Volume 45, No. 4/2007(April)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Bovine colostrum – Therapeutic synergism involving immuno-modulation, nutritional supplementation and antibacterial action?
A.M. Waaga-Gasser
Abstract
A.M. Waaga-Gasser
A.M. Waaga-Gasser
In this issue of the Journal, Struff and Sprotte review the pharmacology and clinical pharmacology of bovine colostrum preparations. Bovine colostrum has properties similar to human colostrum in stimulating the immune system and more than one of the many present constituents seems to be involved. Bovine colostrum preparations also have value as a nutritional supplement and the importance of this in regard to the pharmacological actions is becoming more clearly defined. The quality and safety of bovine colostrum are subjects of paramount importance. Heat treatment during manufacture can remove pathogens but can also impair efficacy. Thus, the material used in clinical investigations has to be carefully selected, processed and tested before use.
Bovine colostrum contains approximately 90 useful components, the most interesting of which are immune factors and growth factors. Colostrum is also a source of vitamins, minerals, amino acids, proteins, fats and carbohydrates for the newborn. The immune factors present include specific antibodies, immunoglobulins, proline-rich polypeptides, lactoferrin, cytokines and trypsin inhibitors, lysozyme, leukocytes, lactoperoxidases and lactalbumins [Thapa 2005]. There are at least four groups of immune-enhancing factors present including growth factors, immunoglobulins, a putative permeability fraction and a fraction containing enzymes and peptides [van Hooijdonk et al. 2000].
Bovine colostrum has therapeutic effects in a variety of chronic infections of bacterial, viral, parasitic and fungal origin but it has also been used as a nutritional supplement to treat chronic fatigue syndrome, infectious diarrhea, sinusitis and fibromyalgia where it boosts the immune responses of the patient. Immunoglobulins in bovine colostrum preparations are thought to bestow protection against enteric infections [Sarkar et al. 1998] and eradicate certain microbial agents in the human gastrointestinal tract, e.g. Cryptosporidium, Shigella and toxin-producing E. coli. Bovine colostrum also contains antibodies against E. coli, Salmonella, Candida and H.-pylori infections [Stephan et al. 1990] where the preparations may prevent H. pylori from attaching to the lipid-binding sites in the gastric mucosa.
Clinical and experimental studies have thrown light on the pathogenic role of endotoxin in Gram-negative sepsis (for review see [Beutler and Rietschel 2003]) and the putative beneficial effects of bovine colostrum in this disease. Severe sepsis, and probably most prolonged critical illnesses, exhibit a paradoxical combination of both an increased activation and a marked depression of the immune system. Sepsis involves an imbalance between pro- and anti-inflammatory mediators produced by toxin-activated inflammatory cells where both proinflammatory mediators as well as immune paralysis are deleterious to the patient. Monoclonal antibodies and antagonists targeted against toxins and mediators have been used to prevent an overshoot in proinflammatory effects but the results have been disappointing [Baumgartner 1991]. Intravenous immunoglobulins on the other hand can increase bactericidal activity in serum by virtue of the neutralizing (endotoxins and exotoxins) and opsonizing IgG and IgM antibodies present and the stimulation of phagocytosis. Mechanisms like these are thought to be responsible for the therapeutic properties of IgG-enriched colostral milk preparations in sepsis since Fitzal and colleagues [2001] could show that when given orally, these preparations attenuate endotoxemia by reducing the intraluminal endotoxin content, reducing bacterial growth, preserving the intestinal wall and preventing the breakdown of the mucosal barrier. Breakdown of the mucosal barrier is a common finding in hemorrhage and leads to hemorrhage-induced endotoxemia [Fitzal et al. 2001]. Orally administered immunoglobulins may inhibit bacterial translocation through the bowel wall in intensive care patients with enteric (Gram-negative) septic shock and the mechanisms involved have been the subject of recent discussion: firstly, the primary site of action of the active immunoglobulins is the upper GI-tract where the translocation of pathogens and their toxins is “blocked”. There are no other comparable therapeutic agents known which can both destroy microbial pathogens and neutralize concomitantly the toxic products of bacterial decay. Secondly, although the mechanism underlying these neutralizing processes is still unclear, the combination of distinct effector molecules and their well-known synergistic actions may have their origin in phylogenetic adaptation and the developments of complex defense mechanisms.
