders considering the short biological half-life of melatonin and its variable bioavailability via the oral route. This study looked at suitable penetration enhancers for the transdermal permeation of melatonin.
The permeation of melatonin was enhanced by all saturated and unsaturated fatty acids across both rat and porcine skin. There was a parabolic relationship between the carbon chain length of saturated fatty acids and the enhancement of melatonin permeation across rat and porcine skin. For rat skin, the maximum flux was observed with undecanoic acid (45.33 μg cm−2h−1) which enhanced the flux of melatonin 8.6 times compared with the control, whereas lauric acid produced the maximum flux of melatonin (24.98 μg cm−2h−1; 4.7 times) across porcine skin. An increase in the number of double bonds in cis-9-octadecanoic acid increased the flux of melatonin across rat skin. In contrast, with porcine skin, the flux of melatonin decreased as the number of double bonds increased, although the flux values were not statistically significant. Treatment of rats with undecanoic acid, oleic acid and linolenic acid for 3 h using Hill top chamber enhanced the transepidermal water loss significantly. The maximum transepidermal water loss was observed with undecanoic acid and linolenic acid among saturated and unsaturated fatty acids, respectively. Nonanoic acid and myristic acid did not cause a significant change in the transepidermal water loss.
The enhancement effect of saturated fatty acids on the permeation of melatonin was dependent on the chain-length of the fatty acid in both rat and porcine skin. While an increase in the number of double bonds in the fatty acid increased the flux of melatonin in rat skin, no significant difference in the flux was observed with porcine skin. The permeation enhancement of melatonin by saturated and unsaturated fatty acids across rat skin was significantly higher than that of porcine skin. A positive correlation was observed between the permeation enhancement effect of the fatty acids across rat skin in-vitro and the transepidermal water loss in rats in-vivo, suggesting that there is a similarity in the mechanism by which fatty acids enhance the permeation of melatonin and in the enhancement of transepidermal water loss.
We conclude that saturated fatty acids such as undecanoic acid or lauric acid which showed maximum permeation across rat and porcine skin, respectively, may be used as potential penetration enhancers in the development of a transdermal delivery system for melatonin.
Cultured Rabbit Corneal Epithelium Elicits Levofloxacin Absorption and Secretion
Authors: Kawazu Kouichi , Midori Yukari , Ota Atsutoshi 
Published: July 2003

Abstract
Evidence for carrier-mediated transport of levofloxacin in the isolated rabbit cornea has been found. However, it is not known whether this mechanism is located in the epithelium or the endothelium. To resolve this question, we have measured the kinetics of levofloxacin uptake in primary cultures of rabbit corneal epithelial cells.
The results indicate that levofloxacin accumulation was time dependent and a steady state was reached after 30min. Maximal uptake occurred from a solution whose pH was 6.5. The uptake process was stereoselective and concentration dependent. In addition to the uptake, secretion of levofloxacin also occurred.
These results indicate that the corneal epithelium is the site of levofloxacin transport mechanisms, mediating both absorption and secretion.
Characterization of the Carrier-mediated Transport of Levofloxacin, a Fluoroquinolone Antimicrobial Agent, in Rabbit Cornea
Authors: Kawazu Kouichi , Midori Yukari , Shiono Hiromitsu , Ota Atsutoshi 
Published: July 2003

Abstract
The cornea presents a formidable barrier to drug penetration. The fluoroquinolone levofloxacin, which is an effective antimicrobial agent, has the potential to be used in the topical treatment of ocular disease. Thus, we sought to characterize how levofloxacin penetrates the cornea. To perform this characterization, we measured the time dependent permeation of levofloxacin across the isolated rabbit cornea using a diffusion chamber, and compared it with antipyrine fluxes.
Levofloxacin permeation into the receiver epithelial-side bathing solution (pH = 6.5) from the donor endothelial-side (pH = 7.4) reached 3.00nmol cm−2 cornea after 2h, whereas in the opposite direction permeation was 1.89nmol cm−2 cornea. Based on the temperature-dependent effects on permeation, the calculated energy of activation for permeation, Ea, was 31.3kcal mol−1, whereas Ea for antipyrine, a marker of diffusion, was 11.0kcal mol−1. The transport of levofloxacin from epithelium to endothelium was concentration-dependent and had both a linear and saturable component. Evaluation of the kinetic parameters, Jmax, apparent Km and kd showed that they were 38.78 pmol min−1 cm−2, 3.83 mM and 0.0135 μL min−1cm−2, respectively.
These results, coupled with the fact that levofloxacin permeation reached a maximum value at pH 6.5, suggest that levofloxacin transport across the cornea is carrier mediated. However, at present, it cannot be ascertained whether such a system is localized in either the corneal epithelial or the endothelial layer.
The Effect of Pregnenolone 16α-Carbonitrile on the Pharmacokinetics and Metabolism of Dapsone in Rats
Authors: Lu Ming , Poloyac Samuel M , Mcnamara Patrick J , Blouin Robert A 
Published: July 2003

