bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Delivery Systems—2. Site‐Specific Drug Delivery Utilizing Monoclonal Antibodies
Authors: Ranade Vasant V. 
Published: March 2013

Monoclonal antibodies (MAbs) are purified antibodies produced by a single clone of cells. They are engineered to recognize and bind to a single specific antigen. Accordingly, when administered, MAbs home in on a particular circulating protein or on cells that bear the correct antigenic signature on their surfaces. It is the specificity of MAbs that has made them valuable tools for health professions.Following the discovery of Kohler and Milstein regarding the method of somatic cell hybridization, a number of investigators have successfully adopted this technique to obtain T‐lymphocyte hybrid cell lines by fusion of activated T (thymus derived) lymphocytes with a T lymphoma cell line leading to an immortalization of a specific differentiated function. The hybrids thus obtained were subsequently shown to produce homogeneous effector molecules with a wide variety of immune functions such as enhancement or suppression of antibody responses, generation of helper T cells, suppressor T cells and cytotoxic T cells.Study of these regulatory molecules has been further shown to provide a greater insight into the genetic, biochemical and molecular mechanisms responsible for cellular development, and the interaction and triggering of various cell types.The successfull application of hybridoma technology has now resulted into several advances in the understanding the mechanism and treatment of diseases, especially cancer and development of vaccines, promotion of organ transplantation and therapy against parasites as well. Since monoclonal antibodies could be made in unlimited supply, they have been used in genetic studies such as mRNA and gene isolation, chromosomal isolation of specific genes, immunoglobulin structure, detection of new or rare immunoglobulin gene products, structural studies of enzymes and other proteins and structural and population studies of protein polymorphisms. In some instances, the monoclonal antibodies have been found to replace conventional antisera for studies of chromosome structure and function, gene mapping, embryogenesis, characterization and biosynthesis of developmental and differentiation antigens. These antigens are those that are specific for various cell types and tissues, species specific antigen, antigens involved in chemotaxis, immunogenetics and clinical genetics including genetically inherited disorders, chromosome aberrations and transplantation antigens.Besides these monoclonal antibodies, their complexes have recently been investigated as exquisitely sensitive probes to be guided to target cells or organs. They have been used to deliver cytotoxic drugs to malignant cells or enzymes to specific cell types. Current research efforts indicate that antibodies against different subsets of T lymphocytes, particularly suppressor lymphocytes will continue to be of great value in the diagnosis and treatment of patients with multiple sclerosis, various heart diseases, different types of leukemias and malaria.
Clinical Pharmacology of Dilevalol (III). A Pharmacokinetic Study of Dilevalol in Elderly Subjects with Essential Hypertension
Authors: Fujimura Akio , Sugimoto Kouichi , Kumagai Yuji , Nakashima Hajime , Ebihara Akio 
Published: March 2013

Dilevalol (100 mg) was given once daily for 8 days in eight elderly subjects with essential hypertension. Blood samples for plasma dilevalol concentrations were taken during an 8‐hour post‐drug period following the first and eighth dosages, and the time to maximum concentration (tmax), maximum plasma concentration (Cmax), distribution half‐life (t1/2α), elimination half‐life (t1/2β) and area under the plasma concentration‐time curve (AUC) were determined.A wide intra‐subject variability was observed in tmax during the repeated administration. A high inter‐subject variability was also demonstrated in tmax, Cmax, t1/2β and AUC during both observation periods. No significant difference was observed, however, in these pharmacokinetic parameters between the first and eighth dosages.These data indicate that the pharmacokinetic profiles of dilevalol are not altered during 8 days of therapy in elderly subjects with essential hypertension. Since elderly subjects are potentially heterogenous in capacities for handling the drug, the observed variability in pharmacokinetic parameters may reflect the heterogeneity in the sample chosen for examination in the current study.
BOOK REVIEWS
Authors: Maggio Beth 
Published: March 2013