On the other hand, it is clear that bovine colostrum is not only a substance with immunological properties but it is also a natural product with characteristics of a balanced dietary supplement, i.e. it contains nutritional components which contribute to the anabolic, energy, vitamin and trace element requirements of the body. Although the duration of treatment with bovine colostrum and intake (dose-response relationships) have not yet been optimized, bovine colostrum preparations could become useful therapeutic agents in severe human diseases involving impairment of immune defense systems. References
Baumgartner JD. Immunotherapy with antibodies to core lipopolysaccharide: a critical appraisal. Infect Dis Clin North Am. 1991; 5: 915-927.
Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxins. Nature Reviews/Immunology. 2003; 3: 169-176.
Fitzal F, Racz I, Hamar J, Redl H, Bahrami S. Immunoglobulin enriched colostral milk reduces gut-derived endotoxemia in a rat hemorrhage model. Eur J Trauma. 2001; 5: 257-263.
Sarkar SA, Casswall TH, Mahalanabis D et al. Successful treatment of rotavirus diarrhea in children with immunoglobulin from immunized bovine colostrum. Pediatr Infect Dis J. 1998; 17: 1149-1154.
Stephan W et al. Antibodies from colostrum in oral immunotherapy. J Clin Chem Biochem. 1990; 28: 19-23.
Thapa BR. Health factors in colostrum. Indian J Pediatr. 2005; 72: 579-581.
van Hoojidonk AC, Kussendrager KD, Steijns JM. In vivo antimicrobial and antiviral activity of components in bovine mild and colostrums involved in non-specific defence. Br J Nutr. 2000; 84 (S-1): 127-134. Correspondence to:
Prof. Dr. A.M. Waaga-Gasser Department of Surgery I, Molecular Oncology and Immunology, University of Würzburg, Oberdürrbacher Straße 61 97080 Würzburg, Germany
Email: Waaga-Gasser@chirurgie.uni-wuerzburg.de
Molecular Target Therapy
Bovine colostrum as a biologic in clinical medicine: a review.
Part I: Biotechnological standards, pharmacodynamic and pharmacokinetic characteristics and principles of treatment
W.G. Struff and G. Sprotte
Abstract
W.G. Struff and G. Sprotte
W.G. Struff and G. Sprotte
Bovine colostrum as a biologic in clinical medicine: a review
Part I: Biotechnological standards, pharmacodynamic and pharmacokinetic characteristics and principles of treatment W.G. Struff1 and G. Sprotte2 1Center for Transfusion Medicine, Münster, German Red Cross Blood
Transfusion Service West gGmbH, Münster, and
2Clinic and Policlinic for Anesthesiology, University of Würzburg, Pain Clinic
for Outpatients, Würzburg, Germany
Mammals supply their newborn before birth, at birth or shortly after birth with antibodies, immunocytes and humoral constituents. This “borrowed immunity” is a form of passive immunization to protect the newborn against environmental pathogens until it establishes its own pathogen recognition and disposal systems. In cows, goats, horses and some other animal species, most immunoglobulins are obtained from the colostrum, the first milk after birth, via the gut but in humans the majority of immunoglobulins, and those of the IgG-class in particular, are acquired from the mother by placental transport in the weeks prior to parturition. It has long been known that the consumption of bovine colostrum by humans has therapeutic effects e.g. in gastrointestinal infections, but only since the second half of the last century has it been possible to prepare stable, standardized preparations of colostrum. These biologics are administered to patients in combination with standard therapies as so-called balanced supportive diets. Investigations with standardized colostrum preparations in animal models of human disease and estimates of bovine IgG activity in the human GI-tract, described in this review, have provided preclinical data supporting the use of bovine colostrum in human diseases. On the other hand, the number of bovine colostrum products with a sufficiently large and reliable database is limited and the precise nature of the therapeutic targets is still being evaluated.Correspondence to:
W.G. Struff Center for Transfusion Medicine Münster German Red Cross Blood Transfusion Service West gGmbH Sperlichstraße 15 48151 Münster, Germany
Email: w.struff@bsdwest.de
Pharmacoeconomics
Cost-effectiveness and cost-utility of insulin glargine compared with NPH insulin based on a 10-year simulation of long-term complications with the Diabetes Mellitus Model in patients with type 2 diabetes in Switzerland
M. Brändle, M. Azoulay and R.-A. Greiner
Abstract
M. Brändle, M. Azoulay and R.-A. Greiner
M. Brändle, M. Azoulay and R.-A. Greiner
