Igor Francetić

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

PurposeThe purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.MethodsComplications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.ResultsClinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.ConclusionsCurrent issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.

Pharmacokinetic Changes in Patients With Oedema

SummaryThe pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t½) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant.The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients.Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t½ increases in these patients.Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of Perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant.In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

Clinical pharmacology consultation: a better answer to safety issues of drug therapy during pregnancy?

PurposeDrug safety classifications give a very basic estimation of risk and should only be used as general guideline when assessing risk of pregnancy-related drug exposure or planning treatment. We conducted a study to assess the strength of association between both the clinical pharmacologists’ risk assessment and the FDA risk categorization, and adverse pregnancy outcomes.MethodsWe retrospectively reviewed records of 1,076 patients consecutively referred to the clinical pharmacology outpatient clinic for pregnancy-related drug exposure (2000–2008). Clinical pharmacologists’ risk assessments were reviewed in relation to FDA drug categorization and available pregnancy outcomes.ResultsOverall, clinical pharmacologists’ risk estimation was in agreement with the FDA risk categorization system in only 28% of consulted women, and in only 9% of women with high-risk exposure (FDA DX). Clinical pharmacologists’ risk assessment confirming high-risk drug exposure had a better positive predictive value for adverse pregnancy outcomes than the FDA DX categorization (25% vs 14% respectively), while the negative predictive values were similar (92% vs 94% respectively). Clinical pharmacologists’ risk assessment was a better predictor of adverse pregnancy outcomes compared with FDA risk categorization (OR 2.11 [95%CI 1.5-3.1; p < 0.001] vs OR 1.52 [95%CI 1.1-2.1; p = 0.014] respectively).ConclusionsAdditional evaluation beyond the FDA drug classification is essential for safer and more rational drug use in pregnancy. Clinical pharmacologists who have undergone rigorous medical training are ideally placed to consult on administration of medicines in pregnant women, thus making the prescribing of treatments in that patient category substantially safer and more rational.

The effects of problem-based learning integration in a course on rational drug use: a comparative study between two Croatian medical schools.

PurposeYoung doctors write prescriptions regularly from their first day of practice. We investigated final-semester students’ perceptions of their training in relation to prescribing in two Croatian medical schools with different clinical pharmacology (CPT) teaching styles (Zagreb: problem-based and Rijeka: lecture-based course).MethodsA total of 315 students (220 in Zagreb, 95 in Rijeka) underwent a 4-week-long course in CPT in the academic year 2006/2007. We compared the impact of different educational methods on student performance using an MCQ assessment. After the training, students completed a paper questionnaire on prescribing skills and knowledge of pharmacotherapy.ResultsStudents in Rijeka were significantly more satisfied with their traditional lecture-based course. Only 56% of Zagreb students and 54% of students from Rijeka felt confident about their prescription-writing skills. Only 8% of Zagreb and none of Rijeka students had written more than six prescriptions during their entire medical curriculum. There was no difference in the participants’ levels of factual knowledge of rational pharmacotherapy.ConclusionThe style of learning about medicines did not affect students’ factual knowledge. Only half of the student cohort felt confident about their ability to prescribe medicines, and few had practiced this skill during their medical training.

Distributed lags time series analysis versus linear correlation analysis (Pearson's r) in identifying the relationship between antipseudomonal antibiotic consumption and the susceptibility of Pseudomonas aeruginosa isolates in a single Intensive Care Unit of a tertiary hospital

The relationship between antibiotic consumption and selection of resistant strains has been studied mainly by employing conventional statistical methods. A time delay in effect must be anticipated and this has rarely been taken into account in previous studies. Therefore, distributed lags time series analysis and simple linear correlation were compared in their ability to evaluate this relationship. Data on monthly antibiotic consumption for ciprofloxacin, piperacillin/tazobactam, carbapenems and cefepime as well as Pseudomonas aeruginosa susceptibility were retrospectively collected for the period April 2006 to July 2007. Using distributed lags analysis, a significant temporal relationship was identified between ciprofloxacin, meropenem and cefepime consumption and the resistance rates of P. aeruginosa isolates to these antibiotics. This effect was lagged for ciprofloxacin and cefepime [1 month (R=0.827, P=0.039) and 2 months (R=0.962, P=0.001), respectively] and was simultaneous for meropenem (lag 0, R=0.876, P=0.002). Furthermore, a significant concomitant effect of meropenem consumption on the appearance of multidrug-resistant P. aeruginosa strains (resistant to three or more representatives of classes of antibiotics) was identified (lag 0, R=0.992, P<0.001). This effect was not delayed and it was therefore identified both by distributed lags analysis and the Pearsons correlation coefficient. Correlation coefficient analysis was not able to identify relationships between antibiotic consumption and bacterial resistance when the effect was delayed. These results indicate that the use of diverse statistical methods can yield significantly different results, thus leading to the introduction of possibly inappropriate infection control measures.

