bluuebunny/crossref_metadata_2025 huggingface dataset:
Bench to Bedside: Pathophysiology of Acute Coronary Syndromes and Implications for Therapy
Authors: Brogan Gerard X.
Published: October 2002

Our understanding of the pathophysiology of unstable angina (UA) and non—ST‐segment elevation (NSTE) myocardial infarction (MI) [commonly referred to as NSTE acute coronary syndrome(s) (ACS)] has evolved considerably over the years, with atherothrombosis playing a pivotal role. This review discusses the molecular interactions in coronary thrombosis that may serve as therapeutic targets for more effective management of these syndromes. The purposes of this review are: 1) to discuss current understanding of the pathophysiology of NSTE ACS; 2) to describe recent studies with novel antithrombotic agents [e.g., low‐molecular‐weight heparin, thienopyridines, glycoprotein (GP) IIb‐IIIa inhibitors] in patients with NSTE ACS; and 3) to highlight recommendations for management of patients with NSTE ACS in the recently updated American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines, including the appropriate use of antithrombotic therapies.
An Alternate Light Source to Detect Semen
Authors: Nelson David G. , Santucci Karen A.
Published: October 2002

The Wood's lamp (WL) has been used in sexual assault evaluations. Recent data have shown that semen does not fluoresce with a WL and that physicians are unable to differentiate semen from other common medicaments using a WL. Objectives: To determine whether physicians could differentiate semen from other products using an alternate light source (ALS), and to investigate whether a brief training period with the ALS would enhance physicians' ability to differentiate between semen and other commonly used products. Methods: An ALS, Bluemaxx BM500, was found to cause semen to fluoresce. Physicians were first asked to use this ALS to identify semen and then to distinguish between a semen sample and other products. Physicians then received a training class on the use of the ALS and were then asked to differentiate semen from other products. Results: All physicians identified the semen as fluorescing and 25% successfully differentiated the semen from the other products using the ALS. Products most commonly mistaken for semen were a hand cream, Castille soap, and bacitracin. After the training session, 83% of the physicians successfully differentiated the semen from other products. The ALS, while not specific for semen identification, was 100% sensitive for it. Conclusions: Physicians instructed in the use of an alternate light source (BM 500) are able to identify semen as fluorescing and can differentiate semen (after a training session) from other commonly used products.
Etiology and Weekly Occurrence of Alcohol‐related Seizures
Authors: Rathlev Niels K. , Ulrich Andrew , Shieh Ted C. , Callum Michael G. , Bernstein Edward , D'Onofrio Gail
Published: October 2002

Objectives: 1) To determine the prevalence of identifiable causes of alcohol‐related seizures other than alcohol withdrawal. 2) To test the hypothesis that patients with alcohol‐related seizures present with greater frequency following Sundays when alcohol is not commercially available. Methods: This was a retrospective chart review of 140 consecutive patients presenting with alcohol‐related seizures during a six‐month period. Identifiable causes of seizures other than alcohol withdrawal and the day of the week of presentation were documented. Results: One hundred forty individual patients were eligible for study. Identifiable causes of seizures other than alcohol withdrawal were found in 53.6% of patients, and they were distributed as follows: 1) current or past history of significant head trauma 25.7%, 2) idiopathic seizure disorder 15.7%, 3) cerebrovascular accident 5.7%, 4) nontraumatic intracranical lesion 3.6%, and 5) toxic/metabolic abnormalities 2.9%. Alcohol is not available for purchase on Sundays because of the “Blue Laws” in Massachusetts. A total of 34.5% of patients with alcohol withdrawal seizures presented on Mondays (p < 0.001). Of patients with identifiable causes of seizures other than alcohol withdrawal, only 16% presented on Mondays (p > 0.10). Conclusions: Approximately 50% of seizures in alcohol‐dependent patients are potentially unrelated to alcohol withdrawal. Patients with alcohol withdrawal seizures presented withgreater frequency on Mondays following the 24‐hour period when alcohol was not commercially available in Boston. This suggests that patients with alcohol withdrawal seizures may present with greater frequency following periods of decreased availability of alcohol.
Manual Measurement of QT Dispersion in Patients with Acute Myocardial Infarction and Nondiagnostic Electrocardiograms
Authors: Calder Kirsten K. , Tomongin Chris , Mallon William K. , Genna Tammy , Bretsky Philip , Henderson Sean O.
Published: October 2002

