Subjective Reasons for Non-Reporting of Adverse Drug Reactions in a Sample of Physicians in Outpatient Care.

INTRODUCTION: Drug safety surveillance strongly depends on the spontaneous reporting of adverse drug reactions (ADRs). A major limiting factor of spontaneous reporting systems is underreporting (UR) which describes incorrectly low reporting rates of ADRs. Factors contributing to UR are numerous and feature country-dependent differences. Understanding causes of and factors associated with UR is necessary to facilitate targeted interventions to improve ADR reporting and pharmacovigilance. METHODS: A cross-sectional questionnaire-based telephone survey was performed among physicians in outpatient care in a federal state of Germany. RESULTS: From n=316 eligible physicians n=176 completed the questionnaire (response rate=55.7%). Most of the physicians (n=137/77.8%) stated that they report ADRs which they have observed to the competent authority rarely (n=59/33.5%), very rarely (n=59/33.5%) or never (n=19/10.8%); the majority (n=123/69.9%) had not reported any ADRs in 2014. Frequent subjective reasons for non-reporting of ADR were (specified response options): lack of time (n=52/29.5%), the subjective evaluation that the required process of reporting is complicated (n=47/26.7%) or requires too much time (n=25/14.2%) or the assessment that reporting of an ADR is needless (n=22/12.5%); within open answers the participants frequently stated that they do not report ADRs that are already known (n=72/40.9%) and they only report severe ADRs (n=46/26.1%). DISCUSSION: Our results suggest a need to inform physicians about pharmacovigilance and to modify the required procedure of ADR reporting or to offer other reporting options.

Post-transplant diabetes mellitus - risk factors and effects on the function and morphology of the allograft.

The incidence of post-transplant diabetes mellitus and its effects on the kidney allograft function and morphology were assessed. Patients were divided into three groups according to their glucose metabolism. Risk factors for diabetes were first assessed, and then changes in renal function were checked. Morphological changes in the allografts were examined by protocol biopsies. The overall incidence of diabetes was 16%. The development of diabetes was influenced significantly by the body mass index, the body weight and the age of the recipient. The incidence of diabetes was 8.6% in patients on cyclosporine A therapy and 28.8% in those on tacrolimus (p < 0.05). As to the morphology of the kidney, a significantly higher proportion of the biopsies showed severe interstitial fibrosis/tubular atrophy (p = 0.0004) and subclinical acute rejection ( p = 0.001) in the diabetic group compared to the normal one. This clinical study has revealed that the adverse effect of diabetes on the allograft can be detected with protocol biopsy before the manifestation of a functional deterioration.

Functional and histopathologic changes in renal transplant patients with new-onset diabetes and dyslipidemia.

BACKGROUND: The principal risk factors for cardiovascular mortality posttransplantation are hyperglycemia, hypertriglyceridemia, obesity, and smoking. METHODS: Among 115 patients, we assessed the risk factors for new-onset diabetes (NODM) and dyslipidemia (NODL), and their effects on the function and histopathologic changes in the allografts at 1 year posttransplantation. RESULTS: When evaluating the risk factors and the initial recipient data, we observed a significant difference in age when comparing normal vs NODM patients (P=.004), normal versus NODL patients (P=.002), and normal versus NODL + NODM patients (P=.0001). The difference in body mass index (BMI) was significant when comparing normal with NODM + NODL patients (P=.003). In regard to immunosuppressive therapy, NODM was significantly more frequent among/prescribed tacrolimus (tac; P=.005), whereas subjects who received cyclosporine (CsA) showed a significantly higher incidence of NODL (P=.001). The triglyceride levels were 3.02 ± 1.51 mmol/L among those on CsA versus 2.15 ± 1.57 mmol/L for (P=.004). The difference also proved to be significant for total cholesterol level: 5.43 ± 1.23 mmol/L versus 4.42 ± 1.31 mmol/L respectively (P=.001). In regard to allograft function a significant difference was noted at 1 year after transplantation between the NODM + NODL and the normal group in serum creatinine level (P=.02) as well as the estimated glomerular filtration rate (P=.004). Among diabetic patients, the serum creatinine level measured at posttransplant year 5 was significantly higher than that in 1 year (212.43 vs 147.00 µmol/L; P=.0003). When assessing morphologic changes in the kidney, we observed significantly more frequent interstitial fibrosis/tubular atrophy in all 3 groups compared with normal function patients. CONCLUSION: Our clinical study suggested that at 1 year after transplantation allograft function is already impaired in the presence of both medical conditions (NODM and NODL). However, in regard to morphology, a single condition (NODM or NODL) was sufficient to produce histologic changes in the kidney.

