Simultaneous determination of drugs in human autopsy material using phase-optimized liquid chromatography.

In legal medicine in many cases drugs are detected in autopsy material without connection to the cause of death, and until now no further investigations have taken place. In our study more than 50 drugs were measured directly in several compartments. The deceased had received continual therapeutic treatment, treatment during an operation or an unsuccessful emergency therapy. Liquid-liquid extraction and an LC-MS/MS method were developed for the determination of these drug concentrations. When measuring many transitions in a biological matrix, two problems should be excluded: ion suppression and too few measurement points per peak. A relatively short operation time and sufficient separation were achieved by column, eluent and gradient optimization with POPLC (phase-optimized liquid chromatography). Various autopsy materials from about 170 cases were investigated. In particular, in nine cases with four or more simultaneously determined drugs, their distribution in the compartments is very interesting for pharmacokinetic examinations. The distribution patterns of the drugs in the compartments of one individual deceased were compared. This meant that the great differences between subjects that are normally encountered these studies could be excluded. Measurements of drug concentrations in human autopsy material deepens knowledge of the respective drugs' pharmacokinetics.

Tobacco use among medical students in Europe: results of a multicentre study using the Global Health Professions Student Survey.

OBJECTIVE: To examine smoking prevalence, knowledge and attitudes, and tobacco cessation training among university students attending European medical schools using the Global Health Professional Students Survey approach. METHODS: A cross-country, cross-sectional study was performed among 12 medical schools in four countries in Europe (Germany, Italy, Poland and Spain). The survey was performed during the second semester of the third year of study from March to May 2009. RESULTS: In total, 2249 subjects entered the study (overall response rate 92%). The overall prevalence of smoking among medical students was 29.3% (95% confidence interval 28.1-34.7), with percentages ranging from 28% in Germany to 31.3% in Italy. This study found that more than two-thirds of medical students believe that health professionals are role models for patients, with different beliefs in Poland (89.6%) and Germany (77.7%) vs Italy and Spain (57.2% and 54.4%, respectively) (P < 0.001). Smoking cessation training at medical school was only reported by 16.5% of students (lowest proportion in Italy, 3.5%) (P < 0.001). In terms of smoking cessation methods, the vast majority (89.8%) of medical students were aware of nicotine patches and gum (highest prevalence in Spain, 96.3%), and 24.4% were aware of the use of antidepressants (highest prevalence in Germany, 33.6%). CONCLUSION: This European survey found that the prevalence of smoking was higher among medical students than the general population. There is a strong need to provide medical students with training in smoking cessation techniques.

[Benefits and risks of current pharmacotherapy in the treatment of type 2 diabetes]. / Nutzen und Risiken der modernen Pharmakotherapie des Typ-2-Diabetes.

The development of new drugs for the treatment of type 2 diabetes (T2DM) and metabolic disorders is currently one of the most innovative areas of drug development. However, a considerable number of newly developed drugs have either not reached the market and were stopped late in development or have been withdrawn after initial approval soon after market authorization due to serious safety concerns. How can drug safety problems be anticipated and, even more important, how can adverse events definitely caused by a drug be differentiated from incidences of naturally occurring diseases? This review article will provide an update about the state of the art treatment of type 2 diabetes and reflect on the newest available study evidence on glitazones, incretin mimetics (GLP-1 agonists and DPP-4 inhibitors), SGLT-2 inhibitors (gliflocines) and pan-PPAR agonists (glitazars). Furthermore, new and still experimental approaches for the treatment of T2DM, such as bardoxolone, salsalate and anakinra will be briefly reviewed.

Distribution of metoprolol in human autopsy material.

In forensic medicine autopsy material is primarily investigated to find out the cause of death. But the results of corresponding toxicology measurements often involve more information. With screening methods drugs were detected not being related to the cause of death. Liquid/liquid extraction and LC/MS/MS methods were used for the determination of drug concentrations. In seven cases metoprolol could be determined in different autopsy materials. In all cases the dosage of the drug was unknown. In cases with oral application probably the patients took a normal customary continuous dosage. Intoxication with metoprolol could be excluded in all cases. The concentrations of metoprolol in blood were all in the therapeutic range. The time between oral intake and death was unknown. Therefore and because of the low number of cases statistic calculations were not meaningful and an individual case study was necessary. In three cases the highest concentration of metoprolol was found in the liver. Probably, metoprolol was taken shortly before the person died. In the other cases the highest concentration of metoprolol was found in urine. This means the elimination process of the drug predominated at the time of death. In all cases the concentrations of metoprolol were similar in the compartments heart blood, venous blood and brain. In this study it was possible to measure the distribution of metoprolol in human directly in several compartments. Measurement of drug concentrations in human autopsy material deepen the knowledge of its pharmacokinetics.

