bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic-pharmacodynamic modelling of human insulin: validity of pharmacological availability as a substitute for extent of bioavailability
Authors: Miyazaki Makoto , Mukai Haruko , Iwanaga Kazunori , Morimoto Kazuhiro , Kakemi Masawo 
Published: July 2003

Abstract
A method for assessing the extent of bioavailability (EBA) of human insulin from pharmacological data was determined. The time course governing increases in the plasma concentration of immuno-reactive insulin (IRI), as well as its pharmacological effects (glucodynamics), was determined after the intravascular administration of varying doses of human insulin. Pharmacokinetic (PK), pharmacodynamic (PD), and link models were constructed to elucidate the quantitative relationship between plasma IRI levels and pharmacological effects. After extravascular administration of the test formulation, only the time course governing the observed pharmacological effects was determined. The pharmacological data was translated into theoretical plasma concentration data, using the PK-PD model. Following this, the area under the theoretical plasma concentration-time curve (AUC) of the test formulation was calculated. The EBA was then estimated against a reference (intravascular) formulation, using a conventional equation. Since the pharmacological effects of insulin were observed to be highly dosing-rate-dependent, the PD model used in this study was modified to apply over a wide range of infusion rates. The results of the PK-PD analysis indicate that the doses administered can be accurately predicted from pharmacological data. To validate this method, the EBAs of controlled release formulations (the Osmotic Mini Pumps) of insulin, subcutaneously administered to the rat, were estimated. The EBA values obtained (92–96%) fell within a reasonable range. The area under the effect-time curves (AUE) obtained following subcutaneous applications of the Osmotic Mini Pump were calculated in a model-independent manner, in addition to pharmacological availabilities (PA), which were estimated against the reference (intravascular) formulations. The estimated PA values varied from 312% to 78%, in accordance with the intravascular input rates of the reference formulations. This indicates that PA should not be used as a substitute for EBA, unless data involving similar intravascular dosing rates to that of the reference formulations is available.
Effect of some hexahydroimidazo[1,2-c]pyrimidines in inflammatory responses involving leucocytes and macrophages
Authors: Vidal A , Ferrándiz M L , Ubeda A , Acero-Alarcon A , Sepulveda-Arques J , Alcaraz M J 
Published: July 2003

Abstract
We have studied the effects of some hexahydroimidazo[1,2-c]pyrimidine derivatives (HIPs) on leucocyte functions in-vitro and we have assayed the anti-inflammatory activity of these compounds in two models of inflammation. All HIPs inhibited the human neutrophil degranulation process and superoxide generation at concentrations in the μM range. In mouse peritoneal macrophages stimulated with lipopolysaccharide, HIP-4 and HIP-5 inhibited nitrite production without affecting prostaglandin E2 (PGE2) accumulation. HIP-4 was also active in the zymosan-injected mouse air pouch model (at 100 nmol/pouch), with significant reductions in leucocyte migration and PGE2 and leukotriene B4 levels in the air pouch exudate. To confirm the anti-inflammatory effects of this compound, we tested HIP-4 orally (10–40 mg kg−1) on carrageenan mouse-paw oedema where it exerted a dose-dependent inhibition of paw swelling with significant reductions of myeloperoxidase and elastase activity and PGE2 levels in paw homogenates. This study demonstrates that some HIPs inhibit leucocyte functions and one of these derivatives (HIP-4) shows anti-inflammatory activity when administered by the oral route, which can be related to inhibition of leucocyte migration.
Role of intracellular calcium in the spermicidal action of 2‘,4’-dichlorobenzamil, a novel contact spermicide
Authors: Patni Anil K , Gupta Sunil , Sharma Ajay , Tiwary Ashok K , Garg Santosh K 
Published: July 2003

