Volume 46, No. 5/2008(May)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Bovine colostrum as a biologic in clinical medicine: A review – Part II: Clinical studies
W.G. Struff and G. Sprotte
Abstract
W.G. Struff and G. Sprotte
1Center for Transfusion Medicine Muenster, German Red Cross Blood Transfusion Service West gGmbH, Muenster, and 2Clinic and Polyclinic for Anesthesiology, University of Wuerzburg, Pain Clinic for Outpatients, Wuerzburg, Germany
The value of bovine colostrum as a biologic in medicine is documented in clinical trials and supported by relatively large databases containing case reports and anecdotal findings. The main actions include an antibacterial effect and modulation of the immune response. The ability of bovine colostrum concentrates (BCC are polyvalent bovine colostrum concentrates produced from the colostrums of several 100 cows) to neutralize lipopolysaccharides, i.e. endotoxins arising from Gram-negative bacterial pathogens and to inhibit enterogenic endotoxemia in animal models as shown in the last review to have its counterpart in patient therapy. Clinical trials with BCC provide evidence that oral application reduces the influx of LPS from the gut and this appears to be a major mechanism underlying its therapeutic effect in patients at risk for Gram-negative septic shock; data from two well-controlled clinical studies with a total of 100 surgical patients have shown that the inhibition of intestinal LPS absorption measured after the application of BCC not only reduced the LPS levels in the peripheral blood but also inflammatory parameters like IL-6 and CRP were found to be diminished. The usual daily dose of the commercially available BCC preparation, Lactobin® (LC1) is 10 – 20 g daily, but higher doses can be used in the majority of patients because of the low incidence of intolerance problems. In chronic diarrhea involving severe forms of secondary immunodeficiencies, patients receiving LC1 were disease-free for about 4 weeks but the response may be lower in patients with AIDS. BCC is effective in infants with hemorrhagic diarrhea caused by infections with enterohemorrhagic E. coli and reduces the likelihood of the disease progressing to a hemolytic uremic syndrome. The safety of newer BCC products obtained from BSE-free regions seems now beyond contention. In the case of LC1, which was used as a commercial dietary foodstuff in Germany until 1992 and tested in three Phase 1 and 5 clinical studies (two trials in patients with secondary immunodeficiencies, one in surgical patients with gastrointestinal disorders, one in patients undergoing open heart surgery and one in pediatric patients with EHEC infections), there were no cases of BSE-associated disease such as the new variant of Creutzfeldt-Jakob disease. Side effects of clinical relevance are limited to possible intolerance to lactose and sensitivity to milk proteins as these are also present in many commonly used foodstuffs. Important synergistic actions with conventional drug therapies have been observed with BCC including a reduction in LPS plasma levels in patients with Gram-negative bacterial infections treated with bactericidal antibiotics. In healthy persons there are only small concentrations of LPS detectable in peripheral blood (normal values: 3 – 10 pg/ ml plasma, i.e. approximately 0.1 EU/ml). In contrast, elevated systemic levels with concentrations > 300 pg/ml are common in patients with severe Gram-negative sepsis and septic shock. Raised LPS levels occur mainly in patients with Gram-negative bacterial infections who have been treated with bacteriocidal antibiotics. The LPS-lowering effects of BCC are probably due to the numerous active components present in BCC which have their origin in the innate humoral and adaptive immune system of their biologic source, the cow.Correspondence to:
Dr. G. Sprotte; Clinic and Polyclinic for Anesthesiology, University of Wuerzburg, Pain Clinic for Outpatients, Josef-Schneider-Straße 6, 97080 Wuerzburg, Germany
Email: Sprotte_G@klinik.uni-wuerzburg.de
Pharmacodynamics
Mucronulatol from Caribbean propolis exerts cytotoxic effects on human tumor cell lines
D. Díaz-Carballo, M. Freistühler, S. Malak, W. Bardenheuer and H.P. Reusch
Abstract
D. Díaz-Carballo, M. Freistühler, S. Malak, W. Bardenheuer and H.P. Reusch