Cost-effectiveness and cost-utility of insulin glargine compared with NPH insulin based on a 10-year simulation of long-term complications with the Diabetes Mellitus Model in patients with type 2 diabetes in Switzerland M. Brändle1, M. Azoulay2 and R.-A. Greiner3 1Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, 2sanofi-aventis (suisse) sa, Meyrin, Switzerland, and 3Health Economics Consultant, Lörrach, Germany
Objective: The objective of this study was to evaluate the cost-effectiveness of insulin glargine compared with NPH insulin in patients with type 2 diabetes and in whom OAD (oral anti-diabetics) had failed in Switzerland. Methods: Long-term diabetes outcomes were simulated with the Diabetes Mellitus Model (DMM) over a period of 10 years. The incidences of long-term complications (micro- and macrovascular events) were simulated for 10,000 patients over 10 years for six different scenarios. The scenarios were based on HbA1c reductions observed in clinical trials. For insulin glargine, HbA1c reductions of 0.96% (pessimistic case) and 1.24% (optimistic case) were simulated for three different HbA1c baseline values (10, 9 and 8%). For NPH insulin the HbA1c reduction was assumed to be 0.84%. A cost model and a utility model were developed in order to use the cumulated incidences of the simulations for the calculation of cost and QALYs (quality-adjusted life years). The unit costs of micro- and macrovascular events were assessed on the basis of published literature and guideline-projected resource-use estimations for Switzerland. Disutility values of diabetes-related long-term complications were derived from the literature. Total direct medical costs or QALYs were assessed by a combination of cumulated incidences of each event up to 10 years with the corresponding unit cost per event (in addition to the acquisition cost) or with disutility values per event, respectively. Events, total cost, and QALYs were discounted at 3%. In scenarios where no savings could be shown for insulin glargine, incremental cost-effectiveness ratios were calculated as the incremental cost per event prevented and the cost per QALY gained. Results: Cost comparison demonstrated that insulin glargine is the dominant strategy for the optimistic case scenario starting at a baseline HbA1c value of 10% as savings in the management of complications exceeded the difference in acquisition costs after 8 years of treatment. Optimistic case scenarios for baseline HbA1c values of 9 and 8% achieved costs per QALY gained amounting to CHF 2,853 and CHF 5,711 and costs per event prevented amounting to CHF 2,054 and CHF 4,899, respectively. Pessimistic case scenarios for baseline HbA1c values of 10, 9 and 8% resulted in costs per QALY gained amounting to CHF 40,441, CHF 45,701 and CHF 49,468 and costs per event prevented amounting to CHF 27,742, CHF 32,451 and CHF 41,620, respectively. Conclusions: This study investigated the long-term health-economic implications of treating type 2 diabetes patients, in whom OAD had failed, with insulin glargine versus NPH insulin in Switzerland. The 10-year simulations demonstrated that the DHbA1c reductions of 0.4 and 0.12% achieved with insulin glargine led to a reduction of long-term complications, mortality and associated costs as well as to an improved quality of life. Insulin glargine proved to be cost-effective and represents good to excellent value for money compared to NPH insulin.Correspondence to:
PD Dr. M. Brändle, M.S. Division of Endocrinology and Diabetes Department of Internal Medicine Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland
Email: Michael.Braendle@kssg.ch
Therapeutics
Antipyretic efficacy and safety of a single intravenous administration of 15 mg/kg paracetamol versus 30 mg/kg propacetamol in children with acute fever due to infection
J.-F. Duhamel, E. Le Gall, M.-L. Dalphin and C. Payen-Champenois
Abstract
J.-F. Duhamel, E. Le Gall, M.-L. Dalphin and C. Payen-Champenois
J.-F. Duhamel, E. Le Gall, M.-L. Dalphin and C. Payen-Champenois