Objective: To determine whether manually measured QT dispersion (QTD) may be a useful diagnostic adjunct for acute myocardial infarction (AMI) in emergency department patients with chest pain (CP) and nondiagnostic initial electrocardiograms (ECGs). Methods: This was a retrospective review of a cohort of patients admitted to the coronary triage unit (CTU) at a large urban facility over a two‐year period (1997‐1999). Cases included all patients with nondiagnostic initial ECGs diagnosed as having AMI by enzymatic criteria. Controls consisted of patients admitted to the CTU who received a final diagnosis of “musculoskeletal pain” at discharge. The QT intervals were measured on the ECGs obtained on presentation. The ECGs were included only if the QT interval could be measured on at least eight out of 12 leads. The QTD was calculated as the difference between the longest and shortest QT intervals in all measured leads. All measurements and calculations were done by a single individual. The QTDs were compared for cases versus controls using 50 msec as a cutoff for the presence of AMI. Results: The study cohort consisted of 36 cases and 124 controls. The QTDs between the two groups were markedly different, with the mean for the cases at 85.5 msec [range: 40 to 200; ±standard deviation (SD) = 39.6] and for the controls 47.1 msec (range: 0 to 120; ±SD = 20.4). The unadjusted odds ratio (OR) of having a QTD greater than 50 msec in the setting of AMI and a nondiagnostic initial ECG in this cohort was 11.9 [95% confidence interval (95% CI) = 5.0 to 28.4; p < 0.0001] and was 12.5 (95% CI = 4.8 to 32.3; p < 0.0001) adjusted for age, gender, and ethnicity. Conclusions: Manually measured QTD is significantly greater in patients with AMI and nondiagnostic ECGs versus healthy controls with musculoskeletal CP. Along with other data, QTD may serve as a useful diagnostic and decision‐making tool in patients with acute CP and nondiagnostic ECGs.
Phase I Study of Temozolomide in Relapsed/Refractory Acute Leukemia
Authors: Seiter Karen , Liu Delong , Loughran Thomas , Siddiqui Ahmad , Baskind Paul , Ahmed Tauseef
Published: October 2002

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia.

PATIENTS AND METHODS: Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m2/d for 7 days or 200 mg/m2/d for 9 days.

RESULTS: Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment.

CONCLUSION: Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.
Initial Clinical Trial of Oral TAC-101, a Novel Retinoic Acid Receptor-Alpha Selective Retinoid, in Patients With Advanced Cancer
Authors: Rizvi Naiyer A. , Marshall John L. , Ness Elizabeth , Hawkins Michael J. , Kessler Craig , Jacobs Helena , Brenckman Wayne D. , Lee Jin S. , Petros William , Hong Waun K. , Kurie Jonathan M.
Published: October 2002

PURPOSE: The goals of this study were to determine the safety, toxicity, and pharmacokinetics of TAC-101, a novel synthetic retinoic acid receptor-alpha (RAR-α) selective retinoid, in patients with advanced cancer.

PATIENTS AND METHODS: Twenty-nine patients at two centers received oral TAC-101 at doses ranging from 12 to 34 mg/m2/d. Pharmacokinetic sampling was performed on days 1 and 28.

RESULTS: The most frequent toxicities were myalgia/arthralgia, fatigue, and triglyceridemia. No dose-limiting toxicities were observed within the first 28 days up to 28 mg/m2. However, seven of 21 patients experienced venous thromboembolic events (VTEs) during TAC-101 treatment. Eight additional patients who received 34 mg/m2 were treated after a hypercoagulable work-up to exclude potential risk factors for VTE, and two of eight patients subsequently experienced VTEs. The maximum tolerated dose was exceeded at 34 mg/m2/d within the first 28 days, with one grade 3 hypertriglyceridemia, two grade 3 myalgia/arthralgia, and one grade 3 fatigue. One patient with advanced non–small-cell lung cancer had a complete response. No other responses were observed. No autoinduction of metabolism was observed with dosing over 28 days.

CONCLUSION: This is the first human clinical study with TAC-101, a RAR-α selective retinoid. Musculoskeletal toxicity and hypertriglyceridemia were observed characteristics of previously studied retinoids. The recommended phase II dose is 24 mg/m2 with this treatment schedule. Alternative treatment schedules and prospective evaluation of thrombotic risk will be investigated in subsequent studies.
Alendronate in the Treatment of Primary Hyperparathyroid-Related Osteoporosis: A 2-Year Study
Authors: Parker C. R. , Blackwell P. J. , Fairbairn K. J. , Hosking D. J.
Published: October 2002

We investigated the effect of alendronate on calcium, PTH, and bone mineral density in 27 female and 5 male patients with primary hyperparathyroidism. The treatment group [n = 14; T score ≤ −2.5 sd at the femoral neck (FN) or T ≤ −1.0 sd plus previous nonvertebral fracture] was given alendronate 10 mg/d for 24 months. The second group (n = 18; T score > −2.5 sd at the FN) was untreated. Biochemistry was repeated at 1.5, 3, 6, 12, 18, and 24 months, and dual-energy x-ray absorptiometry at 12 and 24 months.

There were no significant between-group baseline differences in calcium, creatinine, or PTH. Alendronate-treated patients gained bone at all sites [lumbar spine (LS), 1 yr gain, +7.3 ± 1.7%; P < 0.001; 2 yr, +7.3 ± 3.1%; P = 0.04). Untreated patients gained bone at the LS over 2 yr (+4.0 ± 1.8%; P = 0.03) but lost bone elsewhere. Calcium fell nonsignificantly in the alendronate group between baseline (2.84 ± 0.12 mmol/liter) and 6 wk (2.76 ± 0.09 mmol/liter), with a nonsignificant rise in PTH (baseline, 103.5 ± 14.6 ng/liter; 6 wk, 116.7 ± 15.6 ng/liter). By 3 months, values had reverted to baseline.