Book reviewed in this article:Gastric Protection Rodolfo CheliChloride Channels and Their Modulation by Neurotransmitters and Drugs (Advances in Biochemical Psychopharmacology, Vol. 45) [Biggio, Giovanni, and Costa, Erminio, Editors.Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs. Edited by: Enno Christophers, Erwin Shopf, Albert M. Kligman, and Richard B. Stoughton.Glial Cell Receptors Edited by Harold K. KimelbergAdvances in Second Messenger and Phosphoprotein Research, Volume 21 (Sixth International Conference on Cyclic Nucleotides, Calcium and Protein Phosphorylation, Bethesda, Maryland, September 2–7, 1988) Edited by Robert S. Adelstein, Claude B. Klee, and Martin Rodbell.Advances in Second Messenger and Phosphoprotein Research, Volume 21A, Abstract Volume (Sixth International Conference on Cyclic Nucleotides, Calcium and Protein Phosphorylation, Bethesda, Maryland, September 2–7, 1988) Edited by Robert S. Adelstein, Claude B. Klee, and Martin Rodbell.
Phase I Study of Y‐20811, a New Long‐Acting Thromboxane Synthetase Inhibitor by Oral Administration
Authors: Nakashima Mitsuyoshi , Uematsu Toshihiko , Takiguchi Yoshiharu , Mizuno Atsuhiro , Kanamaru Mitsutaka 
Published: March 2013

The safety, pharmacological action and pharmacokinetics of the thromboxane (TX) synthetase inhibitor Y‐20811, a prospective medication for ischemic vascular disorder, were investigated in Phase I clinical trials in which single and repeated doses were administered orally to 32 healthy adult male volunteers. In the single‐dose study, subjects were given single doses of 2.5, 5, 10, 25, 50, and 100 mg; in the repeated‐dose study, a single dose of 50 mg was administered daily for 5 days.In the repeated‐dose study, slight elevation of liver function test parameters in 1 subject was observed, but throughout the trials, no abnormality attributable to the test drug was found in other routine laboratory tests, subjective and objective findings, vital signs (blood pressure, pulse rate, body temperature, respiration rate), ECG, or bleeding time; nor did any finding indicate a problem concerning the safety of Y‐20811.In both single‐ and repeated‐dose studies, inhibition of the serum TXB2 production and an increase in the 6‐keto‐prostaglandin F1α production during whole‐blood coagulation, and inhibition of arachidonic acid‐induced platelet aggregation were observed from 1 hour after administration of Y‐20811. The duration of these actions was long, the former two lasting 168 hours (1 week) and the latter 48–72 hours or more. Slight inhibition of adenosine diphosphate‐induced secondary platelet aggregation was also observed.The maximum plasma concentration time (tmax) of Y‐20811 was 0.5–1.1 hours. The initial‐phase half‐life (t1/2α) was 0.8–1.1 hours and the final‐phase half‐life (t1/2β) was 4.7–9.2 hours. Maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) increased dose‐dependently. When Y‐20811 was administered after a meal, tmax was delayed and Cmax was decreased, but there was almost no change in AUC. In the repeated‐dose study, plasma concentrations after each administration showed a good conformity with the simulation curve worked out using the pharmacokinetic parameters obtained at the time of the initial dose, indicating that repeated administration did not result in accumulation of the drug.In all dose groups, 47–62% of the dose was excreted in unchanged form and 8–14% was excreted in conjugated form in the urine within 48 hours after administration. No daily change was observed in the 24‐hour urinary excretion with repeated administration.The duration of pharmacological action did not parallel the change in plasma concentration.Oral administration of Y‐20811 was concluded to be safe and well‐tolerated with long‐acting inhibition of the serum TXB2 production and platelet aggregation.
The Influence of Intravenous Cimetidine Dosage Regimens on the Disposition of Theophylline
Authors: Gutfeld Marcia B. , Welage Lynda S. , Walawander Cynthia A. , Wilton John H. , Harrison Nedra J. 
Published: March 2013