Benefits of periodontal therapy when preterm birth threatens.

There is growing evidence that chronic periodontitis may be a risk factor for pre-term birth. The goal of this intervention study was to determine the effect of periodontal treatment on the pregnancy outcome in women with threatening pre-term birth and initial localized chronic periodontitis. Forty-one women with a singleton pregnancy were enrolled in the study. For this treatment group, oral hygiene instruction and periodontal therapy were provided in the third trimester, while those in the control group (42 persons) did not receive any periodontal treatment. In the treatment group, the mean weight of newborns was 3079.0 g, compared with the control group mean of 2602.4 g. The incidence of pre-term birth and low birthweight in the treatment group was significantly less than in the control group (p = 0.015). Periodontal treatment completed before the 35th week appeared to have a beneficial effect on birth weight and time of delivery.

Levofloxacin versus clarithromycin in COPD exacerbation: focus on exacerbation-free interval.

Antibiotic treatment of bacterial exacerbation of chronic obstructive pulmonary disease (COPD) shows some immediate clinical benefits and may also minimise the frequency of further recurrences. Patients (n=511) were enrolled into a randomised double-blind multicentric study comparing the exacerbation-free interval (EFI), efficacy and safety of 7-day levofloxacin versus 10-day clarithromycin in patients with COPD exacerbation. Patients were monitored over a 1-yr period. A total of 434 patients (per protocol population) received the medication for > or =5 days. The median EFI in the per protocol population was 300 days for levofloxacin and 350 days for clarithromycin. For patients with a new documented exacerbation during follow-up (n=223), the median EFI was 100.5 days in the levofloxacin group and 95 days for clarithromycin. No significant differences in EFI between groups could be observed when stratifying the study population according to microbial aetiology and severity of bronchial obstruction. Levofloxacin and clarithromycin showed similar clinical success rates. The bacteriological success rate was significantly higher in the levofloxacin group. Both antibiotics were well tolerated. In summary, levofloxacin was associated with a significantly higher bacteriological eradication rate but similar exacerbation-free interval in patients with chronic obstructive pulmonary disease exacerbation compared to clarithromycin.

Relationship between the occurrence of anti-SSA, anti-SSB autoantibodies and HLA class II alleles from the aspect of in vitro inhibitory effect of glucocorticosteroid on the antibody-dependent cellular cytotoxicity in patients with primary Sjögren's syndrome.

Though at present there is no evidence-based algorithm for the treatment of primary Sjögren's syndrome, it is generally accepted that glucocorticosteroid (GS) therapy must be introduced in cases with severe systemic manifestations. As the side-effects of the GSs are well known, it would be useful to know in advance how the patients will respond to this type of treatment. For this reason we measured the in vitro steroid sensitivity of 29 SS patients using inhibition of antibody dependent cellular cytotoxicity (ADCC) test by methylprednisolone compared to that of 28 controls. SS patients proved to be significantly less sensitive to GSs than controls (inhibition of ADCC reaction: 42.4 vs 53.1%; p < 0.01). This was especially true in SS patients with anti-SSA and/or SSB autoantibody positivity and with HLA-DR2 and/or -DR3 alleles. Comparing the results of the in vitro GS sensitivity and the clinical effectiveness of the previously applied corticosteroid therapy it seems that steroid inhibition of ADCC reaction has a predictive value in determination of in vivo sensitivity to GSs. However, in patients with decreased in vitro GS sensitivity a more expressed in vivo steroid sensitivity cannot be excluded.