In primary hyperparathyroidism, alendronate is well tolerated and significantly improves bone mineral density at the LS (with lesser gains at FN and radius), especially within the first year of treatment. Short-term changes in calcium and PTH resolve by 3 months.
A Randomized Double-Blind Trial to Compare the Efficacy of Teriparatide [Recombinant Human Parathyroid Hormone (1–34)] with Alendronate in Postmenopausal Women with Osteoporosis
Authors: Body Jean-Jacques , Gaich Gregory A. , Scheele Wim H. , Kulkarni Pandurang M. , Miller Paul D. , Peretz Anne , Dore Robin K. , Correa-Rotter Ricardo , Papaioannou Alexandra , Cumming David C. , Hodsman Anthony B.
Published: October 2002

Teriparatide (rDNA origin) injection [recombinant human PTH (1–34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 μg plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P ≤ 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.
Overexpression of Wild-Type Activin Receptor Alk4-1 Restores Activin Antiproliferative Effects in Human Pituitary Tumor Cells
Authors: Danila Daniel C. , Zhang Xun , Zhou Yunli , Haidar Jaafar N. Sleiman , Klibanski Anne
Published: October 2002

Activin is a member of the TGFβ family of cytokines involved in the control of cell proliferation. We have previously shown that the majority of clinically nonfunctioning pituitary tumors do not respond to activin-induced growth suppression. Human pituitary tumors specifically express alternatively spliced activin type I receptor Alk4 mRNAs, producing C-terminus truncated isoforms designated Alk4-2, 4-3, and 4-4. However, it is not known whether these truncated activin receptors suppress activin effects on cell proliferation in human pituitary cells. Therefore, we investigated activin signaling in a human pituitary tumor cell line, HP75, derived from a clinically nonfunctioning pituitary tumor. HP75 cells express activin A mRNA and secrete activin A, as measured by ELISA and a functional bioassay. TGFβ administration decreases the proliferation of HP75 cells, suggesting that the signaling pathway shared by TGFβ and activin is functional in this cell line. However, activin neither inhibits cell proliferation nor stimulates reporter gene expression in HP75 cells, indicating that activin signaling is specifically blocked at the receptor level. HP75 cells express all truncated activin type I receptor Alk4 isoforms, as determined by RT-PCR. Because truncated Alk4 receptor isoforms inhibit activin signaling by competing with the wild-type receptor for binding to activin type II receptors, we hypothesized that overexpression of wild-type activin type I receptor will restore activin signaling. In HP75 cells, cotransfection of the wild-type activin type I receptor Alk4-1 expression vector increases activin-responsive reporter activity. Furthermore, transfection with wild-type activin receptor type I results in activin-mediated suppression of cell proliferation. These data indicate that truncated Alk4 isoforms interfere with activin signaling pathways and thereby may contribute to uncontrolled cell growth. Overexpression of the wild-type Alk4-1 receptor restores responsiveness to activin in human pituitary tumor-derived cells.
Melatonin Synthesis Enzymes in Macaca mulatta: Focus on Arylalkylamine N-Acetyltransferase (EC 2.3.1.87)
Authors: Coon Steven L. , del Olmo Elena , Young W. Scott , Klein David C.
Published: October 2002

Arylalkylamine N-acetyltransferase (AANAT; serotonin N-acetyltransferase, EC 2.3.1.87) plays a unique transduction role in vertebrate physiology as the key interface between melatonin production and regulatory mechanisms. Circulating melatonin is elevated at night in all vertebrates, because AANAT activity increases in the pineal gland in response to signals from the circadian clock. Circadian regulation of melatonin synthesis is implicated in a variety of human problems, including jet lag, shift work, insomnia, and abnormal activity rhythms in blind persons. In this report AANAT was studied in the rhesus macaque to better understand human melatonin regulation. AANAT mRNA is abundant in the pineal gland and retina, but not elsewhere; AANAT mRNA is uniformly distributed in the pineal gland, but is limited primarily to the photoreceptor outer segments in the retina. Day and night levels of pineal and retinal AANAT mRNA are similar. In contrast, AANAT activity and protein increase more than 4-fold at night in both tissues. The activity of hydroxyindole-O-methyltransferase, the last enzyme in melatonin synthesis, is tonically high in the pineal gland, but is nearly undetectable in the retina; hydroxyindole O-methyltransferase mRNA levels exhibited a similar pattern. This supports the view that the source of circulating melatonin in primates is the pineal gland. The discovery in this study that rhesus pineal AANAT mRNA is high at all times is of special importance because it shows that posttranscriptional control of this enzyme plays a dominant role in regulating melatonin synthesis.
Specific Binding of Nicergoline on an α1-like Adrenoreceptor in the Rat Retina
Authors: Lograno M D , Tricarico D , Masciopinto V , Scuderi A C
Published: October 2002

Systemic treatment with nicergoline, an ergoline derivative showing α1-antagonist properties, causes vasodilatation in the eye without apparent untoward cardiovascular effects. In the present work we investigated the ability of nicergoline to inhibit the binding of radiolabeled prazosin in the rat retina and cortex.

We found that nicergoline inhibited [3H]prazosin binding in both tissues, being more potent than unlabelled prazosin in the retinal tissue. The competition curves of the ergoline derivative were well fitted by a one-site model in the cortical tissue, with an IC50 (concentration of the drugs needed to inhibit the binding of labelled prazosin by 50%) of 2.54 times 10−8 M, and by a two-site model in the retinal tissue, with IC50 values of 7.08 times 10−12 M and 1.82 times 10−5 M. 2-(2,6 dimetoxyphenoxyethyl) aminomethyl-1,4-benzodioxane hydrochloride (WB4101) and phentolamine, selective ligands for the high-affinity binding site for prazosin, in particular the α1A-site, fully inhibited prazosin binding in the cortex but only partially inhibited prazosin binding in the retina, being less potent in this tissue than either nicergoline or prazosin.