[Withdrawal in a patient with an implantable drug delivery system in spite of continuation of opiate therapy]. / Entzugserscheinungen bei einem Patient mit intrathekaler Schmerzpumpe trotz Fortführung der Opiattherapie.

A male patient with severe chronic pain has been treated with a combined drug therapy scheme of morphine and clonidine. After cessation of clonidine the patient reported opiate-withdrawal symptoms with agitation, polyuria, diarrhea, and hyperalgesia. It is known that the combination of these two substances causes synergistic analgetic effects. The abrupt cessation of clonidine after a combined administration with morphine seems to lead to a relative decrease in opiate effects and furthermore excite opiate-withdrawal symptoms.

Bleeding events in pulmonary arterial hypertension.

Despite limited evidence from clinical studies, anticoagulant drugs such as vitamin K antagonists (VKA) (e.g., warfarin or phenprocoumon) are widely used in the background treatment of patients with pulmonary arterial hypertension (PAH). According to current guidelines, they are generally accepted as efficacious drugs, although their efficacy is neither supported by randomised controlled trials, nor formally approved by regulatory agencies for use in the specific PAH indication. The use of these drugs is not without problems, as a paradoxical situation has to be managed in the treatment of this condition. On one hand, thrombosis is one of the key pathophysiologic features of PAH (besides vasoconstriction, proliferation and inflammation). On the other hand, the incidence of bleeding events is increased in PAH patients. This applies particularly to PAH that is related to connective tissue diseases, congenital heart disease and chronic thromboembolic pulmonary hypertension. In patients receiving VKA, caution must be observed in particular when concomitantly using prostanoids or sildenafil. Similarly, VKA doses have to be adjusted according to the labelling when using sitaxentan concomitantly. Regular International Normalized Ratio monitoring contributes to the safety of PAH patients on VKA.

[Significance of atopic dermatitis in outpatient medical care. Analysis of health care data from Saxony]. / Bedeutung des atopischen Ekzems in der ambulanten medizinischen Versorgung. Eine Sekundärdatenanalyse.

BACKGROUND: Data on health services utilization by children and adults due to atopic eczema (AE) are scarce, as well as data concerning the epidemiology of AE in adults. METHODS: Utilizing a population-based administrative health care database from Saxony, Germany, that covers comprehensive information on outpatient health care of 2.1 million individuals in 2003 and 2004, this study describes the relevance of AE as the proportion of children and adults with outpatient visits due to AE (ICD10 L20). Age- and sex-stratified prevalences of AE were estimated as the proportion of individuals insured by the Saxony Compulsory Health Insurance (AOK Sachsen), who were diagnosed as having AE at least twice within the study period. RESULTS: Being diagnosed in 15.6% of all children (age<18), AE was the most prevalent chronic-inflammatory condition at all in this age group. The prevalence of AE was 22.8% in one year old children, 8% in adolescents, and 2 to 4% in adults. CONCLUSION: AE is of utmost public health importance in children and adolescents, and also relevant for outpatient healthcare beyond the discipline of dermatology in adults. Despite the higher prevalence in children, approximately 60% of all patients with AE were adults.

Efficacy and tolerability of biologic and nonbiologic systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials.