Abstract
The Na+-Ca2+ exchanger and Ca2+-ATPase pumps reported to be present on the sperm membrane are responsible for maintaining the intracellular Ca2+ concentration that is involved in regulation of sperm function. We have investigated the role of intracellular Ca2+ in the presence of 2′,4′-dichlorobenzamil hydrochloride (benzamil), a Na+-Ca2+ exchange inhibitor, on human sperm motility. The mechanism of the complementary spermicidal action produced by a combination of benzamil and propranolol on human spermatozoa has been investigated also. When administered alone benzamil and propranolol produced a dose- and time-dependent decrease in motility of sperm in ejaculated semen and spermatozoa separated from semen. A combination of benzamil and propranolol exhibited a complementary spermicidal action, thereby resulting in dose reduction of both drugs for obtaining total immotility within 1 min of administration. An increase in the intracellular Ca2+ level was found to contribute to the spermicidal activity. Inhibition of the Na+-Ca2+ exchange system on sperm membrane by benzamil and membrane stabilization by propranolol resulted in accumulation of Ca2+ inside the sperm cells. When the two drugs were used in combination the time required for the total loss of motility of spermatozoa was significantly reduced due to a similar mechanism of action of both drugs.
Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrrioxamine (desferoxamine) in rat liver homogenates
Authors: Gitto Eloisa , Tan Dun-Xian , Reiter Russel J , Karbownik Malgorzata , Manchester Lucien C , Cuzzocrea Salvatore , Fulia Francesco , Barberi Ignazio 
Published: July 2003

Abstract
The pharmacological effects of melatonin, vitamin E, vitamin C, glutathione and desferrioxamine (desferoxamine) alone and in combination on iron-induced membrane lipid damage in rat liver homogenates were examined by estimating levels of malondialdehyde and 4-hydroxyalkenals (MDA + 4-HDA). Individually, melatonin (2.5–1600 μM), vitamin E (0.5–50 μM), glutathione (100–7000 μM) and desferrioxamine (1–8 μM) inhibited lipid peroxidation in a concentration-dependent manner. Vitamin C had both a pro-oxidative (25–2000 μM) and an antioxidative (2600–5000 μM) effect. The IC50 (concentration that reduces damage by 50%) values were 4, 10, 426, 2290 and 4325 μM for vitamin E, desferrioxamine, melatonin, glutathione and vitamin C, respectively. The synergistic actions of melatonin with vitamin C, vitamin E, and glutathione were systematically investigated. When melatonin was combined with vitamin E, glutathione, or vitamin C, the protective effects against iron-induced lipid peroxidation were dramatically enhanced. Even though melatonin was added at very low concentrations, it still showed synergistic effects with other antioxidants at certain concentrations. Furthermore, melatonin not only reversed the pro-oxidative effects of vitamin C, but its efficacy in reducing lipid peroxidation was improved when it was combined with prooxidative concentrations of vitamin C. The results provide new information in terms of the possible pharmacological use of the combination of melatonin and classical antioxidants to treat free radical-related conditions.
Responsiveness, affinity constants and receptor reserves for serotonin on aortae of aged normotensive and hypertensive rats
Authors: Doggrell Sheila A , Chen Ying-yu 
Published: July 2003

Abstract
We have previously shown that the potency and affinity constants (KA values) for serotonin (5-HT) are greater, and the 5-HT2A-receptor reserve is lesser, on the aorta of 6-month-old spontaneously hypertensive rats (SHRs) compared with age-matched Wistar Kyoto normotensive (WKY) rats. The present study was undertaken to investigate whether these parameters are altered on the aorta with ageing and as hypertension progresses to heart failure. The effects of phenoxybenzamine on the serotonergic responses of the aortae of 24-month-old WKY rats and SHRs were determined. On WKY rat aorta, ageing from 6 to 24 months was associated with an increase in sensitivity and affinity for serotonin, and a loss of 5-HT2A-receptor reserve. On SHR aorta, ageing from 6 to 24 months was also associated with an increase in sensitivity and affinity for serotonin, but a loss of 5-HT2A-receptor reserve. The sensitivity to serotonin was greater on the 24-month-old SHR aorta (pD2 6.53) than age-matched WKY rat aorta (pD2 5.89). On the aorta of the 24-month-old WKY rats, the KA value for serotonin was 4.5 times 10−6 M, and the receptor occupancies required for 20 and 50% maximum responses were 12 and 29%, respectively. There was a similar affinity, but greater receptor reserves, for serotonin on the aorta of age-matched SHRs. In summary, we have shown changes in sensitivity, affinity and 5-HT2A-receptor reserves for serotonin on the aorta with ageing and in hypertension/heart failure.
Synthesis of new arylaminoquinoxalines and their antimalarial activity in mice
Authors: Rangisetty J B , Gupta C N V H B , Prasad A L , Srinivas P , Sridhar N , Parimoo P , Veeranjaneyulu A 
Published: July 2003

