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Intrathecal injections of 50 to 100 micro g of (N-acetylmuramyl-L-alanyl-D-isoglutamine) muramyl dipeptide (MDP)/rabbit dose-dependently triggered tumor necrosis factor alpha (TNF-alpha) secretion (12 to 40,000 pg/ml) preceding the influx of leukocytes in the subarachnoid space of rabbits. Intrathecal instillation of heat-killed unencapsulated R6 pneumococci produced a comparable leukocyte influx but only a minimal level of preceding TNF-alpha secretion. The stereochemistry of the first amino acid (L-alanine) of the MDP played a crucial role with regard to its inflammatory potential. Isomers harboring D-alanine in first position did not induce TNF-alpha secretion and influx of leukocytes. This stereospecificity of MDPs was also confirmed by measuring TNF-alpha release from human peripheral mononuclear blood cells stimulated in vitro. These data show that the inflammatory potential of MDPs depends on the stereochemistry of the first amino acid of the peptide side chain and suggest that intact pneumococci and MDPs induce inflammation by different pathways.

The underlying mechanisms of reactive macrophage activation syndromes (rMAS) are not understood in detail, and there is no specific treatment. This observational study was prompted by intravenous immunoglobulin (IVIG), dramatically halting two distinct rMAS episodes in the same patient. We evaluated the potential benefits of IVIG administration in treating fulminant rMAS and the usefulness of monitoring serum ferritin levels as an indication for emergency treatment with IVIG. Ten females and 10 males experiencing 22 episodes of rMAS were recruited on the basis of serum ferritin levels >or=10,000 microg/l and/or direct evidence of haemophagocytosis in 11 intensive care units in secondary and tertiary care hospitals in Switzerland between October 1993 and May 2000. In individual patients, serially measured ferritin was closely related to disease activity. Abrupt increases of up to >100,000 microg/l could be observed within hours. Rapid and profound beneficial effects of emergency IVIG treatment were seen in 12 episodes of rMAS accompanied by a prompt decrease of serum ferritin. IVIG produced partial or delayed improvements in 5 patients. No apparent effects were seen in 5 patients. IVIG was only successful if started early during the ferritin run-up to peak values. In conclusion, IVIG is effective in at least a subgroup of adult rMAS when started at the beginning of the macrophage activation process. The monitoring of serum ferritin levels might be helpful in detecting macrophage activation in order to commence IVIG treatment early enough., (Copyright 2001 Wiley-Liss, Inc.)

Cephalosporins in aqueous solutions generate degradation products that inhibit in vitro HIV-1 replication in cell lines, as well as in primary cells (lymphocytes and macrophages). This effect is observed at concentrations that do not interfere with the normal functions of these cells. Upon chromatographic fractionation of an aqueous solution of hydrolysed ceftazidime, a high molecular weight fraction (MW 8000) with antiviral activity was isolated. The exact chemical nature of the active component responsible for the anti-HIV activity in vitro appears to be complex and is currently unknown. Inhibition of HIV-1 reverse transcriptase and RNase H activity was observed, however, higher concentrations than those needed to inhibit HIV replication were required. The inhibitory action of the hydrolysed ceftazidime was manifested during the early phase of the HIV-1 life-cycle. Despite a lack of a direct effect of the CD4/gp120 interaction, HIV-1 mediated cell fusion was inhibited by the hydrolysed ceftazidime, suggesting that the active principle acts in a very early stage of the viral life-cycle.

Linezolid, a new oxazolidinone antibiotic, showed good penetration (38+/-4%) into the meninges of rabbits with levels in the CSF ranging from 9.5 to 1.8 mg/L after two i.v. injections (20 mg/kg). Linezolid was clearly less effective than ceftriaxone against a penicillin-sensitive pneumococcal strain. Against a penicillin-resistant strain, linezolid had slightly inferior killing rates compared with the standard regimen (ceftriaxone combined with vancomycin). In vitro, linezolid was marginally bactericidal at concentrations above the MIC (5 x and 10 x MIC).