BACKGROUND: The comparative efficacy and tolerability of conventional and biologic treatments for moderate-to-severe plaque psoriasis are unknown. OBJECTIVES: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) reporting efficacy of systemic treatments approved for moderate-to-severe psoriasis by means of the Psoriasis Area and Severity Index (PASI). METHODS: We identified relevant articles by systematic electronic searches (Cochrane Library, Medline, Embase, Scopus). Efficacy was defined as proportion of participants with >or= 75% decrease in PASI (PASI-75) at primary efficacy measurement (week 8-16). PASI-75 response rates of double-blind placebo-controlled trials were summarized as risk differences (RDs) and pooled using random effects models. Tolerability was assessed from rates of withdrawals and adverse events. RESULTS: Twenty-four RCTs totalling 9384 patients were analysed qualitatively. Sixteen double-blind placebo-controlled trials were eligible for meta-analysis. Infliximab was significantly superior to all other interventions [RD 77%, 95% confidence interval (CI) 72-81%]. Adalimumab (RD 64%, 95% CI 61-68%) was superior to ciclosporin (RD 33%, 95% CI 13-52%), efalizumab (RD 24%, 95% CI 19-30%), etanercept 50 mg twice weekly (RD 44%, 95% CI 40-48%) and etanercept 25 mg twice weekly (RD 30%, 95% CI 25-35%). Efalizumab was significantly less efficacious than fumaric acid esters (RD 48%, 95% CI 32-64%). Rates of withdrawals due to adverse events were highest for methotrexate and fumaric acid esters. CONCLUSIONS: The efficacy of systemic agents approved for moderate-to-severe psoriasis differs considerably both within and between biologics and nonbiologics. Infliximab is most efficacious, followed by adalimumab. Patients receiving infliximab have an excess chance of 77% over placebo to achieve PASI-75 response. Published evidence questions regulatory guidelines that recommend biologics as second-line therapy for moderate-to-severe plaque psoriasis.

Determination of denaverine and its metabolites in urine samples by liquid chromatography-tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometric (LC-MS-MS) method was developed for the determination of the neurotropic-musculotropic spasmolytic agent denaverine and five of its metabolites in urine. In a first step beta-glucuronidase was used to cleave glucuronides in the human urine. After that samples containing denaverine and its phase I metabolites were extracted and cleaned up using an automated solid phase extraction method. An external calibration was used. The analytes were measured employing the multiple reaction-monitoring mode (MRM). The linear dynamic range for denaverine and its five metabolites determination was demonstrated from lower limit of quantification (8.0 ng/ml) to at least 500 ng/ml. The presented method is suitable for pharmacokinetic or toxicokinetic studies. With the help of reference substances some additional potential metabolites could be excluded in the urine samples. To look for additional unknown metabolites the LC-MS-MS system operated on one hand in the precursor ion mode using typical product ions of denaverine and of its metabolites and on the other hand in the product ion mode using postulated protonated molecules [M+H](+). With the help of the chromatographic behaviour and typical fragment ions of the unknown metabolites it was possible to elucidate their structures. Nine until now unknown metabolites were found in the urine samples. However, without reference substances a quantification of these analytes was not possible.

Characterization of vascular reactivity in dorsal hand veins after oral rosiglitazone treatment in healthy subjects.

OBJECTIVE: In clinical studies with diabetic patients thiazolidinediones have been shown to restore abnormal vascular function which might be attributed to improved blood sugar control or to restoration of vascular endothelium and smooth muscle responsiveness. The present study was undertaken to investigate whether rosiglitazone modulates vascular responsiveness to different vasoactive agents and exerts renin-angiotensin-system (RAS)-inhibiting properties in healthy subjects in vivo. METHODS: 24 healthy male subjects were randomized to receive either rosiglitazone or placebo. Venoconstrictor responses to angiotensin II (Ang II) and phenylephrine, and endothelium-dependent response to histamine and insulin, and endothelium-independent response to glyceroltrinitrate were compared using the dorsal hand vein compliance method. Effects on the RAS were investigated by plasma level determinations of Ang II and angiotensin-(1-7). Treatment effects on the systemic arterial system were investigated by standardized pulse-wave-analysis. RESULTS: Rosiglitazone significantly inhibited venoconstrictor responses to Ang II by 19% (-70% vs. -51% constriction, p = 0.034) and in the presence of rosiglitazone the ED80 for phenylephrine was increased (ED80: 317 A+/- 86 ng vs. 531 A+/- 102 ng; p = 0.010). Rosiglitazone treatment was without effect on endothelium-dependent dilation, blood pressure, pulse-wave-velocity and plasma angiotensin peptide levels. CONCLUSIONS: The data of the present study in veins of healthy subjects are consistent with data from in vitro and animal studies supporting a direct effect of rosiglitazone on venous tone by modulation of the vascular smooth muscle response via AT1-receptor-downregulation.

Stroke risk screening of adults with hypertension: prospective cross-sectional study in primary care.