1Abteilung Klinische Pharmakologie, Ruhr-Universität Bochum, 2Universitätsklinikum Essen, Klinik für Augenheilkunde, Essen and 3Innere Klinik und Poliklinik, Tumorforschung, Universitätsklinikum Essen, Germany
Objective: Mucronulatol is one of the most cytotoxic substances present in Caribbean propolis. This work aimed at initially characterizing the biological effects of mucronulatol in cancer cell lines comprehending both wildtype and resistant sublines. Materials and methods: An RP-HPLC technique was employed to separate and purify mucronulatol. IC50 values were determined using the sulforhodamine B (SRB) proliferation assay. FACS-based cell cycle studies were carried out combining propidium iodide staining and 5-bromo-2’-deoxyuridine incorporation. Cell cycle regulator proteins were detected by Western blotting. The transcription of genes of interest was analyzed using RT-PCR. Results: In MDR1–/MDR3+ cells, mucronulatol exhibited cytotoxicity in the range of 2.7 – 10.2 µg/ml, while no cytotoxic effects were observed in MDR1+ systems at up to 100 µg/ml. Cytometric studies revealed that mucronulatol promoted a global reduction in all cell cycle phases, with a remarkable increase of the apoptotic sub-G1 population. Immunoblotting showed that mucronulatol induced an up-regulation of p21Cip1 and p27Kip1 while down-regulating cyclin E and CDK4 in a drug concentration-dependent manner. No effect on topoisomerase I was observed, while we detected an altered expression of topoisomerases II-α/β. RT-PCR studies showed that 2-fold the IC50 in HCT8 colon carcinoma cells was sufficient for altering the expression pattern of genes in this cell line, including topoisomerase I, thymidilate synthase, EGF receptor and c-myc, amongst others. Conclusion: Here, we demonstrate for the first time that mucronulatol exerts cytotoxicity in cancer cell lines by targeting the control of cell cycle progression, indicating that the mechanism of action of this compound involves interference with the cell cycle machinery.Correspondence to:
Dr. D. Díaz-Carballo; Abteilung Klinische Pharmakologie, Ruhr-Universität, Bochum, Universitätsstraße 150, 44801 Bochum, Germany
Email: david.diaz-carballo@rub.de
Clinical Trials
A Phase I study of CR002, a fully-human monoclonal antibody against platelet-derived growth factor-D
T. Hawthorne, L. Giot, L. Blake, B. Kuang, R. Gerwien, G. Smithson, W. Hahne, T. Mansfield, G.C. Starling, P. Pochart, D. Hoelscher and Y.-D. Halvorsen
Abstract
T. Hawthorne, L. Giot, L. Blake, B. Kuang, R. Gerwien, G. Smithson, W. Hahne, T. Mansfield, G.C. Starling, P. Pochart, D. Hoelscher and Y.-D. Halvorsen
1CuraGen Corporation, Branford, CT and 2Pharmaceutical Product Development (PPD), Austin, TX, USA
Objective: To investigate the safety, pharmacokinetics (PK), binding activity and immunogenicity of CR002, a human monoclonal antibody (mAb) directed against platelet-derived growth factor-D (PDGF-D), administered as a single intravenous (i.v.) infusion over a range of doses. Subjects: 40 healthy male subjects received increasing doses of CR002 at 0.3, 1, 3, 10, 30 mg/kg or placebo. Method: This was a randomized, double-blind, placebo-controlled, dose-escalation Phase I study. The trial had a duration of 90 days, with dosing on Day 1 and follow-up visits on Days 2, 4, 7, 14, 21, 30, 45 and 90. Serum was collected for PK, binding activity and immunogenicity analysis at screening and up to Day 90. Safety was recorded throughout the study by performing laboratory tests, recording vital signs and electrocardiograms (ECGs), by monitoring the occurrence of adverse events (AEs). The use of concomitant medications was also recorded. Results: All 40 subjects received CR002 or placebo, and completed the trial. No dose-limiting toxicities (DLTs) occurred, the maximum tolerated dose (MTD) was not reached and was estimated as > 30 mg/kg. There were no deaths during this study and no SAEs or other significant AEs reported. The most frequent drug-related treatment-emergent AE (TEAE) was headache in 4 of 30 subjects (13.3%) in the CR002 group vs. 0 of 10 subjects in the placebo group. CR002 exhibited linear PK parameters, had a long half-life (t1/2 in the range 15.5 – 48.1 days) and a volume of distribution at steady state in the range 4.7 – 6.5. Free PDGF-D in the serum bound to CR002 in a reversible manner, as shown in the lowest dose cohort. However, levels of total circulating PDGF-D remained constant throughout the study. There were no anti-CR002 