Abstract
The purpose of this study was to evaluate the effect of pregnenolone 16α-carbonitrile (PCN) on the interconversion pharmacokinetics and metabolism of dapsone. To determine microsomal CYP3A activity and protein, eight rats (4 PCN, 4 corn oil) received a 1mg kg−1 intravenous bolus dose of dapsone, followed by blood and urine sampling. The formation clearance of dapsone hydroxylamine (CLf DDS-NOH) was calculated from the obtained samples. Interconversion pharmacokinetics estimates were obtained after 10 rats (5 PCN, 5 control) received 1mg kg−1 dapsone or 1.17 mg kg−1 monoacetyldapsone, with a 24-h wash-out.
Results from the interconversion analysis demonstrated that PCN significantly increased systemic clearance (CLs) of dapsone, but not its interconversion. The in-vivo/in-vitro correlation study demonstrated that PCN significantly increased CLs of dapsone (8.55 to 16.39mL min−1; P &lt;0.01) and CLf DDS-NOH (0.13 to 0.18mL min−1; P &lt; 0.01). PCN treatment produced a 69% increase in CYP3A protein, and increased 6β- and 2β-hydroxytestosterone formation rates. Significant correlations were found between CLf DDS-NOH and either 6β- (r2 = 0.925), 2β-hydroxytestosterone (r2 = 0.92), or CYP3A1/2 protein (r2 = 0.60).
We conclude that PCN treatment produces significant increases in CLs (dapsone) and CLf (DDS-NOH) in rats. These changes were not due to changes in the reversible metabolism of dapsone. These results suggest that the formation clearance of dapsone hydroxylamine reflects alterations in CYP3A activity, despite the fact that it accounted for a small part of the systemic clearance of dapsone.
Comparison of Cyclosporin A and Tacrolimus Concentrations in Whole Blood between Jejunal and Ileal Transplanted Rats
Authors: Ogino Yoshinori , Kobayashi Eiji , Fujimura Akio 
Published: July 2003

Abstract
Most immunosuppresive drugs are absorbed from the intestine after oral administration, although there is some difference of bioavailability between ileum and jejunum. Using an orthotopic segmental small bowel transplantation (SBT) model an rats, we studied the pharmacokinetic profiles of cyclosporin A and tacrolimus concentrations after oral intake, comparing jejunal and ileal transplanted rats.
Two types of segmental SBT (jejunal and ileal SBT) in a syngeneic combination were performed. After oral administration of cyclosporin A (10 mg kg−1) or tacrolimus (5 mg kg−1), pharmacokinetic data were obtained from the long-surviving rats transplanted with segmental SBT. To determine the effect of additional bile on cyclosporin absorption, an emulsion of cyclosporin A with fresh bile juice was re-challenged on segmental SBT rats before killing. A histological study was also performed by use of the intestinal grafts from the killed SBT rats.
A higher concentration of cyclosporin A was observed in the ileum-grafted rats than in the rats which received the jejunal grafts. Oral bioavailability of cyclosporin A in ileal SBT rats tended to be increased by addition of fresh bile juice, but that in jejunal SBT rats did not change. On the other hand, there was no significant difference of tacrolimus concentration between jejunum- and ileum-transplanted rats. Histological studies showed that the superficial mucosal layer of both grafts, but especially the ileal graft, was markedly elongated compared with that of normal intestine.
The present study showed that cyclosporin A was more actively absorbed from ileum than from jejunum in SBT, but tacrolimus was absorbed equally from both sites. These data suggest that cyclosporin A concentration is satisfactorily controlled in the segmental ileal graft, while there is no difference of tacrolimus absorption between ileal and jejunal graft.
The Mechanisms of Immune Suppression by High-pressure Stress in Mice
Authors: Fujiwara R , Shibata H , Komori T , Yokoyama M M , Okazaki Y , Ohmori M 
Published: July 2003