OBJECTIVES: There is a lack of current epidemiological data on the risk of cerebrovascular disease associated with arterial hypertension. We therefore aimed to assess the risk factor profile of hypertensive patients in primary care in various age groups, and to calculate their corresponding risk of stroke. METHODS: A total of 2482 primary-care practices throughout Germany included 47,394 consecutive unselected patients with diagnosed hypertension in a cross-sectional prospective observational study. In addition to demographic characteristics, participating primary-care physicians documented known risk factors for stroke using standardized questionnaires. The 10-year prospective risk of first stroke was then calculated according to the Framingham Stroke Risk Score. MAIN OUTCOME MEASURES: Patients were evenly balanced for sex (females 51%), and the mean age was 66.5 years. Mean systolic (SBP)/diastolic (DBP) blood pressure was 147/86 mmHg. Only 29.1% of patients had an SBP <140 mmHg, and 60.2% had a DBP <90 mmHg. The most prevalent risk factors were a positive family history of cardiovascular disease (46.1%), diabetes mellitus (36.1%), coronary artery disease (34.4%), and left ventricular hypertrophy (33.3%). Drug treatment was given as combination therapy in 73.5% of the total cohort of patients. The mean 10-year risk of stroke was 26% in the total cohort (0-19% in 50.6% of patients, 20-49% in 32.7%, and > or =50% in 16.7%). CONCLUSIONS: Co-morbidities relevant for total stroke risk are very prevalent among typical primary-care patients, confirming a substantial burden of disease in this setting. The resulting risk of stroke is substantial. The need for more aggressive BP control and treatment of modifiable risk factors is confirmed by our results.

Induction of intestinal P-glycoprotein by St John's wort reduces the oral bioavailability of talinolol.

St John's wort (SJW) is known to induce cytochrome P450 (CYP) 3A4 and P-glycoprotein through pregnane X-receptor activation. Our study evaluated the effects of long-term SJW administration on oral and intravenous pharmacokinetics of the nonmetabolized in vivo probe of P-glycoprotein, talinolol, in relation to intestinal P-glycoprotein expression. In a controlled, randomized study (N=9), the pharmacokinetics of oral (50 mg) and intravenous talinolol (30 mg) was determined before and after 12 days SJW (900 mg daily, Jarsin 300). Duodenal biopsies were taken and MDR1 genotypes assessed. SJW reduced the oral talinolol bioavailability by 25% (P=0.049) compared with water control. A 93% increase in oral clearance (P=0.177) and a 31% reduction in area under the serum concentration time curve (AUC; P=0.030) were observed. Renal and nonrenal clearance (CLNR), elimination half-life, peak serum drug concentration (Cmax), and time to reach Cmax were not significantly altered. After intravenous talinolol, SJW affected only CLNR (35% increase compared with water, P=0.006). SJW increased MDR1 messenger ribonucleic acid (mRNA) as well as P-glycoprotein levels in the duodenal mucosa. Subjects with the combined MDR1 genotype comprising 1236C>T, 2677G>T/A, and 3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and displayed an attenuated inductive response to SJW as assessed by talinolol disposition. Long-term SJW decreased talinolol AUC with a corresponding increase in intestinal MDR1 expression, suggesting that SJW has a major inductive effect on intestinal P-glycoprotein. Interestingly, the magnitude of induction appeared to be affected by MDR1 genotype.

Unmet needs in the diagnosis and treatment of dyslipidemia in the primary care setting in Germany.

OBJECTIVES AND METHODS: DETECT is a cross-sectional study of 55,518 unselected consecutive patients in 3188 representative primary care offices in Germany. In a random subset of 7519 patients, an extensive standardized laboratory program was undertaken. The study investigated the prevalence of cardiovascular disease, known risk factors (such as diabetes, hypertension and dyslipidemia and their co-morbid manifestation), as well as treatment patterns. The present analysis of the DETECT laboratory dataset focused on the prevalence and treatment of dyslipidemia in primary medical care in Germany. Coronary artery disease (CAD), risk categories and LDL-C target achievement rates were determined in the subset of 6815 patients according to the National Cholesterol Education Program (NCEP) ATP III Guidelines. RESULTS: Of all patients, 54.3% had dyslipidemia. Only 54.4% of the NCEP-classified dyslipidemic patients were diagnosed as 'dyslipidemic' by their physicians. Only 27% of all dyslipidemic patients (and 40.7% of the recognized dyslipidemic patients) were treated with lipid-lowering medications, and 11.1% of all dyslipidemic patients (41.4% of the patients treated with lipid-lowering drugs) achieved their LDL-C treatment goals. In conclusion, 80.3% of patients in the sample with dyslipidemia went undiagnosed, un-treated or under-treated.