antibodies detected in subjects dosed with CR002. Conclusions: CR002 was safe and well-tolerated at all doses tested as a single i.v. administration. The MTD was estimated to be above 30 mg/kg, the highest dose tested. CR002 had a long half-life, low clearance and a limited tissue distribution. Although total levels of PDGF-D at all dose levels remained relatively constant, there was no detectable circulating free PDGF-D after CR002 administration. At the lowest CR002 dose tested (0.3 mg/kg), PDGF-D was detectable again by Day 21 and the levels increased near to pre-infusion levels by Day 90. In this study, CR002 was not immunogenic during the 90-day study period.Correspondence to:
Y.-D. Halvorsen, PhD; CuraGen Corporation, 322 E. Main Street, Branford, CT 06405, USA
Email: yhalvorsen@ccib.mgh.harvard.edu
Clinical Trials
Clinical and social correlates with the use of depot antipsychotic drugs in outpatients with schizophrenia in China
Y.-T. Xiang, Y.-Z. Weng, C.-M. Leung, W.-K. Tang and G.S. Ungvari
Abstract
Y.-T. Xiang, Y.-Z. Weng, C.-M. Leung, W.-K. Tang and G.S. Ungvari
1Beijing Anding Hospital, Capital Medical University, Beijing and 2Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
Background: To date, no study has investigated the use of depot antipsychotic medication (DA) in Chinese outpatients with schizophrenia. This study explored the frequency and sociodemographic and clinical correlates of DA in schizophrenia outpatients in both Hong Kong (HK) and Beijing (BJ), China. Methods: 505 clinically stable outpatients with schizophrenia were randomly selected and interviewed in HK and BJ using standardized assessment instruments. Their basic sociodemographic and clinical data and psychotropic drug prescriptions were collected at the time of a diagnostic interview. Results: 117 (23.2%) patients were prescribed DA, 36.1 and 10% of the HK and BJ samples, respectively. Prescription of DA was associated with a history of suicide, less use of clozapine, more frequent antipsychotic polypharmacy (APP), more frequent admissions, and study site (HK vs. BJ). In multiple logistic regression analysis, study site, less frequent prescription of clozapine, history of suicide, and more frequent use of APP remained significantly associated with DA. Conclusion: There was wide variation in the frequency of DA prescribing between HK and BJ even though the ethnic and clinical characteristics of the two samples were nearly identical. This suggests that sociocultural and economic factors, as well as traditions in psychiatric training and practice all played a role in determining the use of DA.
Correspondence to:
Dr. Y.-T. Xiang; Department of Psychiatry, Shatin Hospital, Shatin, N.T. Hong Kong SAR, China
Email: xyutly@cuhk.edu.hk
Pharmacokinetics
A study of dose-proportionality in the pharmacokinetics of the oral direct renin inhibitor aliskiren in healthy subjects
D. Limoges, H.A. Dieterich, C.-M. Yeh, S. Vaidyanathan, D. Howard and W.P. Dole
Abstract
D. Limoges, H.A. Dieterich, C.-M. Yeh, S. Vaidyanathan, D. Howard and W.P. Dole
1Novartis Pharma AG, Basel, Switzerland, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ and 3Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA
Objective: To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension. Methods: This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 – 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and Cmax were analyzed to determine dose-proportionality using the power model, parameter = A*(Dose)β, where A = intercept and β = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 – 600 mg were 90% confidence intervals (CI) for β contained within the range 0.89 – 1.11. Results: AUC and Cmax values increased with increasing doses of aliskiren. Both AUC and Cmax were associated with high variability (coefficient of variation 55 – 64% for AUC and 59 – 117% for Cmax). The estimated proportionality coefficients (β) for AUC0-¥, AUC0-t and Cmax were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 – 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and Cmax, respectively. All doses of aliskiren were well tolerated. Conclusions: Exposure to aliskiren was greater than proportional over the dose range of 75 – 600 mg. Over the therapeutic dose range of 150 – 300 mg approved for the treatment of hypertension, AUC and Cmax increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.