Absolute levels of MDR-1, MRP, and BCL-2 MRNA and tumor remission in acute leukemia.

Mononuclear cells prepared from peripheral blood or bone marrow of 119 AML and 28 ALL patients prior and following therapy were analyzed for absolute transcript levels of the chemoresistance genes mdr-1 and MRP, and the proto-oncogene bcl-2, by validated contamination-protected quantitative RT-PCR. In newly diagnosed AML mainly tumors of the granulocytic lineage (FAB M1-M2) expressed increased mdr-1 mRNA amounts. The MRP gene was expressed in all investigated samples without relation to a particular FAB class. High initial expression of both genes did not confer a poor prognosis even at high number of CD34+ cells. Data compared prior to and after therapy start (paired samples) revealed that AML patients who did not respond to therapy (NR) expressed increased levels of mdr-1 mRNA, as well as MRP and bcl-2 cDNA normalized to GAPDH reference transcripts, when compared to patients achieving complete remission (CR; p = 0.003, 0.008 and 0.0005, respectively). In ALL-NR the mdr-1 and bcl-2 genes were entirely more active after induction chemotherapy. Arbitrary cut-off values were established in order to delimit pathological from non-pathological gene expression. 59% of studied AML and 33% of ALL-NR exceeded the arbitrary values (mdr-1: > 2 amol/microgram RNA, MRP: > 10 zmol/amol GAPDH, bcl-2: > 5 zmol/amol GAPDH) for one and 11% of AML-NR for two parameters. Only 17% of the AML-CR and none of the ALL-CR group were above these limits. The results indicate that high individual activity of usually one, rarely two of the investigated genes might be associated with poor clinical outcome in treated acute leukemia.

[Inpatient treatment costs of exacerbated chronic obstructive lung disease]. / Stationäre Behandlungskosten der exazerbierten chronisch obstruktiven Lungenerkrankung.

Economic aspects are of increasing importance in health care. However, treatment expenditures for most diseases are unknown. We performed a detailed cost analysis for the treatment of the exacerbated chronic obstructive pulmonary disease (ECOPD) in our department. For one year, all patients admitted because of exacerbated chronic obstructive pulmonary disease were included in this study. The workload was assessed for each patient by time keeping. Diagnostic and therapeutic procedures were considered according to the price list of the German hospital association. From 101 patients included into the study, 100 were evaluable. The median duration of inpatient hospitalisation amounted to 18 days (range: 4 to 210 days). Median total cost was DM 7680.- and mean cost DM 11900.-. This consisted of non-medical cost items (36%), personnel expenditures (29%), laboratory tests (14%), respiratory and cardiovascular laboratory (7%), radiology (5%) and pharmacy cost (7%). Endoscopy, external diagnostics and medical reports amounted to 2.8% of the expenditure. Treatment cost correlated with the duration of stay, but hardly with lung function and blood gases, these being independent of age and sex, but significantly higher in case of bronchiectasis, enterobacteriae, cor pulmonale or intensive care. The proportion of the pharmacy expenditures was rather small, and hence this is not a primary target for the realisation of major savings.

Rickets in two hand-reared polar bear (Ursus maritimus) cubs.

Two polar bear (Ursus maritimus) cubs born at the Denver Zoological Gardens were abandoned by a primiparous mother. Lethargic and extremely chilled, the cubs were transported to the zoo hospital for intensive care and hand rearing. Both cubs developed rickets. Dietary changes were instituted, and both cubs completely recovered with the exception of a bowed right femur (genu varum) in the female cub.

Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function.