Smart textiles: a new drug delivery system for symptomatic treatment of a common cold.

Smart textiles provide the possibility of being coated with cineole, menthol, and camphor. Due to over-the-counter availability, ethereal oils are frequently used to treat a common cold. The existing pharmaceutical forms entail the risk of oral ingestion by children, which can cause severe intoxications. This risk could be limited by a smart textile application. Prior to applicability tests in children, the principal traceability of smart textile-applied ethereal oils at their site of action in the alveoli has to be demonstrated. Therefore, a crossover trial (ointment vs smart textiles) with 6 healthy volunteers was carried out as a proof-of-concept study. As a result, the principle proof is given that smart textile-applied ethereal oils are available at their site of action. Because of the volatility of the active ingredients, a close-fitting textile form has to be developed for further clinical development of smart textiles to achieve higher concentrations in the alveoli. Slower liberation properties and a more convenient skin sensation in comparison to available pharmaceutical forms may provide advantages for the applicability in both children and adults.

Determination of propiverine and its metabolites in rat samples by liquid chromatography-tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometric (LC-MS-MS) method was developed and validated for the determination of the anticholinergic and antimuscarinc drug propiverine and eight of its metabolites in serum, urine, faeces and different tissue samples of rats. Samples containing propiverine and its metabolites in serum and urine and in the supernatants of faeces and tissue homogenates were extracted and cleaned up using an automated solid phase extraction (SPE) method. An external calibration was used. The analytes were measured employing the multiple reaction monitoring mode (MRM). A sufficient response over the range of 10-1000 ng/ml was demonstrated. The lower limit of quantification of the nine substances was 10 ng/ml. The presented method is suitable for pharmacokinetic or toxicokinetic studies. To look for additional unknown metabolites, the LC-MS-MS system operated in the precursor ion mode using typical product ions of propiverine and of its metabolites. With the help of the chromatographic behaviour and typical fragment ions of the unknown metabolites, it was possible to elucidate their structure. Five until now unknown metabolites were found in the urine and faeces samples. However, without reference substances, a quantification of these analytes was not possible.

Prednisolone concentration in the cochlea of patients with perilymph fistula.

After iv administration of 200 mg prednisolone in patients with perilymph fistula, concentrations of the drug in the cochlea were determined. A specially adapted LC method was used for analysis. Mean concentrations of prednisolone in the perilymphe reached 95 ng/ml after 15-25 min, and 338 ng/ml after 30-45 min. The values reached 8 and 41% of the corresponding serum concentrations, respectively.

Expression of the glutathione enzyme system of human colon mucosa by localisation, gender and age.

BACKGROUND: The glutathione S-transferases (GST) can metabolise endogenous and exogenous toxins and carcinogens by catalysing the conjugation of diverse electrophiles with reduced glutathione (GSH). Variations of GST enzyme activity could influence the susceptibility of developing cancers in certain areas of the gastrointestinal tract. AIMS: The expression of the components of the glutathione system in the colon was investigated with respect to age, gender and localisation. METHODS: Biopsies of macroscopically normal mucosa from both proximal and distal colon were collected from 208 patients (106 females, 102 males; mean age 61 years), who underwent colonoscopy for various clinical reasons. GSH content, total GST enzyme activity and the levels of the GST isoenzymes glutathione S-transferase P1 (GSTP1) and glutathione S-transferase M1 (GSTM1) were determined. RESULTS: GST enzyme activity, GSH and GSTP1 levels decreased significantly from proximal to distal colon (GST activity: 264 vs. 244 nmol/min/mg protein, p < 0.001, GSH content: 32 vs. 30 nmol/mg protein, p = 0.022 and GSTP1 levels: 2.25 vs. 2.10 mug/mg protein, p < 0.001). In female patients there was a significant stepwise increase of GST-activities and GSTP1 levels from the age of under 50 years to over 70 years. Oral sex hormone substitution among female patients between 50 and 70 years suppressed GST-activities and GSTP1 content. CONCLUSIONS: The GSH-system in the colonic mucosa is expressed at a lower level in the distal colon (sigma) than in the colon transversum; whether this small difference translates into variations of incidence of colorectal cancer remains to be seen. Females express higher enzyme levels as they grow older, while in males no significant age effects were found. Elderly females might be better equipped with protective GSH-enzymes in the colon than males and this could contribute to the lower incidence of colorectal carcinomas in females.