The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml. h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml. h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml. h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml. h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0. 22 Delta log(10) CFU/ml. h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.

Grepafloxacin, a new fluoroquinolone, produced bactericidal activity comparable to that of vancomycin and ceftriaxone in the treatment in rabbits of meningitis caused by a pneumococcal strain highly resistant to penicillin (MIC 4 mg/L) (triangle uplog(10) cfu/mL*h for grepafloxacin, -0.32 +/- 0.15; dose, 15 mg/kg iv; triangle uplog(10) cfu/mL*h for vancomycin, -0.39 +/- 0.18; dose, 2 x 20 mg/kg iv; triangle uplog(10) cfu/mL*h for ceftriaxone, -0.32 +/- 0. 12; dose, 125 mg/kg iv). Higher doses of grepafloxacin (30 mg/kg and 2 x 50 mg/kg) did not improve the killing rates. The combination of grepafloxacin with vancomycin was not significantly superior to monotherapies (P > 0.05). In vitro, grepafloxacin was bactericidal at concentrations above the MIC. Using concentrations around the MIC, addition of vancomycin to grepafloxacin showed synergic activity.

Derailed T-cell activation can give rise to life-threatening macrophage activation, the final common pathway of the different forms of reactive macrophage activation syndromes (rMAS). Besides inappropriate activation of the immune system, impaired termination of immune responses might be another mechanism leading to rMAS. The Fas (CD95)/Fas ligand (CD95 ligand) system functions in turning off immune responses by executing activation-induced cell death (AICD). Soluble Fas (sFas) and Fas ligand (sFasL) can interfere with their corresponding membrane-bound counterparts, qualifying them as potential parameters of impaired immune termination. Hence, sFas and sFasL were analyzed in sera of rMAS patients. We show that soluble Fas/CD95 (sFas) is elevated >2 SD over the mean of controls in all 8 rMAS episodes studied (mean 12.08 +/- 6.12 ng/mL, range 3.7-20.2; controls 2.46 +/- 0.49, range 1.5-2.9). sFasL was detected during five rMAS episodes (0.70 +/- 0.49 ng/mL, range 0.16-1.28; controls all below the limit of detection of 0.1). In addition, both parameters decrease during convalescence, reflecting clinical evolution. In conclusion, sFas seems to be consistently elevated during acute rMAS. sFasL is detected only in a subgroup of our adult rMAS patients extending the recent finding of sFasL elevation in a majority of children with macrophage activation syndromes (Hasegawa et al. Blood 1998;91(8):2793-2799). By interfering with AICD, sFas and sFasL might contribute to the pathogenesis of at least a subset of rMAS., (Copyright 2000 Wiley-Liss, Inc.)

Cefepime, a broad-spectrum, fourth-generation cephalosporin, showed excellent CSF penetration with levels ranging between 10 and 16 mg/L after two intravenous injections (100 mg/kg). The bactericidal activity of cefepime (-0.60 +/- 0.28 Deltalog(10) cfu/mL/h) was superior to that of ceftriaxone (-0.34 +/- 0.23 Deltalog(10) cfu/mL/h, P < 0.05) and vancomycin (-0.39 +/- 0.19 Deltalog(10) cfu/mL/h, P < 0.05) in the treatment of rabbits with meningitis caused by an isolate highly resistant to penicillin (MIC of penicillin G: 4 mg/L). The addition of vancomycin to both cephalosporins did not significantly increase the killing rate compared with monotherapies (P > 0.05). Similar results were obtained in time-killing experiments in vitro.