STUDY OBJECTIVE: In patients with severe COPD, acute infective exacerbations are frequent. Streptococcus pneumoniae and Haemophilus influenzae are the most commonly isolated bacteria in sputum cultures from these patients. We hypothesized that in patients with advanced disease, Gram-negative bacteria other than H influenzae play at least an equally important role. METHODS: We evaluated clinical data and sputum culture results from 211 unselected COPD patients admitted to our hospital with an acute infective exacerbation of COPD. One hundred twelve patients fulfilled our protocol criteria of reliable microbiologic results and reproducible lung function tests; the patients were categorized according to the recently published three stages of severity. RESULTS: Lung function tests revealed an FEV1 of > or =50% of the predicted value in 30 patients (stage I), an FEV1 of 35% to <50% of the predicted value in 30 patients (stage II), and an FEV1 of < or =35% of the predicted value in 34 patients (stage III). Bacteria were classified into three groups: group 1 contained S pneumoniae and other Gram-positive cocci; group 2, H influenzae and Moraxella catarrhalis; and group 3, Enterobacteriaceae and Pseudomonas spp. For all patients together, the most frequently isolated bacteria were group 3 organisms (Enterobacteriaceae and Pseudomonas spp, 48.2%), followed by group 1 organisms (S pneumoniae and other Gram-positive cocci, 30.4%), and group 2 organisms (H influenzae and M catarrhalis, 21.4%). In stage I patients, 14 of 30 had bacteria from group 1, seven of 30 had group 2, and nine of 30 had group 3. In stage II patients, eight of 30 had group 1 bacteria, 10 of 30 had group 2, and 12 of 30 had group 3. In stage III patients, 12 of 52 had group 1 bacteria, seven of 52 had group 2, and 22 of 52 had group 3. The three groups of bacteria causing infective exacerbations were unevenly distributed among the three severity stages of lung function (p=0.016). CONCLUSION: There is a correlation between deterioration of lung function and the bacteria isolated from patients with infective exacerbations of COPD. In acute infective exacerbations, Enterobacteriaceae and Pseudomonas spp are the predominant bacteria in patients with an FEV1 < or =35% of the predicted value.

Hypertrophic osteoarthropathy in a blesbok (Damaliscus dorcas phillipsi).

A 4.5-yr-old female blesbok (Damaliscus dorcas phillipsi) was radiographed following the appearance of lameness and swelling of the right front fetlock. Radiographic interpretation at that time was osteoarthritis caused by periosteal proliferation of the right metacarpus with periarticular osteophytes surrounding the fetlock. No treatment was initiated. Gradual abdominal enlargement over several months was interpreted as evidence of pregnancy. Six months after the initial lameness complaint, the blesbok suddenly collapsed and was unable to stand. Physical examination revealed a large firm mass occupying most of the abdomen that was found to be inoperable. Following exploratory laporotomy, the blesbok was euthanized. At necropsy, the mass weighed 17 kg. It had probably caused the animal's collapse. Histologically, the bony lesions of the right metacarpus, seen radiographically at the previous examination, were consistent with hypertrophic osteoarthropathy and may have been a sequela of the intra-abdominal mass.

[Pulmonary melioidosis in a German Southeast Asia tourist]. / Pulmonale Melioidose bei einem deutschen Südostasientouristen.

HISTORY AND CLINICAL FINDINGS: A patient who returned from a 3-year stay in Thailand and India one year ago, was admitted with fever of 38.5 degrees C and productive cough for the last four weeks. He remembered wounding his foot three years ago in India with contamination by soil. Subsequently, recurrent pustulae appeared on his feet. One such pustule was found on admittance. The clinical examination showed low body weight, without further abnormalities. INVESTIGATIONS: The blood examinations revealed high inflammation parameters and ruled out any immunodeficiency. Smouldering infiltrates in the upper lobes were found on the chest radiography. Sputum was free of acid fast bacilli and no mycobacterial DNA was detected by polymerase chain reaction. Bronchoscopy showed a normal endobronchal situation, Burkholderia pseudomallei were found to grow from specimens of bronchial mucus. TREATMENT AND COURSE: Under the empirical treatment with ampicillin/sulbactam, we could not find any response. After switching to Ceftazidime and trimethoprim/sulfamethoxazol (TMP/SMZ) we observed quick clinical improvement and normalisation of the inflammation parameters and notable radiological response over three weeks. We continued a five months TMP/SMZ therapy after discharge in order to prevent relapses. CONCLUSION: For travellers and immigrants from Southeast Asia presenting smouldering infiltrations of the upper lobes, one should include Melioidosis in the differential diagnosis.