Abstract
2-Arylaminoquinoxalines were prepared by the condensation of 2-chloroquinoxaline with the appropriate Mannich bases in the presence of HCl. To synthesize the Mannich bases, 4-acetamidophenol was reacted with formaldehyde and dialkylamine to yield 3-[(dialkylamino) methyl]-4-hydroxyacetanilide, followed by hydrolysis. Antimalarial activities of the new arylaminoquinoxalines were evaluated against the rodent malaria parasite Plasmodium yoelii at a dose of 75 mg kg−1. Three compounds synthesized (2-[3-[(diethylamino) methyl]-4-hydroxy-anilino]-quinoxaline dihydrochloride (2b), 2-[3-[(pyrrolidinyl) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2f), and 2-[3-[(piperidinyl) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2g)) showed moderate antimalarial activity.
Spray-dried insulin particles retain biological activity in rapid in-vitro assay
Authors: Patel Neha , Craddock Bridget L , Staniforth John N , Tobyn Michael J , Welham Melanie J 
Published: July 2003

Abstract
The purpose of this study was to rapidly determine, without the use of extensive animal studies, whether biological activity is retained after spray drying insulin with two excipients, lactose and xanthan gum. This was achieved by the detection of protein kinase B (PKB), which is activated by phosphorylation in response to insulin binding to cellular receptors. A myeloid cell line was cultured and stimulated with the reconstituted insulin powders. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was then utilised to allow in-vitro detection of phosphorylated PKB using an anti-phospho-PKB antibody. A single band specific to phosphorylated PKB was found on the Western blots, indicating that the active conformation of insulin was retained when spray dried in combination with lactose and with xanthan gum over the spray-drying inlet temperature range of 110–170°C. Evidence of inactivation/denaturation was observed when insulin was spray dried at an inlet temperature of 200°C. The assay may be of use as a more rapid and economic means to screen insulin formulations for inhalation and other purposes as opposed to conventional monitoring of blood glucose levels in animals.
Rectal antinociceptive properties of alverine citrate are linked to antagonism at the 5-HT1A receptor subtype
Authors: Coelho Anne-Marie , Jacob Luc , Fioramonti Jean , Bueno Lionel 
Published: July 2003

Abstract
Serotonin (5-HT) is considered as a major mediator causing hyperalgesia and is involved in inflammatory reactions and irritable bowel syndrome. Alverine citrate may possess visceral antinociceptive properties in a rat model of rectal distension-induced abdominal contractions. This study was designed to evaluate the pharmacological properties of alverine citrate in a rat model of rectal hyperalgesia induced by 5-HTP (5-HT precursor) and by a selective 5-HT1A agonist (8-OH-DPAT) and to compare this activity with a reference 5-HT1A antagonist (WAY 100635). At 4 h after their administration, 5-HTP and 8-OH-DPAT increased the number of abdominal contractions in response to rectal distension at the lowest volume of distension (0.4 mL). When injected intraperitoneally before 8-OH-DPAT and 5-HTP, WAY 100635 (1 mg kg−1) blocked their nociceptive effect, but also reduced the response to the highest volume of distension (1.6 mL). Similarly, when injected intraperitoneally, alverine citrate (20 mg kg−1) suppressed the effect of 5-HTP, but not that of 8-OH-DPAT. However, when injected intracerebroventricularly (75 μg/rat) alverine citrate reduced 8-OH-DPAT-induced enhancement of rectal distension-induced abdominal contractions. In-vitro binding studies revealed that alverine citrate had a high affinity for 5-HT1A receptors and a weak affinity for 5-HT3 and 5-HT4 subtypes. These results suggest that 5-HTP-induced rectal hypersensitivity involves 5-TH1A receptors and that alverine citrate acts as a selective antagonist at the 5-HT1A receptor subtype to block both 5-HTP and 8-OH-DPAT-induced rectal hypersensitivity.
Human lactoferrin: a novel therapeutic with broad spectrum potential
Authors: Weinberg Eugene D 
Published: July 2003

Abstract
Lactoferrin (Lf), a natural defence iron-binding protein, has been found to possess antibacterial, antimycotic, antiviral, antineoplastic and anti-inflammatory activity. The protein is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervico—vaginal mucus and seminal fluid. Additionally, Lf is a major constituent of the secondary specific granules of circulating polymorphonuclear neutrophils (PMNs). The apoprotein is released on degranulation of the PMNs in septic areas. A principal function of Lf is that of scavenging free iron in fluids and inflamed areas so as to suppress free radical-mediated damage and decrease the availability of the metal to invading microbial and neoplastic cells. Mechanisms of action of Lf in addition to iron deprivation are also described. Administration of exogenous human or bovine Lf to hosts with various infected or inflamed sites has resulted in some prophylactic or therapeutic effects. However, an adverse response to the protein might occur if it were to stimulate antibody production or if it were to provide iron to the invading pathogen. The recombinant form of human Lf has become available and development of the product for use in a wide range of medical conditions can now be anticipated.
Skin hydration and possible shunt route penetration in controlled estradiol delivery from ultradeformable and standard liposomes
Authors: El Maghraby Gamal M M , Williams Adrian C , Barry Brian W 
Published: July 2003