Effect of high dose verapamil on restenosis after peripheral angioplasty.

OBJECTIVES: We sought to determine whether treatment with high dose verapamil prevents restenosis in patients at high risk for reoccurrence after successful percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Restenosis is the major limitation of PTCA. Calcium antagonists have demonstrated some potential as inhibitors of this process. METHODS: A total of 98 patients with peripheral occlusive arterial disease (POAD), stable angina pectoris, mild hypertension and at least one additional risk factor increasing the likelihood of restenosis after angioplasty were selected for this placebo-controlled, double-blind, randomized trial. Verapamil (240 mg twice daily) or placebo was taken for 6 months. Efficacy variables assessed before and after angioplasty and at 6 weeks and 6 months after PTCA included thickness of the intima/media complex degree of stenosis, interventricular septal thickness, crurobrachial pressure ratios of dorsalis pedis and posterior tibial arteries, distance to claudication and total vessel diameter. RESULTS: No significant intergroup differences emerged before or immediately after PTCA. Six weeks after angioplasty, a significant thickening of the intima/media complex in the treated vascular segment of 14.3% occurred in the placebo group versus 0% among verapamil patients (p < 0.01). At 6 months, the intima/media thickness was 35.7% greater in the placebo group but had decreased by 14.3% in the verapamil group (p < 0.001). At 6 months, a marked reduction in septal thickness was observed in the verapamil group versus that in the placebo group (p < 0.001). The rate of restenosis was also significantly lower in the verapamil group (p < 0.001). Few minor side effects were reported. CONCLUSIONS: In patients with POAD at increased risk for restenosis, the administration of high dose verapamil prevented recurrent stenosis for 6 months after successful peripheral angioplasty and was well tolerated.

Short- and long-term results after thrombolytic treatment of deep venous thrombosis.

OBJECTIVES: The goal of this study was to assess the short- and long-term efficacy of different thrombolytic therapy regimens in patients with leg or pelvic deep venous thrombosis (DVT). BACKGROUND: It is unclear whether locoregional or systemic thrombolysis is superior in treating acute leg DVT or even whether lysis is more effective than anticoagulation therapy in preventing postthrombotic syndrome. METHODS: A total of 250 patients averaging 40 years of age with acute DVT were randomized into five groups to receive full heparinization (1,000 IU/h) and compression treatment, with four groups also administered locoregional tissue plasminogen activator (20 mg/day) or urokinase (100,000 IU/day) or systemic streptokinase (3,000,000 IU daily) or urokinase (5,000,000 IU daily). All groups then received anticoagulation and compression treatment for one year. Primary efficacy criteria included the change after one year in the number of closed vein segments and the occurrence of postthrombotic syndrome. RESULTS: Systemic thrombolytic therapy significantly reduced the number of closed vein segments after 12 months in patients with acute DVT compared with conventional treatment (p < 0.05). Postthrombotic syndrome also occurred with less frequency in systemically treated patients versus controls (p < 0.001). High-dose thrombolysis led to better rates of complete recanalization after seven days (p < 0.01) than locoregional lysis. However, 12 patients receiving thrombolysis (9 systemic, 3 local) suffered major bleeding complications; 9 patients on systemic treatment developed pulmonary emboli. CONCLUSIONS: Systemic thrombolytic treatment for acute DVT achieved a significantly better short- and long-term clinical outcome than conventional heparin/anticoagulation therapy but at the expense of a serious increase in major bleeding and pulmonary emboli. Given the inherent risks for such serious complications, systemic thrombolysis, although effective, should be used selectively in limb-threatening thrombotic situations.

Cytotoxic therapy and pregnancy.

The use of cytotoxic agents during pregnancy may be unavoidable in order to ensure maternal survival-despite the dangers to the developing fetus. We review 217 such cases published between 1983 and 1995, classifying them into 5 groups according to whether the cytotoxic drugs were used to treat leukaemias, malignant lymphomas, severe rheumatic diseases, gynaecological/breast neoplasms, or other grave conditions. Various factors, such as the drug type, dose, and timing to exposure to gestational age, are analysed with respect to the outcome of these pregnancies (teratogenicity, stillbirths, spontaneous abortions, prematurity, etc.). These results are then integrated in order to determine whether one can predict the individual risk of abnormality for the newborn when cytotoxic agents must be administered to pregnant women faced with a malignancy or other serious condition.