Serum bactericidal activities and comparative pharmacokinetics of meropenem and imipenem-cilastatin.

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.

Subpopulations of alveolar macrophages in smokers and nonsmokers: relation to the expression of CD11/CD18 molecules and superoxide anion production.

We were previously able to show that the number of alveolar macrophages (AM) expressing CD11/CD18 molecules is increased in smokers compared with nonsmokers and related to the superoxide anion (O2-) production of these cells. Since it has been demonstrated that AM are a heterogeneous cell population that can be separated by density, we performed this study to investigate the expression of CD11/CD18 molecules and O2- production in relation to cell density of AM from smokers and nonsmokers. AM were obtained by bronchoalveolar lavage (BAL) from smokers (n = 32) and nonsmokers (n = 20). Subpopulations were isolated using discontinuous Percoll density-gradient centrifugation with four densities (fraction 1: 1.030; fraction 2: 1.040; fraction 3: 1.050; and fraction 4: 1.070 g/ml). Expression of CD11/CD18 on freshly isolated cells and on AM before and after density centrifugation was studied using peroxidase-antiperoxidase staining. The contribution of AM subpopulations to O2- production in smokers was determined by monitoring the reduction of ferricytochrome C to ferrocytochrome C. We obtained 0.92 +/- 0.1 x 10(5) AM/ml BAL in nonsmokers and 2.4 +/- 0.3 x 10(5) AM/ml in smokers. Recovery after density centrifugation was > or = 72%. The absolute number of AM in smokers was significantly increased in fractions 3 and 4 (median 4.37 x 10(6) and 2.05 x 10(6), respectively) compared with nonsmokers (median 1.26 x 10(6) and 0.7 x 10(6), respectively) (p < 0.05). In both smokers and nonsmokers, fractions 3 and 4 showed a comparable increase in the percentage of CD11/CD18-positive AM compared with fractions 1 and 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Changing role of carbapenems in the treatment of lower respiratory tract infections.

The acquisition of antibiotic-resistance genes by virtually all major bacterial pathogens is currently a world-wide phenomenon. This problem is especially evident in nosocomial lower respiratory tract infections (LRTI). Carbapenems like imipenem and meropenem offer interesting antibacterial activities and beta-lactamase-stability, as well as adequate pharmacokinetic characteristics, to cover most of the pathogens involved in moderate to severe community-acquired and nosocomial LRTI. In contrast to imipenem, meropenem is not nephrotoxic and offers the advantage of greater stability against renal dehydropeptidase-I, so no concomitant application of an enzyme inhibitor is necessary. Meropenem can also be given by intravenous infusion or injection without the nausea and vomiting often associated with the administration of imipenem/cilastatin. Preliminary results with meropenem in LRTI show excellent cure rates and good tolerance for this new carbapenem.

OpenLabs: the application of advanced informatics and telematics for optimization of clinical laboratory services.

OpenLabs has four major objectives: to improve the efficiency and effectiveness of clinical laboratory services by the integration of Knowledge Based Systems (KBSs) with Laboratory Information Systems (LISs) and equipment; to provide and implement standard solutions for Electronic Data Interchange (EDI) between laboratories and other medical systems; to specify a fully Open architecture for an integrated Clinical LIS and demonstrate the integration of various KBS modules on the open architecture platform; and to demonstrate the integration of OpenLabs modules with existing LISs.