Abstract
Human skin delivery of estradiol from ultradeformable and traditional liposomes was explored, comparing occlusive and open application, with the aim of examining the role of skin hydration. Partially hydrated epidermis was used for open hydration, but fully hydrated membranes were used for occluded studies. In addition, we developed a novel technique to investigate the role of shunt route penetration in skin delivery of liposomal estradiol. This compared delivery through epidermis with that through a stratum corneum (SC)/epidermis sandwich from the same skin with the additional SC forming the top layer of the sandwich. This design was based on the fact that orifices of shunts only occupy 0.1% of skin surface area and thus for SC/epidermis sandwiches there will be a negligible chance for shunts to superimpose. The top SC thus blocks most shunts available on the bottom membrane. If shunts play a major role then the delivery through sandwiches should be much reduced compared with that through epidermis, taking into consideration the expected reduction owing to increased membrane thickness. After open application, both ultradeformable and traditional liposomes improved estradiol skin delivery, with the ultradeformable liposomes being superior. Occlusion reduced the delivering efficiency of both vesicle types, supporting the theory that a hydration gradient provides the driving force. Shunt route penetration was found to play only a very minor role in liposomal delivery. In conclusion, full hydration of skin reduces estradiol delivery from liposomes and the shunt route is not the main pathway for this delivery.
Effect of herbal teas on hepatic drug metabolizing enzymes in rats
Authors: Maliakal Pius P , Wanwimolruk Sompon 
Published: July 2003

Abstract
We have investigated the effect of herbal teas (peppermint, chamomile and dandelion) on the activity of hepatic phase I and phase II metabolizing enzymes using rat liver microsomes. Female Wistar rats were divided into six groups (n = 5 each). Three groups had free access to a tea solution (2 %) while the control group had water. Two groups received either green tea extract (0.1 %) or aqueous caffeine solution (0.0625 %). After four weeks of pretreatment, different cytochrome P450 (CYP) isoforms and phase II enzyme activities were determined by incubation of liver microsomes or cytosol with appropriate substrates. Activity of CYP1A2 in the liver microsomes of rats receiving dandelion, peppermint or chamomile tea was significantly decreased (P &lt; 0.05) to 15 %, 24 % and 39 % of the control value, respectively. CYP1A2 activity was significantly increased by pretreatment with caffeine solution. No alterations were observed in the activities of CYP2D and CYP3A in any group of the pretreated rats. Activity of CYP2E in rats receiving dandelion or peppermint tea was significantly lower than in the control group, 48 % and 60 % of the control, respectively. There was a dramatic increase (244 % of control) in the activity of phase II detoxifying enzyme UDP-glucuronosyl transferase in the dandelion tea-pretreated group. There was no change in the activity of glutathione-S-transferase. The results suggested that, like green and black teas, certain herbal teas can cause modulation of phase I and phase II drug metabolizing enzymes.
Pharmacokinetic behaviour of cisplatin in peritoneal fluid after intraperitoneal administration of cisplatin-loaded microspheres
Authors: Tamura Takshi , Imai Jun , Matsukawa Yasuhisa , Horikiri Yuji , Suzuki Takehiko , Yoshino Hiroyuki , Ike Osamu 
Published: July 2003