Our results suggest that a binding component of α1-adrenoceptors is expressed to a lesser extent in the retina than the cortex, leading to a reduced response of the retinal tissue to prazosin, and more particularly to WB4101 and phentolamine. The selective binding of the nicergoline on this retinal adrenoreceptor may explain the peculiar efficacy of the drug in ocular pathophysiology.
Comparison of the Vasorelaxing Effect of Cromakalim and the New Inodilator, Levosimendan, in Human Isolated Portal Vein
Authors: Pataricza János , Höhn József , Petri András , Balogh Ádám , Papp Julius Gy
Published: October 2002

In the present study the vasorelaxing capacity of cromakalim, an ATP-sensitive potassium-channel (KATP channel) activator, and that of levosimendan, a new positive inotropic and vasodilating drug with calcium sensitizing and potassium-channel-activating properties, were compared in human isolated portal vein.

Based on the 50% effective concentrations (EC50), levosimendan was found to be about 16-fold more potent (EC50 = 0.281 ± 0.03 μM) as a relaxing agent than cromakalim (EC50 = 4.53 ± 0.12 μM) in noradrenaline-precontracted portal venous preparations. Glibenclamide, the known inhibitor of KATP channels, was able to prevent the cromakalim-induced venodilation completely. Glibenclamide (15 μM) decreased the quasi-maximal effect of levosimendan (at 1.27 μM by about 60%) and also the effects of those submicromolar concentrations of the inodilator (at 0.1 μM by 23%, at 0.3 μM by 27% and at 0.7 μM by 19%, on average) which were therapeutically effective in preliminary human studies.

These findings indicate that, in the human portal vein, both cromakalim and levosimendan are powerful vasorelaxants and that a considerable part of the relaxing effect induced by levosimendan is of cromakalim type.
Protection of Mitochondrial Functions against Oxidative Stresses by Isoflavans from Glycyrrhiza glabra
Authors: Haraguchi Hiroyuki , Yoshida Nobukazu , Ishikawa Harumi , Tamura Yukiyoshi , Mizutani Kenji , Kinoshita Takeshi
Published: October 2002

Isoflavan derivatives, glabridin (1), hispaglabridin A (2), hispaglabridin B (3), 4′-O-methylglabridin (4) and 3′-hydroxy-4′-O-methylglabridin (5), isolated from Glycyrrhiza glabra, were investigated for their ability to protect liver mitochondria against oxidative stresses.

Mitochondrial lipid peroxidation linked to respiratory electron transport and that induced non-enzymatically were inhibited by these isoflavans. Hispaglabridin A (2) strongly inhibited both peroxidations and 3′-hydroxy-4′-O-methylglabridin (5) was the most effective at preventing NADH-dependent peroxidation. 3′-Hydroxy-4′-O-methylglabridin (5) protected mitochondrial respiratory enzyme activities against NADPH-dependent peroxidation injury. Dihydroxyfumarate-induced mitochondrial peroxidation was also prevented by this isoflavan.

Isoflavans from G. glabra were shown to be effective in protecting mitochondrial function against oxidative stresses.
Synthesis and Anti-inflammatory Effect of Chalcones
Authors: Hsieh Hsin-Kaw , Tsao Lo-Ti , Wang Jih-Pyang , Lin Chun-Nan
Published: October 2002

The process of degranulation of mast cells and neutrophils contributes to inflammatory disorders. Activation of microglial cells and macrophages is believed to be involved in inflammatory, infectious and degenerative diseases of the CNS. Combining the potent inhibition of chemical mediators released by the degranulation of mast cells or neutrophils and from the activated microglial cells or macrophages, would lead to a promising antiinflammatory agent for the treatment of peripheral and central inflammation. A series of chalcone derivatives have been reported to have potent anti-inflammatory activity. In an effort to continually develop potent anti-inflammatory agents, novel series of chalcones, 2′-hydroxy- and 2′,5′-dihydroxychalcones were synthesized and their inhibitory effects on the activation of mast cells, neutrophils, microglial cells and macrophages were evaluated in-vitro. The chalcones were prepared by Claisen-Schmidt condensation of appropriate acetophenones with an appropriate aromatic aldehyde. The alkoxychalcones were prepared with appropriate hydroxychalcones and alkyl iodide and the dihydroxychalcones were prepared by hydrogenation of an appropriate chalcone with Pd/C.

Almost all of the hydroxychalcones exhibited potent inhibitory effects on the release of β-glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe/cytochalasin B (fMLP/CB). Of the hydroxychalcones, compound 1 was the most potent inhibitor of the release of β-glucuronidase (IC50=1.6 ± 0.2 μM) and lysozyme (IC50=1.4 ± 0.2 μM) from rat neutrophils stimulated with fMLP/CB. Almost all of the 2′,5′-dialkoxychalcones exhibited potent inhibitory effects on nitric oxide (NO) formation from murine microglial cell lines N9 stimulated with lipopolysaccharide (LPS). Of these, compound 11 showed the greatest effect (IC50=0.7 ± 0.06 μM).