The influence of the method of cimetidine administration on theophylline disposition was studied in nine healthy, cigarette smoking male volunteers. The treatment phases consisted of: A) theophylline alone, B) theophylline plus intermittent cimetidine therapy (300 mg IV every 6 hr), and C) theophylline in combination with continuous infusion cimetidine (50 mg/hr). Theophylline (4.8 mg/kg) was administered intravenously as aminophylline over 30 minutes during each treatment phase. During study phases B and C subjects received 48 hours of cimetidine therapy beginning 24 hours prior to theophylline dosing. Blood samples for determination of theophylline concentrations were collected serially over 24 hours. Serum theophylline concentrations were determined in duplicate using fluorescence polarization immunoassay (Abbott Diagnostic TDx®).The average age of the subjects was 27.4 ± 4.7 years, and the individual smoking histories ranged from 0.5 to 1.5 packs per day (average 0.89 ± 0.33). The mean (±SD) body weight was 79.1 ± 8.2 kg and all subjects were within 20% of their ideal body weight. Theophylline pharmacokinetic parameters were determined using noncompartmental analysis. ANOVA for repeated measures and Tukey's multiple comparison test were used for statistical analysis. The mean (±SD) theophylline clearance for each of the treatment groups was: 1.4 ± 0.4, 1.2 ± 0.3, and 1.2 ± 0.2 ml/min/kg for phases A, B and C, respectively.Cimetidine decreased the clearance of theophylline, however, theophylline clearance was not statistically different between regimens B and C. Thus, the method of cimetidine administration (intermittent versus continuous infusion) did not influence the magnitude of the drug‐drug interaction.
Pharmacokinetic and Biopharmaceutic Aspects of Once Daily Treatment with Metoprolol CR/ZOK: A Review Article
Authors: Sandberg Anders , Abrahamsson Bertil , Regårdh Carl‐Gunnar , Wieselgren Ingrid , Bergstrand Robert 
Published: March 2013

In the development of a new controlled release preparation and its subsequent assessment there are a number of factors that need to be considered both related to the drug itself and to the pharmaceutical preparation. This review describes the biopharmaceutical and pharmacokinetic properties of metoprolol CR/ZOK, a recently introduced formulation of a widely used beta1‐selective adrenoceptor antagonist intended for once daily usage.The metoprolol CR/ZOK preparation provides reproducible dissolution and absorption properties resulting in stable plasma concentrations with minimum fluctuations over a 24‐hour dosage interval. This has been shown in extensive studies comprising over 200 healthy volunteers. Considerations for a new drug preparation such as bioavailability and variability in relation to a standard treatment and the clinical significance of taking the drug with food and in increasing doses, are potential concerns that do not seem to be a problem for the therapeutic use of metoprolol CR/ZOK. Furthermore, the pharmacokinetic data achieved in young healthy subjects appear to be relevant for the treatment of patients, as shown by the consistent plasma concentration profiles obtained in elderly and in hypertensive patients.
Pharmacokinetic and Pharmacodynamic Evaluation of Metoprolol Controlled Release (CR/ZOK) 50 mg in Young Subjects
Authors: Wieselgren Ingrid , Lundborg Per , Sandberg Anders , Olofsson Bertil , Bergstrand Robert 
Published: March 2013

In this steady state, cross‐over study, the bioavailability and beta1‐blocking effects of metoprolol CR/ZOK 50 mg, conventional metoprolol 50 mg tablets and placebo were evaluated in 12 healthy male subjects (mean age 25 years) after once daily treatment in 5 days. The drugs were administered in a randomized order. The beta1‐blocking effect was defined as percent reduction from baseline in exercise heart rate.The plasma concentration‐time profile following metoprolol CR/ZOK 50 mg administration was more even compared to conventional metoprolol tablets, with significantly lower Cmax (mean: 71 vs 221 nmol/L) and significantly higher Cmin (mean; 39 vs 6 nmol/L) for the CR/ZOK formulation. This difference in plasma concentrations was also well reflected by a significantly lower fluctuation index for metoprolol CR/ZOK 50 mg compared with the conventional 50 mg tablet (mean: 69 vs 529%). There was, however, no difference in systemic bioavailability between the two metoprolol formulations (90% confidence limits: 86–106%).The beta1‐blockade was also more even after metoprolol CR/ZOK 50 mg compared to conventional tablets with a significantly lower Emax (mean: 14 vs 19%) and higher Emin (mean: 9 vs 0%) for CR/ZOK. The total effect over a dosage interval, defined as area under the effect curve, was significantly higher for metoprolol CR/ZOK compared to conventional tablets (90% confidence limits: 123–213%).In conclusion, once daily administration of metoprolol CR/ZOK 50 mg to young healthy subjects resulted in smooth plasma concentration and produced a significant beta1‐blocking effect for 24 hours. Once daily treatment of metoprolol CR/ZOK 50 mg might therefore be a useful and clinically effective dose.
Pharmacokinetic and Pharmacodynamic Properties of Controlled Release (CR/ZOK) Metoprolol in Healthy Oriental Subjects: A Comparison with Conventional Formulations of Metoprolol and Atenolol
Authors: Darmansjah Iwan , Wong Ellick , Setiawati Arini , Moeloek Dangsina , Irawati Dewi , Siagian Minarma , Muchtar Armen 
Published: March 2013