Antipyretic efficacy and safety of a single intravenous administration of 15 mg/kg paracetamol versus 30 mg/kg propacetamol in children with acute fever due to infection J.-F. Duhamel1, E. Le Gall2, M.-L. Dalphin3 and C. Payen-Champenois4 1CHU Caen, Pediatric Service, Caen, 2Hôpital Sud, Pediatric Service, Rennes, 3CHR Saint-Jacques, Besançon, and 4Bristol-Myers Squibb, Rueil-Malmaison, France Objectives: An intravenous formulation of paracetamol and an intravenous formulation of propacetamol (prodrug of paracetamol) were compared in children with acute fever due to infection in order to determine the antipyretic efficacy and safety during the 6-hour period after administration. Methods: A total of 67 patients aged 1 month to 12 years and with a rectal body temperature between 38.5 °C and 41 °C, were randomized to receive either intravenous paracetamol 15 mg/kg (n = 35) or propacetamol 30 mg/kg (n = 32) under double-blind conditions. Results: The non-inferiority of intravenous paracetamol compared to propacetamol was demonstrated (non-inferiority margin = 0.5 °C) by the median body temperature reduction of 1.9 °C in the intravenous paracetamol group and the reduction of 2.05 °C in the propacetamol group. The difference in the incidence of local adverse events was statistically significant (p = 0.0134) with more local adverse events in the propacetamol group (9, 28.1%) than in the intravenous paracetamol group (2, 5.7%). Conclusion: This double-blind, randomized, clinical trial demonstrates the non-inferiority of a single administration of 15 mg/kg intravenous paracetamol in comparison to 30 mg/kg propacetamol in terms of body temperature reduction in children aged 1 month to 12 years with acute fever due to infection. It confirms the better local safety of intravenous paracetamol in comparison to propacetamol.Correspondence to:
Pr. J.-F. Duhamel, MD CHU Caen Pediatric Service Avenue Georges Clémenceau 14033 Caen cedex, France
Email: duhamel-jf@chu-caen.fr
Therapeutics
Efficacy of a single evening dose of a syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate in subjects with multiple common cold symptoms
H. Mizoguchi, A. Wilson, G.R. Jerdack, J.D. Hull, M. Goodale, J.M. Grender and B.A. Tyler
Abstract
H. Mizoguchi, A. Wilson, G.R. Jerdack, J.D. Hull, M. Goodale, J.M. Grender and B.A. Tyler
H. Mizoguchi, A. Wilson, G.R. Jerdack, J.D. Hull, M. Goodale, J.M. Grender and B.A. Tyler
Objective: The aim of this study was to evaluate the efficacy of a single night-time dose of a syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate in subjects with multiple cold symptoms. Materials: A syrup containing 15 mg dextromethorphan hydrobromide, 7.5 mg doxylamine succinate, 600 mg paracetamol and 8 mg ephedrine sulfate (Wick MediNait® produced by WICK Pharma, Germany, a subsidiary of Procter & Gamble GmbH; test syrup) or placebo (placebo syrup) for oral administration. Methods: This was a randomized, double-blind, placebo-controlled, multi-center, parallel design study. At enrollment, eligible subjects had to have at least moderate nasal congestion and a runny nose, at least mild cough and at least mild pain with one or more of the following: sore throat, sore chest, headache or body pain/aches. Subjects were randomized into either Group T (test syrup) or Group P (placebo syrup). On the evening of enrollment, subjects rated baseline symptoms, ingested the assigned study product and completed symptom-relief assessments at 3 hours post-dosing. Within one hour of awakening the following morning, subjects completed night-time symptom relief and sleep satisfaction assessments. All symptoms were recorded using an Interactive Voice Response system. Treatment comparisons were made after adjusting for the severity of baseline symptom using analysis of covariance. Results: Of 485 subjects who took the study product, 432 (224 in Group T; 208 in Group P) were evaluable for analysis. For the primary endpoint (composite of nasal congestion/runny nose/cough/pain relief scores 3 hours post-dosing), subjects in Group T had clinically and statistically significantly greater relief than Group P (p = 0.0002). Each individual symptom score also showed statistically significant improvement at this time point (p £ 0.017). The next morning, Group T continued to show clinically and statistically significant benefits over Group P on the composite score and each of the individual symptoms (p £ 0.003). Evidence of benefit with the test syrup was also seen in the higher score for overall night-time relief (p < 0.0001) and greater satisfaction on sleep (p = 0.002) compared to placebo syrup. Improvement in individual symptoms after 3 hours was obtained in 16 – 42% more subjects in Group T than in Group P, whereas the percentage of subjects in Group T having Good or Very Good relief the morning after dosing increased by 25 – 68% compared to subjects in Group P. 14 subjects (5 in Group T; 9 in Group P) reported AEs but none of these occurred with an incidence greater than 1%. There were no serious AEs. Conclusions: The results confirm the multi-symptom benefit of a single dose of the test syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate and support its role as an effective and convenient therapy for symptoms of nasal congestion, runny nose, cough and pain/body aches associated with the common cold and for increasing sleep quality disturbed by the common cold.Correspondence to:
H. Mizoguchi, PhD
The Procter & Gamble Company
11510 Reed Hartman Highway
Cincinnati, OH 45241-9974, USA
Email: Mizoguchi.H@pg.com
Therapeutics
Monitoring effects of direct FXa-inhibitors with a new one-step prothrombinase-induced clotting time (PiCT) assay: comparative in vitro investigation with heparin, enoxaparin, fondaparinux and DX 9065a
J. Graff, B. Picard-Willems and S. Harder
Abstract
J. Graff, B. Picard-Willems and S. Harder
J. Graff, B. Picard-Willems and S. Harder
Selective, direct factor Xa-inhibitors are an emerging new class of antithrombotic drugs but their application in therapy may require adequate laboratory monitoring. A recently introduced assay for monitoring anti-FXa-activity using Russell’s viper venom is based on the prothrombinase-induced clotting time (PiCT). In this study comparative data on the performance of PiCT using direct and indirect FXa-inhibitors and measurements of FXa-activity and aPTT are reported. Methods: Whole citrated blood samples from six healthy volunteers were pre-incubated with UFH (0 – 1.0 IU/ml), enoxaparin (0 – 10 µg/ml), fondaparinux (0 – 1.0 µg/ ml) and DX 9065a (0 – 10 µg/ml). PTT, FXa-activity and PiCT in plasma were determined on an ACL coagulation analyzer. PiCT was done with both a 180-sec incubation period before recalcification (2-step), and without (1-step). FXa-activity was based on a chromogenic assay (S2222). Results: FXa-activity was reduced 10 – 40% by the lowest concentration and by 80 – 95% by the highest concentration of all agents. At the highest concentration the maximum prolongation in aPTT exceeded 120 sec with UFH, enoxaparin and DX 9065a but was only marginally prolonged (increase 39 ± 3 sec) by fondaparinux. Prolongation in PiCT was significantly different when the two PiCT-methods were compared e.g. at 1.0 IU/ml UFH, 137 ± 25 (1-step) vs. 187 ± 32 sec (2-step) (p < 0.001); at 10 mg/ml enoxaparin 83 ± 9 sec vs. 130 ± 15 (p < 0.001); at 1.0 µg/ml fondaparinux 48 ± 5 sec vs. 73 ± 9 sec (p < 0.001); at 10 µg/ml DX 9065a 28 ± 3 vs. 25 ± 2 (p < 0.01), respectively. The 2-step method was unable to detect a prolongation in the effects of DX 9065a, and at concentrations < 5 mg/ml clotting times were even shorter (e.g. 13 ± 1 sec at 1.0 µg/ml DX 9065a) than the baseline readings (20 ± 2 sec). Conclusions: Only the 1-step method (i.e. without pre-incubation) seems suitable for the monitoring of new, direct selective FXa-inhibitors.Correspondence to:
Prof. Dr. S. Harder
Institute for Clinical Pharmacology at the Pharmazentrum
Frankfurt
University Hospital Frankfurt/Main
Theodor-Stern-Kai 7
60590 Frankfurt am Main, Germany
Email: harder@em.uni-frankfurt.de
Pharmacodynamics
Statins alter oxidant-antioxidant status and lower exercise-induced oxidative stress
S. Delliaux, J.G. Steinberg, G. Bechis, F. Paganelli, C. Oliver, N. Lesavre and Y. Jammes
Abstract
S. Delliaux, J.G. Steinberg, G. Bechis, F. Paganelli, C. Oliver, N. Lesavre and Y. Jammes
S. Delliaux, J.G. Steinberg, G. Bechis, F. Paganelli, C. Oliver, N. Lesavre and Y. Jammes
Data on effects of statins on resting oxidant-antioxidant status are contradictory and no study has been published on the effects of statins on exercise-induced oxidative stress. We carried out a 6-month longitudinal study in 10 dyslipidemic patients receiving 10 mg/day atorvastatin and 13 healthy sedentary subjects. Thiobarbituric acid reactive substances (TBARS) and reduced ascorbic acid (RAA) were measured in plasma at rest and every 5 minutes after submaximal isometric thumb adduction and handgrip sustained until exhaustion. At inclusion, resting TBARS and RAA levels in controls and patients did not differ and exercise increased TBARS and decreased RAA. Atorvastatin reduced resting TBARS and RAA levels in a time-dependent but lipid-independent manner. The main effect was a post-exercise increase in TBARS, without affecting the post-exercise RAA levels. The reduction in oxidative stress occurred earlier in oxidative muscles involved in thumb adduction. In conclusion, atorvastatin lowers resting oxidant-antioxidant activity: exercise-induced oxidative stress occurs mainly in muscles having a high oxidative capacity.Correspondence to:
Pr. Y. Jammes Laboratoire de Physiopathologie Respiratoire EA 2201 Institut Jean Roche Faculté de Médecine Bd. Pierre Dramard 13916 Marseille cedex 20, France
Email: Jammes.y@jean-roche.univ-mrs.fr