The present results demonstrated that most of the chalcone derivatives have an anti-inflammatory effect. The inhibitory effects of dialkoxychalcones, 10–12 on inflammation are probably not due to the inhibition of mast cells and neutrophil degranulation, but are mediated through the suppression of NO formation from N9 cells.
Baicalin Synergy with β-Lactam Antibiotics Against Methicillin-resistant Staphylococcus aureus and Other β-Lactam-resistant Strains of S. aureus
Authors: Liu Iain X , Durham David G , Richards R Michael E
Published: October 2002

Bacterial resistance to antibiotics is a serious global problem and includes strains of β-lactam-resistant Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Novel antimicrobials and/or new approaches to combat the problem are urgently needed. The Chinese herb Xi-nan Huangqin (Scutellaria amoena CM. Wright) has been used in traditional Chinese medicine to treat a wide range of infectious diseases. In this study we have examined the antibacterial action of baicalin, a flavone isolated from the herb.

When combined with 16 μg mL−1 baicalin, minimum inhibitory concentrations (MICs) of benzylpenicillin against MRSA and penicillin-resistant S. aureus were reduced from 125 and 250 μg mL−1 to 4 and 16 μg mL−1, respectively. This activity of baicalin was dose-dependent. Viable counts showed that the killing of MRSA and β-lactam-resistant S. aureus cells by 10 to 50 μgm mL−1 ampicillin, amoxycillin, benzylpenicillin, methicillin and cefotaxime was potentiated by 25 μg mL−1 baicalin.

From the study it was concluded that baicalin has the potential to restore the effectiveness of β-lactam antibiotics against MRSA and other strains of β-lactam-resistant S. aureus. In view of its limited toxicity baicalin offers potential for the development of a valuable adjunct to β-lactam treatments against otherwise resistant strains of microorganisms.
Design, Synthesis and Evaluation of N-Basic Substituted 3-Hydroxypyridin-4-ones: Orally Active Iron Chelators with Lysosomotrophic Potential
Authors: Liu Zu D , Khodr Hicham H , Lu Shu L , Hider Robert C
Published: October 2002

To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentate 3-hydroxypyridin-4-ones with basic chains have been synthesized. As the turnover of ferritin iron is centred in the lysosome, such strategy is predicted to increase chelator efficacy of bidentate ligands.

The pKa values of the ligands together with their distribution coefficients between 1-octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been determined. The in-vivo iron mobilization efficacy of these basic 3-hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model. No obvious correlation was observed between efficacy and the pKa value of the side chain, although those with pKa > 7.0 tended to be more efficient than those with pKa < 7.0. The imidazole-containing molecules are much less effective than the tertiary amine derivatives. A dose-response study suggested that basic pyridinones are relatively more effective at lower doses when compared with N-alkyl hydroxypyridinones.

Optimal effects were observed with the piperidine derivatives 4h and 4i. The derivative 4i at a dose of 150 μmol kg−1 was more effective than 450 μmol kg−1 deferiprone, the widely adopted clinical dose.
In-vitro Metabolism of Retinoic Acid by Different Tissues from Male Rats
Authors: Ahmad Mobasher , Ahmadi Masoud , Nicholls Paul J , Smith H John
Published: October 2002

Significant differences between the metabolism of retinoic acid by different tissues might be an important determinant of the effectiveness of a systemically administered inhibitor at a particular tissue site. Here the metabolism of retinoic acid has been studied in microsomal fractions from different tissues (liver, kidney, intestinal mucosa, lung, skin, brain) of the male rat to determine their relative metabolic activity.

Kinetic analysis revealed major differences between the activity of different tissue microsomes. This is shown by the Vmax values for the metabolism of retinoic acid—liver (102 ± 39.0 pmol (mg protein)−1 min−1) was 100 times more active than the lung (1 ± 0.03 pmol (mg protein)−1 min−1), which was the least active. The range of Km values for microsomes from the different tissues was narrow (0.48–1.40 μM). Taking into account the mass of the tissue, the gross activity ranking for metabolism of retinoic acid was liver>>skin = kidney > brain > intestinal mucosa>>lung.

It is concluded that metabolism of administered retinoic acid occurs mainly in the liver but that cellular retinoic acid levels in some other tissues (skin, kidney, brain) could be reduced (metabolized) to such an extent that higher levels might be observed after the use of inhibitors of retinoic acid metabolism.
A Mechanism of Vasodilatory Action of Polyamines and Acetylpolyamines: Possible Involvement of their Ca2+ Antagonistic Properties
Authors: Myung Chang-Seon , Blankenship James W , Meerdink Denis J
Published: October 2002

Polyamines, a class of low-molecular weight organic polycations, have been shown to produce relaxing effects in vascular smooth muscles, although the mechanism has not been carefully examined. In this study, the mechanism of vascular action of polyamines and their metabolites, acetylpolyamines, was pharmacologically examined in the rabbit isolated thoracic aorta focusing on an endothelium-dependent component of vasodilatation and Ca2+ influx through plasma membrane channels.