The steady state pharmacokinetics and pharmacodynamics of metoprolol controlled release tablets 100 mg CR/ZOK, was compared with those of metoprolol conventional tablets 100 mg (CT) and atenolol 50 mg (ATL) in ten healthy Oriental men. The study was of double‐blind, cross‐over placebo controlled design. The three study drugs and placebo were given in a random order once daily for 4 consecutive days with 1‐week wash‐out between each period. Treadmill exercise tests were performed and blood samples were obtained at fixed intervals after the fourth dose of each treatment.There was less fluctuation in the plasma level—time profile after CR/ZOK than CT and ATL. Plasma concentrations were significantly higher on CR/ZOK than CT at 24 hours after dosing. The relative bioavailability of CR/ZOK to CT was 69.0%.CR/ZOK achieved relatively more uniform beta‐blocking effect over the dose interval. Compared to CT and ATL, the peak effect after CR/ZOK was less pronounced and the beta‐blockade after 24 hours more effective.
A Double‐Blind Comparison of Metoprolol CR/ZOK 50 mg and Atenolol 50 mg Once Daily for Uncomplicated Hypertension
Authors: Klein Gernot , Berger Jürgen , Olsson Gunnar , Menzel Tomas 
Published: March 2013

In a double‐blind study with parallel groups, the clinical bioequivalence of the antihypertensive effect of metoprolol CR/ZOK (controlled release formulation) 50 mg and atenolol 50 mg in ordinary tablets given once daily for uncomplicated hypertension was investigated. Clinical bioequivalence was defined as difference in blood pressure reduction less than 8 mmHg. The study involved 195 patients, 98 on metoprolol CR/ZOK and 97 on atenolol. All patients were taken off antihypertensive therapy during a 2‐week placebo run‐in period. Thereafter the patients were randomly allocated to metoprolol CR/ZOK 50 mg or atenolol 50 mg for 4 weeks. In patients with a diastolic blood pressure remaining above 90 mmHg, the dose was increased to 100 mg daily of the respective drug. After 4 weeks treatment with 50 mg of the two therapies, blood pressure and heart rate was significantly reduced in both treatment groups. At this dose, clinical bioequivalence was found regarding both blood pressure and heart rate reductions. After 8 weeks of therapy (100 mg doses given to 31 in the metoprolol group and 43 in the atenolol group), clinical bioequivalence according to stated definition was found for blood pressures and heart rate reductions, although the reductions of systolic and diastolic blood pressures at rest as well as diastolic blood pressure during exercise were significantly greater in the metoprolol group. In an evaluation of the responder rate after the 8 weeks of treatment, 89% of the patients in the metoprolol CR/ZOK group and 74% in the atenolol group (P < .05) had a diastolic blood pressure reduction to 90 mmHg or less.In conclusion, metoprolol CR/ZOK 50 mg and atenolol 50 mg in a dosage once daily was shown to be clinically bioequivalent. After doubling the dose in those patients who did not respond with a reduction of diastolic blood pressure to 90 mmHg or less on the 50 mg doses, blood pressure reduction was greater in the metoprolol group, although within the limits of defined clinical bioequivalence. Antihypertensive response rate was higher with metoprolol CR/ZOK than atenolol treatment.
BOOK REVIEWS
Authors: Maggio Beth 
Published: March 2013

Book reviewed in this article:Antiepileptic Drugs Third Edition. Editors: R. Levy, R. Mattson, B. Meldrum, I. Penry, and F. DreifussNeuropeptide Y (Karolinska Institute Nobel Conference Series). Editors: Viktor Mutt, KjeiI Fuxe, Tom as Hokfelt, and Jan M. Lundberg.Platelets and Vascular Occlusion Serono Symposia Publications from Raven Press, Vol. 54. Editors: Carlo Patrono and Garret A. FitzGerald.Principles of Clinical Toxicology Thomas A. Gossel and J. Douglas Bricker.New Therapeutic Strategies in Hypertension (Perspectives in Hypertension, Vol. 3) Editors: Norman M. Kaplan, Barry M. Brenner, and John H. Laragh.Presentation of Clinical Data Bert Spilker and John Schoenfelder.Hypertension: Pathophysiology, Diagnosis, and Management Editors: John H. Laragh and Barry M. Brenner.
Metabolic Effects of the Combination of Captopril and Hydrochlorothiazide in Hypertensive Subjects
Authors: Perani Guido , Martignoni Alessandra , Muggia Chiara , Ferrari Tommaso , Simonich Paolo , Pompei Raffaella , Marchesi Eugenia , Finardi Giorgio 
Published: March 2013