Abstract
The objective of this study was to establish a pharmacokinetic model for the estimation of unchanged cis-dichlorodiammine-platinum (II) (CDDP) concentration in peritoneal fluid after intraperitoneal administration of cisplatin-loaded microspheres (CDDP-MS) and to elucidate the accuracy of this model by comparisons between actual and simulated values after intraperitoneal administration of CDDP-MS. We developed a method enabling the precise and quick assessment of the drug concentration in the peritoneal cavity. The pharmacokinetic parameters obtained after intravenous bolus injection at a dose of 2 mg kg−1 were total body clearance (1026 mL h−1 kg−1), elimination rate constant (3.24 h−1) and distribution volume of systemic circulation (316.7 mL kg−1). After an intraperitoneal bolus injection at a dose of 5 mg kg−1, the absorption rate constant from the peritoneal cavity (3.64 h−1) and the distribution volume of the peritoneal cavity (13.5 mL kg−1) were determined. The protein-binding rate constant in ascites was 0.58 h−1. Using these pharmacokinetic parameters, we established a pharmacokinetic model consisting of two compartments. Administration of CDDP-MS at a dose of 10 mg kg−1, which released CDDP over 7 days in-vitro, yielded sustained concentrations of unchanged CDDP (1–2 mg mL−1) in the peritoneal cavity that persisted for 7 days, and that were predictable by applying the in-vitro dissolution profile to the pharmacokinetic model. The findings obtained from this study are useful for understanding the basic pharmacokinetic characteristics of unchanged CDDP in the peritoneal cavity and may also be important in the development of optimized CDDP-MS formulations.
Effect of instillation method on the absorption of phenolsulphonphthalein as a model drug from the liver and small intestinal serosal surface in rats
Authors: Nishida Koyo , Yoshida Yayoi , Mukai Takahiro , Kawakami Shigeru , Sakaeda Toshiyuki , Nakashima Mikiro , Sasaki Hitoshi , Nakamura Junzo 
Published: July 2003

Abstract
We have examined the effect of the instillation method on the absorption of a drug from the liver and the small intestinal serosal surface in rats. We performed continuous microinstillation via an infusion pump and bolus instillation via a syringe, using phenolsulphonphthalein (phenol red) as the model drug. After continuous microinstillation of phenolsulphonphthalein 2.35 mg in 235 μL for 5 min on the liver and small intestinal serosal surface in rats, the AUC (area under the curve) of the plasma concentration profile up to 60 min was significantly higher compared with bolus instillation. A similar trend was observed after continuous microinstillation of phenolsulphonphthalein 2.35 mg in 117.5 μL for 2.5 min. The calculated absorption rate constants (Ka) after continuous microinstillation of phenolsulphonphthalein based on a two-compartment model with first-order absorption were higher than those after bolus instillation on the liver and small intestinal serosal surface at either instillation concentration. Moreover, Ka was increased after continuous microinstillation of 2.35 mg in 117.5 μL at either instillation site. Instillation of phenolsulphonphthalein on the liver surface resulted in a 1.2- to 2.3-fold higher Ka compared with the small intestinal serosal surface. This tendency was marked after continuous microinstillation of 2.35 mg in 117.5 μL. In conclusion, absorption could be enhanced by instilling a small amount of drug solution on the liver surface gradually and continuously, suggesting a promising approach for instillation site-selective drug delivery in the peritoneal cavity.
In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer's disease
Authors: Perry Nicolette S L , Houghton Peter J , Sampson Julia , Theobald Anthony E , Hart Stephen , Lis-Balchin Maria , Hoult J Robin S , Evans Patricia , Jenner Peter , Milligan Stuart , Perry Elaine K 
Published: July 2003

Abstract
Salvia lavandulaefolia Vahl. (Spanish sage) essential oil and individual monoterpenoid constituents have been shown to inhibit the enzyme acetylcholinesterase in-vitro and in-vivo. This activity is relevant to the treatment of Alzheimer's disease, since anticholinesterase drugs are currently the only drugs available to treat Alzheimer's disease. Other activities relevant to Alzheimer's disease include antioxidant, anti-inflammatory and estrogenic effects. Results of in-vitro tests for these activities are reported here for S. lavandulaefolia extracts, the essential oil and its major constituents. Antioxidant activity (inhibition of bovine brain liposome peroxidation) was found in the EtOH extract of the dried herb (5 mg mL−1) and the monoterpenoids (0.1 M) α- and β-pinene and 1,8-cineole. Thujone and geraniol had lower antioxidant effects, while camphor had no antioxidant effects. Possible anti-inflammatory activity (eicosanoid inhibition in rat leucocytes) was found in the EtOH extract (50 μg mL−1) and was shown by the monoterpenoids α-pinene and geraniol (0.2 mM), but not 1,8-cineole, thujone or camphor. Possible estrogenic activity (via induction of β-galactosidase activity in yeast cells) was found in the essential oil (0.01 mg mL−1) and the monoterpenoid geraniol (0.1–2 mM). 1,8-Cineole, α- and β-pinene and thujone did not exhibit estrogenic activity in this analysis. These results demonstrate that S. lavandulaefolia, its essential oil and some chemical constituents have properties relevant to the treatment of Alzheimer's disease and provide further data supporting the value of carrying out clinical studies in patients with Alzheimer's disease using this plant species.