In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Trovafloxacin, a new fluoroquinolone, produced bactericidal activity (-0.33 +/- 0.13 delta log10 CFU/ml.h; intravenously [i.v.] administered dose, 15 mg/kg) comparable to that of vancomycin (-0.39 +/- 0.18 delta log10 CFU/ml.h; i.v. admininistered dose, 20 mg/kg) in the treatment of experimental meningitis in rabbits due to a pneumococcal strain highly resistant to penicillin (MIC of penicillin G, 4 micrograms/ml). The combination of both drugs significantly increased (P < 0.05) the killing rate (-0.60 +/- 0.23 delta log10 CFU/ml.h) compared to that produced by either monotherapy. These results were also confirmed in vitro.

In 3 divisions of internal medicine of teaching hospitals of the Comprehensive Hospital Drug Monitoring (CHDM) Foundation Bern/St Gallen, 42,920 patients consecutively admitted between 1974-1991 were investigated for adverse drug reactions. Of these 16,150 patients (38%) had received at least one systemically administered antibacterial drug during the hospital stay. Antibiotic-associated colitis included the following diagnoses: pseudomembranous colitis, hemorrhagic colitis and milder forms of colitis. We collected the data of these patients by searching for all diagnoses which might represent antibiotic-associated colitis (from the list of WHO adverse drug reaction terminology). 9 individual patients with one episode of probable antibiotic-associated colitis were found. In 5 of these cases, only one drug given during the hospital stay seemed to be implicated. An additional 32 patients were admitted with antibiotic-associated colitis in relation to treatment with the same groups of drugs before hospital admission. Based on the exposure pattern of the 9 patients with antibiotic-associated colitis compared to all patients exposed during hospital stay, we estimated the following frequencies related to the drug groups with at least 1,000 patients exposed: for all antibacterial chemotherapeutics 0.6/1000 (0.25-1.06); all penicillins 0.6/1000 (0.22-1.32), for benzyl-, phenoxy-, ureido-, isoxazolyl penicillins and methicillin 2.0/1000 (0.42-5.92) and aminopenicillin or analogues, with or without clavulanic acid 0.6/1000 (0.18-1.35). For cephalosporins the frequency is 1.4/1000 (0.17-5.12). Under sulfonamides combined with trimethoprim or related substances (5077 exposed patients) and fluoroquinolones (1043 exposed patients) no case was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the case of a 74-year-old patient with HLA-B27 negative spondylarthropathy presenting with acute disseminated vascular occlusions. The presence of livedo reticularis prompted a search for antiphospholipid antibodies which were found to be markedly elevated. Histopathological examination revealed noninflammatory vascular obstruction. The clinical evolution was rapidly fatal in spite of corticosteroid treatment. Livedo reticularis can be an important diagnostic clue to various types of underlying disease. Increased levels of antiphospholipid antibodies have been associated with thrombosis and thromboembolism, especially in the context of autoimmune diseases such as systemic lupus erythematosus. This paper reports antiphospholipid antibody-associated noninflammatory vascular occlusions in a patient with HLA-B27 negative spondylarthropathy. The pathogenetic mechanism of antiphospholipid antibody-mediated vascular occlusions is not completely understood and optimal therapy remains to be defined.