Both polyamines and acetylpolyamines (except N1-acetylputrescine, which produced no response or very slight contraction) caused concentration-dependent relaxation in pre-constricted aortic rings containing an intact endothelium. Aortic rings denuded of endothelium were also responsive to both polyamines and acetylpolyamines. Inhibitors of nitric oxide (reduced haemoglobin and Nω-nitro-l-arginine methyl ester), vasodilator prostaglandins (indomethacin) and guanylyl cyclase (methylene blue) did not affect the relaxation induced by both polyamines and acetylpolyamines in either endothelium-intact or -denuded aortic rings. Both polyamines and acetylpolyamines inhibited the concentration-dependent contraction for phenylephrine and K+. The Ca2+ agonist Bay K 8644 induced concentration-dependent contraction in segments of rabbit aorta partially depolarized with 15 mm KCl, and both polyamines and acetylpolyamines relaxed the Bay K 8644-induced contraction in a concentration-dependent manner. Interestingly, both polyamines and acetylpolyamines also decreased contractions evoked by the Ca2+ ionophore A23187. The concentration-response curve to exogenous Ca2+ in K+-depolarization medium (K+ = 120 mm) was shifted to the right by both polyamines and acetylpolyamines. The response elicited by Ca2+ was increased by Bay K 8644 (10−6  m), and this potentiation was also inhibited by both polyamines and acetylpolyamines.

The results indicate that both polyamines and acetylpolyamines can induce vasorelaxation of rabbit thoracic aorta by an endothelium-independent mechanism in-vitro and relax vascular smooth muscle by acting at the plasma membrane level, decreasing the influx of Ca2+. Therefore, polyamines and acetylpolyamines may have Ca2+ antagonistic properties which may, in part, be involved in the mechanism of rabbit aortic vascular smooth muscle relaxation.
The Influence of Crystallization Conditions on the Morphology of Lactose Intended for Use as a Carrier for Dry Powder Aerosols
Authors: Zeng Xian Ming , Martin Gary Peter , Marriott Christopher , Pritchard John
Published: October 2002

Lactose has been widely used as a carrier for inhalation aerosols. The carrier morphology is believed to affect the delivery of the drug. The aim of this study was to investigate the effects of crystallization conditions on the morphology of α-lactose monohydrate intended for use as the carrier for dry powder aerosols.

The crystallization of lactose was carried out from aqueous solutions at different supersaturations, temperatures, different stages of crystallization and in the presence of different water-miscible organic solvents. The majority of lactose crystals were found to be either tomahawk-shaped or pyramidal after crystallization at an initial lactose concentration between 33–43% w/w, but these became prismatic if the lactose concentration was increased to 50% w/w. A further increase in the lactose concentration to 60% w/w led to the preparation of elongated cuboidal crystals. Higher initial lactose concentrations tended to result in the crystallization of more elongated particles. Crystallization at 40°C was shown to prepare lactose crystals with a more regular shape and a smoother surface than those crystallized at 0°C. Lactose particles generated during the later stage of crystallization were found to be more regular in shape with a smoother surface than those prepared in the earlier stage. The addition of 10% (v/v) methanol or ethanol or acetone to the mother liquor increased the growth rate of lactose particles whereas addition of propanol or glycerine inhibited the rate of crystal growth. Lactose crystals prepared in the presence of glycerine were more regularly shaped with a smoother surface than those prepared in the presence of ethanol or acetone. All the resultant crystals were shown to comprise α-lactose monohydrate.

Lactose crystals could be prepared with a precisely defined morphology by means of carefully controlling the crystallization conditions.
Mono- and Biphasic Plasma Concentration-time Curves of Mesalazine from a 500 mg Suppository in Healthy Male Volunteers Controlled by the Time of Defecation before Dosing
Authors: Vree Tom B , Dammers Erik , Exler Peter S , Maes Robert A A
Published: October 2002

This study was based on data from a bioequivalence study (n = 24) of two different formulations of suppositories containing 500 mg mesalazine (formulation I and II), with a similar dissolution profile in phosphate buffer pH 6.8. There was a large intra- and inter-subject variability in the plasma concentration-time curves of mesalazine from both suppositories.

The aim of the investigation was to identify the parameters that caused the observed large variations in release and absorption of mesalazine in the rectum.

Plasma mesalazine and acetylmesalazine, and urine acetylmesalazine concentrations were determined according to validated methods involving HPLC analysis with coulometric detection. Lower limit of quantitation values were respectively 10.4 and 19.4 ng mL−1 in plasma and 0.96 μg mL−1 in urine. The time of defecation before and after insertion was recorded.

There was a clear distinction between subjects who showed monophasic mesalazine release/absorption and those who showed biphasic and more extended release/absorption. With formulation I there was a correlation between time of defecation before dosing and the type of absorption, monophasic and biphasic absorbers showed a significant difference in the time of defecation, e.g. 9.7 ± 5.6 h vs 18.8 ± 11.9 h (P = 0.0218). The impact of time of defecation before dosing was non-significant with formulation II, 16.7 ± 7.2 h vs 15.1 ± 4.2 h (P = 0.67). The impact of the time elapsed between administration and time of defecation after the insertion of the suppository was not significant for the type of release/absorption.