Correspondence to:
W.P. Dole, MD; Novartis Institutes for Biomedical Research Inc., 400 Technology Square, Building 605-820, Cambridge, MA 02139, USA
Email: bill.dole@novartis.com
Bioavailability Section
Bioequivalence of vildagliptin/metformin fixed-dose combination tablets and a free combination of vildagliptin and metformin in healthy subjects
Y.-L. He, S. Paladini, H. Sabia, J. Campestrini, Y. Zhang, S. Leon, M. Ligueros-Saylan and V. Jarugula
Abstract
Y.-L. He, S. Paladini, H. Sabia, J. Campestrini, Y. Zhang, S. Leon, M. Ligueros-Saylan and V. Jarugula
1Novartis Institutes for Biomedical Research Inc., Cambridge, MA, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, and 3Novartis Pharma S.A., Rueil-Malmaison, France
Objective: To assess the bioequivalence of vildagliptin/metformin fixed-dose combination tablets (at doses of 50/500, 50/850 and 50/1,000 mg) with free combination of the individual drugs in healthy subjects. Methods: The pharmacokinetics of vildagliptin and metformin following administration of a fixed-dose combination tablet of vildagliptin/metformin at doses of 50/500 mg (Study I), 50/850 mg (Study II) and 50/1,000 mg (Study III) compared with administration of the individual drugs as free combinations were investigated. All three studies were open-label, single-center, randomized, two-period, two-treatment crossover studies in healthy subjects. Results: Pharmacokinetic parameters (AUC0-¥, Cmax, tmax, t1/2 and CL/F) for vildagliptin and metformin across the three studies were similar whether vildagliptin and metformin were administered as a single fixed-dose combination tablet (vildagliptin/metformin 50/500, 50/850 or 50/1,000 mg) or as the respective individual tablets. The point estimates and 90% CI of the geometric mean ratios for vildagliptin and metformin Cmax, AUC0-t, and AUC0-¥ were all within the predefined bioequivalence range of 0.80 – 1.25. Administration of the vildagliptin/metformin combination tablets was well tolerated; the incidence of adverse events was similar to that observed with the respective free combinations of vildagliptin and metformin, and the most common individual adverse events were mild gastrointestinal events, which are commonly observed with metformin treatment. Conclusions: The fixed-dose combination tablet of vildagliptin/metformin is bioequivalent to administration of the individual drugs as a free combination at dose levels of 50/500, 50/850 and 50/1,000 mg and is well tolerated. Consequently, the fixed-dose combination tablets are considered therapeutically equivalent and exchangeable to the free combination in clinical practice. Furthermore, the fixed-dose combination tablets are expected to enhance convenience and thereby improve compliance and improve glycemic control for patients with Type 2 diabetes on both medications.
Correspondence to:
Y.-L. He, PhD, DMSc; Exploratory Development, Novartis Institutes for Biomedical Research Inc., 400 Technology Square, Building 605, Cambridge, MA 02139-3584, USA
Email: yanling.he@novartis.com
Bioavailability Section
Comparative bioavailability of two cetirizine tablet formulations in Indonesian healthy volunteers
Y. Harahap, B. Prasaja, E. Indriati, W. Lusthom and Lipin
Abstract
Y. Harahap, B. Prasaja, E. Indriati, W. Lusthom and Lipin
1Department of Pharmacy, Faculty of Mathematics and Science, University of Indonesia, Depok, 2Clinisindo Laboratories, Jakarta and Indonesia
Aim: To compare the bioavailability of two cetirizine tablet (10 mg) formulations (Zyrtec® from UCB Pharma, Spain as a reference formulation and Ryvel® from Novell Pharmaceutical Laboratories, Indonesia as a test formulation). Material and methods: The study was conducted according to an open, randomized, two-period crossover design with a 1-week washout period. Eighteen volunteers participated and all completed the study successfully. Blood samples were obtained prior to dosing and at 0.25, 0.5, 1, 2, 3, 5, 8, 12, 24 and 30 hours after drug administration. Plasma concentrations of cetirizine were monitored using high-performance liquid chromatography over a period of 30 hours after administration. The pharmacokinetics parameter AUC0–30h, AUC0–¥ and Cmax were tested for bioequivalence after log-transformation of data and ratios of tmax were evaluated non-parametrically. Result: The point estimates and 90% confidence intervals for AUC0–30h, AUC0–¥ and Cmax were 108.23% (101.90 – 114.95%), 108.11% (101.91 – 114.68%) and 99.71% (90.18 – 110.25%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products an the US Food and Drug Administration guidelines. Conclusion: These results indicate that two medications of cetirizine are bioequivalent and, thus, may be prescribed interchangeably.Correspondence to:
Dr. Y. Harahap, MS; Department of Pharmacy, Faculty of Mathematic and Science, University of Indonesia, Depok, 16424 Indonesia
Email: yahdiana03@yahoo.com