Inadequate Use of Preventive Strategies in Patients Receiving NSAIDs

AbstractObjective: Little is known about the factors that influence the decision to use NSAIDs in combination with gastroprotective drugs. The aims of this observational study were to evaluate the extent to which NSAID users are prescribed concomitant gastroprotective drug regimens (‘preventive strategies’), and to determine how patient risk factors for NSAID-associated gastrointestinal toxicity and physician prescribing preferences influenced the decision to prescribe a gastroprotective drug in combination with an NSAID. Design and patients: The study was conducted on 29 June 2004 and comprised 109 eligible adult patients hospitalised at the Clinical Hospital Center, Zagreb. Use of NSAIDs and gastroprotective drugs, risk factors for NSAID-associated gastrointestinal toxicity, and physician prescribing preferences were monitored throughout the study. Results: Sixty-six percent of patients receiving proton pump inhibitors or histamine H2-receptor antagonists with NSAIDs had no risk factors for gastrointestinal toxicity. Furthermore, 29% of patients who used NSAIDs had risk factors for gastrointestinal toxicity but were not receiving gastroprotective drugs. Even though patients at risk of NSAID-associated gastrointestinal complications had higher odds of receiving preventive strategies (odds ratio 1.25), the absolute rate of utilisation of these therapies in at-risk populations was unacceptably low (69%). However, the strongest independent correlation for gastroprotective drug use was the prescribing physician, with an odds ratio of 6.40. Conclusion: This study demonstrates that an individual physician’s prescribing style largely determines the odds of receiving preventive strategies with NSAID treatment and is more important than the patient’s risk factors for gastrointestinal toxicity.

IS REFERRING PATIENTS WITH A POSITIVE HISTORY OF ALLERGIC DRUG REACTIONS OR ATOPY FOR ALLERGY TESTING TO LOCAL ANESTHETICS JUSTIFIED

Although no more than 1% of adverse reactions to local anesthetics (LA) are thought to be immunologically mediated, many patients continue to be referred to allergy clinics for allergy workup. We evaluated the impact of a history of drug hypersensitivity or atopy on results of allergy testing to LA, with the aim of determining the appropriateness of allergy testing to LA in such patients. We retrospectively analyzed medical records of 112 consecutive patients referred for allergy testing to LA in a 9-year period (1996-2005). Intradermal tests with diluted (1:10) LA were performed to identify patients at risk for immunoglobulin E (IgE)-mediated hypersensitivity reaction. The odds for being testpositive were calculated with regard to the defined risk factors (atopy, history of adverse reactions to LA or other drugs, underlying autoimmune disease). Eleven of 112 patients (9.8%) tested positive for allergy to LA. Atopy, history of adverse reactions to LA or other drugs and underlying autoimmune disease did not increase the odds for being test-positive. The prevalence of multiple drug hypersensitivity, IgE values and eosinophil count were not significantly higher among the patients who tested positive as compared to the patients who tested negative. According to our data, allergy testing to LA is not justified in patients with atopy or histories of adverse drug reactions other than to LA. Further studies using validated methods of allergy testing to LA coupled with analysis of defined risk factors are needed to definitively establish the indications for referral of patients for allergy testing to LA.

Online learning applied to a course on rational therapeutics: an international comparison between final year students of two medical schools

Poor prescribing is probably the most common cause of preventable medication errors and many of these events involve junior doctors. In 2009, an electronic problem‐based therapeutics course developed at the University of Michigan Medical School (UMMS) was translated and adapted for use at the University of Zagreb Medical School (UZMS).

Avoiding concomitant prescription of drugs with a potential for interaction: mission impossible?

OBJECTIVE The increased prevalence of multi-drug therapy increases the risk of drug interactions. We conducted a study with the aim of evaluating the prevalence of prescribing potentially interacting drug combinations, their severity, mechanism, and in particular, their clinical relevance, in medical inpatients at two Croatian university hospitals. METHODS A cross-sectional study was conducted that included all medical inpatients receiving >= 2 drugs. Data were analyzed for 200 predefined drug-drug combinations compiled from the Micromedex data-base and literature. Two rating scales were used, one indicating the severity of a potential drug-drug interaction (pDDI) (minor, moderate, major), and the other assessing its clinical relevance (1: contraindicated; 2: avoidable; 3: consider risk-benefit ratio; 4: hardly avoidable). RESULTS The prescribing patterns were similar between evaluated hospitals. The prevalence of pDDIs was 46%. The mean number of drugs prescribed per patient was 6.2 (± 95% CI 5.9 - 6.5). Out of 200 predefined pDDIs, 96 were found in our study population with mean 2.8 pDDIs per patient (± 95% CI 2.4 - 3.1). Out of 478 single identified pDDIs, most were of moderate and major severity (56% and 33%, respectively). However, only 9% out of them were considered completely avoidable, 57% were considered hardly avoidable, and for 35% the consideration of risk-benefit ratio was recommended. Most pDDIs were classified as pharmacodynamic by mechanism of interaction (45%). Age and number of prescribed drugs were significant risk factors for prescription of potentially interacting drug combinations (OR 1.01 (± 95% CI 1.001 - 1.03) and OR 1.46 (± 95% CI 1.33 - 1.59), respectively). CONCLUSIONS Despite the high prevalence of pDDIs, only 1 in 10 was considered avoidable.