The plasma concentration-time curves of the metabolite ran parallel to that of the parent drug, the more parent drug was released/absorbed, the more was acetylated (P = 0.0013) and excreted into the urine (P = 0.0004). After absorption the compound was metabolized into acetylmesalazine, and renally excreted (12–13% of the dose). Monophasic release/absorption resulted in 7.1% metabolite with I and 10.3% with II (P = 0.0004), while biphasic release/absorption gave 16.8% metabolite with I and 15.5% with II. The renal clearance of the metabolite acetylmesalazine was independent of the observed defecation patterns (300 mL min−1, P > 0.8), stool composition, and type of absorption.
Possible Underestimation of the Channel Conductance Underlying Pinacidil-induced K+ Currents Using Noise Analysis in Pig Urethral Myocytes
Authors: Teramoto Noriyoshi , Brading Alison F , Ito Yushi
Published: October 2002

Electrophysiological and pharmacological properties of the pinacidil-induced K+ currents in isolated cells from pig urethra were investigated using patch-clamp techniques.

Pinacidil (100 μM) induced an outward current at −50 mV which gradually decreased. Under current-clamp conditions, 100 μM pinacidil induced a hyperpolarization that was sustained. This suggests that activation of only a few channels can hyperpolarize the membrane. At a holding potential of −50 mV, glibenclamide inhibited the pinacidil-induced current with a single exponential time course.

Unitary current recordings in symmetrical 140 mM K+ conditions demonstrated that pinacidil activates a 43-pS, glibenclamide-sensitive K+ channel (i.e. KATP channel). Analysis of the basal noise of the pinacidil-induced macroscopic currents from −90 mV to −30 mV yielded estimates of channel conductance (6pS) which were much smaller, and probably an underestimate.

These results indicate that pinacidil induces a glibenclamide-sensitive K+ current through only one type of K+ channel (KATP channel) in pig urethra.
Therapeutic Monitoring of Warfarin: the Appropriate Response Marker
Authors: Costa I M , Soares P J , Afonso M , Ratado P , Lanao J M , Falcão A C
Published: October 2002

Warfarin is a 4-hydroxycoumarin anticoagulant drug used for the prevention and management of thromboembolic and vascular diseases. It acts through the inhibition of the vitamin K-dependent transcarboxylation reactions that convert precursors of clotting factors into their active form. Appropriate use of warfarin requires patient monitoring and dosage adjustments, to ensure its safety and efficacy. The aim of this work was to clarify the relationship between traditional (prothrombin time, usually expressed as the international normalized ratio; INR) and alternative (clotting factors II and X) warfarin response markers to establish their usefulness for therapeutic drug monitoring.

Seventy adult outpatients, aged between 31 and 86 years old, were involved in the study. All subjects received warfarin in a monotherapy regimen and had been on a stable dosing schedule for at least two weeks to assure a steady-state condition. A total of 81 prothrombin times (expressed as INR), and factor II and factor X activity were simultaneously determined. Eleven patients presented repeated measurements at different time periods under the same dosing regimen. The results obtained from regression and cluster analysis showed a close relationship between factors II and X (r = 0.73), a weak correlation between INR and both factor II (r = −0.35) and factor X (r = −0.36), and a very slight dependency between warfarin and the response markers used. In addition, it seems that independent of the selected response marker, in long-term warfarin therapy, reproducible responses can be obtained over time if a steady-state condition is achieved. The coefficients of variation for factors II and X were greater (35.44 and 37.93%, respectively) than INR (14.50%), indicating that INR is a more precise measure than either factor II or factor X.

In conclusion, INR appears to be the most appropriate warfarin response marker for therapeutic drug monitoring due to its universality, objectivity as a direct physiological effect measurement, and the available information regarding appropriate endpoints. However, when INR values are not in accordance with patient response therapy, factor II and factor X should be considered as an alternative to optimize warfarin therapy.
Protective Effect of Erdosteine Against Hypochlorous Acid-induced Acute Lung Injury and Lipopolysaccharide-induced Neutrophilic Lung Inflammation in Mice
Authors: Hayashi Ken-Ichi , Hosoe Hisashi , Raise Toshihiko , Ohmori Kenji
Published: October 2002

The effect of erdosteine, a mucoactive drug, on hypochlorous acid (HOCl)-induced lung injury, and the lipopolysaccharide (LPS)-induced increase in tumour necrosis factor-α (TNF-α) production and neutrophil recruitment into the airway, was investigated.

Male BALB/c mice were orally administered erdosteine (3–100 mg kg−1), ambroxol hydrochloride (ambroxol) (3–30 mg kg−1), S-carboxymethyl-L-cysteine (S-CMC) (100–600 mg kg−1) or prednisolone (10 mg kg−1), 1h before intratracheal injection of HOC1 or LPS. In the HOCl-injected mice, erdosteine markedly suppressed increases in the ratios of lung wet weight to bodyweight and lung dry weight to bodyweight, whereas the other mucoactive drugs ambroxol and S-CMC had little effect. Erdosteine also inhibited the LPS-induced neutrophil influx, although it did not affect the increased level of TNF-α in the bronchoalveolar lavage fluid.

The results suggest that attenuation of reactive oxygen species and neutrophil recruitment is involved in the clinical efficacy of erdosteine in the treatment of chronic bronchitis.
Pharmacokinetics and Toxicodynamics of Cisplatin and Its Metabolites in Rats: Relationship between Renal Handling and Nephrotoxicity of Cisplatin
Authors: Hanada Kazuhiko , Ninomiya Kimie , Ogata Hiroyasu
Published: October 2002

The renal handling of cisplatin and its metabolites and the relationship between the pharmacokinetics of these platinum species in the kidney and nephrotoxicity in rats were studied by carrying out pharmacokinetic-pharmacodynamic analysis.