Abstract
The effects of high-pressure stress on the induction of anti-sheep red blood cells (SRBC) and of plaque-forming cells (PFC), and on thymus weight, were studied in BALB/c mice in-vivo and in-vitro.
The efficacy of high-pressure stress in suppressing PFC and thymic involution was maximum when the stress was applied 1 h day−1 for 2 days before immunization with SRBC. Both effects were blocked by administration of indomethacin, atropine, naloxone or phentolamine before the first application of stress, whereas hexamethonium and propranolol had no such effect. Hexamethonium, naloxone and propranolol administered before the second application of high-pressure stress blocked both effects. Prostaglandin and acetylcholine given 24 h before application of high-pressure stress caused a marked reduction in PFC count, but not in thymus weight. The reduced PFC count caused by acetylcholine was blocked by pretreatment with indomethacin. When adrenaline was injected 24 h after application of high-pressure stress a marked reduction in PFC was observed, but without thymic involution. When adrenaline was injected 24 h after prostaglandin injection the PFC count was also markedly reduced, but not thymus weight. The decrease in PFC caused by two exposures to stress or one exposure to stress plus injection of adrenaline was blocked by diethylcarbamazine before the second exposure to stress or the injection of adrenaline. In addition, normal spleen cells were induced as suppressor cells when incubated with the serum of stressed mice, but not when supplemented with anti-leukotriene C4, D4 antibody.
These data suggest that mice fall into a pre-stress condition via the release of prostaglandin after the first stress, and then immunosuppression is induced in these prestressed mice via the release of leukotriene C4, D4, caused by the activation of the autonomic nervous system by the second exposure to stress.
Time-dependent Striatal Dopamine Depletion after Injection of 6-Hydroxydopamine in the Rat. Comparison of Single Bilateral and Double Bilateral Lesions
Authors: Ben Valérie , Blin Olivier , Bruguerolle Bernard 
Published: July 2003

Abstract
For future investigation of possible perturbation of circadian rhythm in animal models of Parkinson's disease we needed an animal model providing lasting 80–100% striatal dopaminergic depletion in rats, but without induced mortality. We have thus compared the effects of a single hydroxydopamine bilateral striatal lesion (SB-hydroxydopamine) with those of a double hydroxydopamine bilateral lesion (DB-hydroxydopamine) at the same dose (16 μg/striatum) by HPLC determination of dopamine and 3,4-dihydrophenylacetic acid (dopac) levels in the striatum.
Two weeks after neurosurgery, SB-hydroxydopamine and DB-hydroxydopamine induced dopaminergic depletion of at least 81% compared with control groups. After eight weeks striatal dopaminergic depletion was only 60.97% in SB-hydroxydopamine rats, suggesting a compensatory phenomenon, whereas in DB-hydroxydopamine rats dopaminergic loss was stable at 88%. For the DB-hydroxydopamine group the dopac/dopamine ratio was significantly increased at week 2 only, whereas no significant change was observed for other groups. This increase might be explained by increased dopamine turnover.
We have demonstrated that striatal DB-hydroxydopamine injection induces lasting 80–100% neuronal loss, close to that observed in the disease in man, without induced mortality, and provides a tool which meets our experimental requirements.
Oestrogenic Compounds Modulate Cytokine-induced Nitric Oxide Production in Mouse Osteoblast-like Cells
Authors: Van Bezooijen Rutger L , Van Der Bent Chris , Papapoulos Socrates E , Lowik Clemens W G M 
Published: July 2003

AbstractNitric oxide (NO) is a mediator of bone metabolism with effects on both bone resorption and formation. Its production by both the constitutive and inducible isoforms of nitric oxide synthase (NOS) is affected by oestrogen in several types of cell and in tissues other than bone cells. Recently, oestrogens were found to increase basal NO production by osteoblasts via enhanced activity or expression, or both, of NOS-3. Inflammatory cytokines, however, increase NO by increasing the expression of NOS-2.In this study we have examined whether cytokine-induced NO production by osteoblastic cells was affected by oestrogenic compounds by studying the effect of 17β-oestradiol and the anti-oestrogens ICI164,384 and 4-hydroxytamoxifen on cytokine-induced NO production in oestrogen receptor positive MC3T3-E1 osteoblast-like cells. Combinations of the inflammatory cytokines interleukin-1β, tumour necrosis factor-α, and interferon-γ with lipopolysaccharide stimulated NO production up to 11-fold. This cytokine-induced NO production was further increased dose-dependently by the anti-oestrogens ICI164,384 and 4-hydroxytamoxifen (133.3±3.2% and 146.0±13.2%, respectively). 17β-Oestradiol either had no effect on or slightly inhibited cytokine-induced NO production. It did, however, dose-dependently counteract the stimulatory effect of the anti-oestrogens. Concentrations of 17β-oestradiol needed to prevent the stimulatory effect of 4-hydroxytamoxifen were ca tenfold that of ICI164,384.These findings show that, in addition to the stimulatory effect of oestrogen on basal NO production by NOS-3, cytokine-induced NO production is also affected by oestrogenic compounds in osteoblasts.