The medium‐term (16 weeks) effects of the combination of captopril and hydrochlorothiazide (HCTZ) on some metabolic indexes, particularly on plasma lipoproteins, were evaluated in 20 mild to moderate hypertensive outpatients.After a 4‐week wash‐out period, the subjects were given one tablet of a new commercially available fixed combination once/daily (i.e., captopril 50 mg + HCTZ 25 mg). The dose could be titrated to a maximum of one tablet twice daily according to individual blood pressure responses.Both systolic and diastolic blood pressure significantly decreased at week 4 and showed a further decrease thereafter; the rate of responders (diastolic blood pressure at or below 90 mm Hg at the end of the study) was very high (90%).The only metabolic change was a small though significant increase in HDL cholesterol (P < .05), almost entirely due to an increase in the denser HDL3 subfraction. The atherogenic fractions, namely total cholesterol, LDL cholesterol, and apoprotein B, showed no significant changes. Plasma triglycerides underwent a transient increase at week 8 (P < .05) but thereafter fell. Plasma glucose, creatinine, uric acid, and potassium were unchanged.The fixed combination of captopril and HCTZ seems highly effective in lowering blood pressure and seems devoid of untoward metabolic effects. Its overall impact on the coronary risk profile in hypertensive subjects seems therefore to be favorable.
Use of Serum Theophylline Level as a Guide to Optimum Therapy in Patients with Chronic Obstructive Lung Disease
Authors: Ashutosh Kumar , Bajaj Randhir , Cho Chaidong , Sangani Geeta 
Published: March 2013

Blood and urine samples were collected simultaneously with measurements of pulmonary function at 2‐hour intervals for 8 hours after oral administration of short‐acting (SAT) and long‐acting theophylline (LAT) preparations in 15 patients with stable chronic obstructive lung disease (COLD) on long‐term maintenance theophylline therapy. The relationship between pulmonary function tests, serum theophylline level, plasma and urinary adenosine 3′5′ cyclic monophosphate (cAMP) was examined.The highest forced expiratory volume in one second FEV1 was obtained with STL of 12.8 μg/ml ± 5.21 SD and 9.14 μg/ml ± 6.15 (P <.05) after administration of SAT and LAT, respectively. A further increase in serum theophylline level (STL) offered no therapeutic benefit, and, in fact, was associated with a fall in FEV1 in many instances. Plasma or urinary cAMP measurements did not correlate with STL. STL at which the best pulmonary function is achieved is quite variable in patients with COLD on maintenance theophylline therapy, is frequently less than 10 μg/ml, and can be determined only by repeated measurements of pulmonary function at different STL. Therefore measurements of STL are of limited value in guiding treatment with theophylline.
Influence of Captopril on Urinary Excretion of Furosemide in Hypertensive Subjects
Authors: Fujimura Akio , Shimokawa Yoji , Ebihara Akio 
Published: March 2013

Influence of captopril on urinary excretion of furosemide was examined in a placebo‐controlled, crossover design. Furosemide (20 mg) was injected intravenously in eight hypertensive subjects with pretreatment with captopril (25 mg) or matching placebo. Urine samples for furosemide and sodium were collected during the following intervals: −60 ∼ 0, 0 ∼ 60, 60 ∼ 120, and 120 ∼ 180 minutes after furosemide. Blood samples for plasma renin activity (PRA) and angiotensin II (AII) were obtained, and blood pressure was measured at −60, 0, 60, 120, and 180 minutes after furosemide.No significant difference was observed in urinary excretion of furosemide, volume or sodium between these trials. Although PRA increased following furosemide with captopril, as predicted plasma AII did not increase. Blood pressure significantly decreased following the combined therapy, but not furosemide alone.These data indicate that the urinary excretion of furosemide and its subsequent diuretic effects are not influenced by captopril.