Rats received cisplatin intravenously as a bolus (2–10 mgkg−1) or by constant infusion (55 and 140 μg min−1 kg−1). After intravenous administration of each platinum species, the platinum concentrations of unchanged cisplatin and its mobile and fixed metabolites were determined separately. Nephrotoxicity was estimated by measuring the blood urea nitrogen (BUN) levels and the sigmoid Emax model was used to determine the relationship between pharmacokinetic parameters and BUN levels 5 days after cisplatin administration.

Cisplatin and its mobile metabolites in plasma distributed more rapidly and extensively into the kidney (mean apparent kidney-to-plasma concentration ratios were 2.69 and 7.12 mL (g tissue)−1, respectively) than into the liver (less than 1 mL (g tissue)−1). Concomitant administration of mobile metabolites did not significantly alter the disposition of cisplatin. Nephrotoxicity, estimated by measuring BUN levels, appeared to be related to the plasma concentration of intact cisplatin, not total platinum, because mobile metabolites formed from cisplatin showed little nephrotoxicity. The sigmoid Emax model showed the maximum BUN level reached after cisplatin administration was related to the area under the renal cisplatin concentration-time curve (AUCk).
Solubilization of meso-Tetraphenylporphyrin Photosensitizers by Substitution with Fluorine and with 2,3-Dihydroxy-1-propyloxy Groups
Authors: Songca Sandile P , Mbatha B
Published: October 2002

The tetra(hydroxyphenyl)porphyrins (5,10,15,20-tetrakis(2-hydroxyphenyl)porphyrin (3), 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (4), and 5,10,15,20-tetrakis(4-hydroxy-phenyl)porphyrin (5) and the tetrahydroporphyrins (5,10,15,20-tetrakis(2-fluoro-3-hydroxy-phenyl)porphyrin (6), 5,10,15,20-tetrakis(2,4-difluoro-3-hydroxyphenyl)porphyrin (7), and 5,10,15,20-tetrakis(3,5-difluoro-4-hydroxyphenyl)porphyrin (8)) have been reported as potential photosensitizers for photodynamic therapy. In particular, the tetrahydropor-phyrin 7, which has been in Phase III clinical trials for three years in the USA and Canada, has shown great promise for primary and recurrent head and neck cancer. It is expected to be on the market soon. A potentially limiting property of compounds 3–8 is their hydrophobicity, which renders them insoluble in aqueous media. We therefore set out to develop an approach for their solubilization in aqueous media.

The first attempt was to prepare analogues with fluorine substituents at the positions ortho to each of the four hydroxy groups on the meso-phenyl rings. This was expected to increase the acidity of the ortho hydroxy groups, and therefore the solubility of the compounds in hydroxylic media. This structural alteration resulted in a slight but significant decrease in the partition coefficients.

The second attempt was substitution of each of the hydroxy groups on the phenyl rings with 2,3-dihydroxy-l-propyloxy groups. This structural alteration resulted in a substantial decrease in the partition coefficients.

To harness the combined effect of these two structural variations porphyrins were prepared containing both 2,3-dihydroxy-l-propyloxy and ortho fluorine groups on the meso-phenyl rings. The partition coefficients decreased by more than two orders of magnitude. The most significant decrease was due to the substitution with 2,3-dihydroxy-l-propyloxy groups, rather than the substitution with fluorine, although fluorination alone contributed significantly. The effect of this method was demonstrated most clearly by comparison of the partition coefficients of meta and para isomers of these porphyrins.
Time-dependent Nephrotoxicity Associated with Daily Administration of Cisplatin in Mice
Authors: To Hideto , Kikuchi Atsumi , Tsuruoka Shuichi , Sugimoto Koichi , Fujimura Akio , Higuchi Shun , Kayama Fujio , Hara Kyoko , Matsuno Koji , Kobayashi Eiji
Published: October 2002

The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6 mg kg−1) for 5 days at four time points (0400, 1000, 1600 and 2200h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared.

In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.

The results showed diurnal variations in cisplatin toxicity, with the 0400 and 1600h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 0400 and 1600 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 0400 and the 1600h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 1600h group than in the 0400h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS.
Antihyperglycaemic effect of Diamed, a herbal formulation, in experimental diabetes in rats
Authors: Pari L , Ramakrishnan R , Venkateswaran S
Published: October 2002

Diamed is a herbal formulation composed of the aqueous extracts of three medicinal plants (Azardirachta indica, Cassia auriculata and Momordica charantia). We have investigated Diamed for its possible antihyperglycaemic action in rats with alloxan-induced experimental diabetes. Oral administration of Diamed (1.39 (0.25 g), 1.67 (0.30 g) or 1.94 (0.35 g) mL kg−1) for 30 days resulted in a significant reduction in blood glucose, glycosylated haemoglobin, and an increase in plasma insulin and total haemoglobin. The effect was highly significant after administration of the 1.94 mL (0.35 g) g−1 body weight dose. Diamed also prevented a decrease in body weight. An oral glucose tolerance test was performed in experimental diabetic rats in which there was a significant improvement in glucose tolerance in the animals treated with Diamed. The effect was compared with 600 μg kg−1 glibenclamide. The results showed that Diamed had antihyperglycaemic action in experimental diabetes in rats.