Penicillins, cephalosporins and other betalactam antibiotics are widely used antibacterial drugs. Recently it was found that some of them also have effects on proliferating eukaryotic cells (Neftel, K.A. and Hübscher, U. (1987) Antimicrob. Agents Chemother. 31, 1657-1661), and one such effect was shown to be the inhibition of DNA polymerase alpha (Huynh Do,U., Neftel, K.A., Spadari, S. and Hübscher, U. (1987) Nucl. Acids Res. 15, 10495-10506). The data suggested that degradation products of betalactam antibiotics were responsible for the inhibitory effect on DNA polymerase alpha. There is some confirmation at the structural level, since we found that penicillin binding proteins, the natural target of the cephalosporins, share amino-acid homologies to DNA polymerases and also to reverse transcriptase from HIV1 (Hafkemeyer, P., Neftel, K.A. and Hübscher, U. Meth. Find. Exp. Clin. Pharmacol. 12, 43-46, 1990). We have purified and determined the structure of one product from the cephalosporin Ceftazidim and found one molecule (HP 0.35) that did not interfere with eukaryotic cell proliferation but rather had a specific inhibitory effect on the RNase H activity of human immunodeficiency virus 1 (HIV1) and feline immunodeficiency virus (FIV) reverse transcriptases, while the DNA polymerising activity of these enzymes was not affected. RNases H from HeLa cells, calf thymus and Escherichia coli on the other hand were much less affected by HP 0.35. The inhibitory concentration of 50% (IC50) was more than 10 times lower compared to those of all cellular RNases H. We therefore tested the effect of HP 0.35 on in vitro lentivirus infection as exemplified by FIV-infection of CD(4+)-cat lymphocytes in cell culture. Under conditions where cell proliferation was absolutely unaffected, HP 0.35 was able to inhibit FIV-infection in CD(4+)-cat lymphocytes. Moreover, preincubation of these lymphocytes with HP 0.35 rendered the cells completely unsusceptible to FIV-infection. These data suggest that a degradation product of a clinically used betalactam antibiotic might represent an effective inhibitor class for lentiviral RNase H.

Antidrug IgG antibodies have been detected in some patients receiving amodiaquine (AQ). Antidrug antibodies were detected in 6/7 patients who experienced serious well-defined adverse drug reactions during malaria prophylaxis and in 7/22 patients who received comparable doses of the drug (at least 400 mg weekly x 6) but did not present with clinical adverse drug reactions. In contrast antidrug antibodies were not detected in 7 patients who received the drug for treatment (1.0-1.2 g total over 3 days). The specificity of the IgG response was defined by hapten inhibition experiments (IC50 value for AQ ranged between 0.050 and 0.282 microM) which suggest that the antibody recognised the drug linked to cysteine residues in protein via the 4-hydroxyanilino side chain. The data show that AQ is immunogenic in man and are consistent with the hypothesis that idiosyncratic adverse reactions to the drug have an immunological aetiology.

Side effects in general and in particular to antiinfective therapy are obviously hardly predictable and a causal relationship is seldom firmly established. The handling of untoward reactions may be improved if a subpopulation which can be identified is at particular risk for a given reaction. A clear assessment of dose and time dependency of untoward reactions is important in this context. Agranulocytosis seen with (i) beta-Lactam-antibiotics, (ii) vancomycin and (iii) amodiaquine can exemplify how simultaneous investigations of epidemiological and experimental aspects lead to identification of a subpopulation at risk.

Heat induced radial segmentation of leukocyte nuclei is an in vitro phenomenon accompanying inflammatory diseases. We studied 62 patients with suspected polymyalgia rheumatica (PMR) to determine, whether heat induced radial segmentation can help in discriminating PMR from other conditions. At the initial presentation patients with PMR had more radial segmentation formation than patients with other inflammatory conditions. Prednisone induced a rapid and marked decrease in radial segmentation formation in patients with PMR. This latter finding was much less marked in patients with other inflammatory conditions. We conclude that heat induced radial segmentation at the initial presentation and during prednisone treatment can help in discriminating PMR from other inflammatory conditions.

We describe two female patients presenting with spontaneous peritonitis and fulminant Streptococcus pyogenes (Strep. pyogenes) septicemia and shock. Both patients recovered completely upon immediate antibiotic therapy, initially with broad range combination therapy effective against Strep. pyogenes, which was switched to penicillin G when culture results became available. This isolated strain in case 1 was M-type 28, which is the M-type most often isolated from vaginal swabs (as commensal) and from blood from patients with puerperal sepsis. Patient 1 had signs and symptoms of a toxic shock-like syndrome, including rapid onset of fever and shock, skin rash, desquamation of palms and soles, and multisystem involvement with vomiting, diarrhea, myalgia, renal failure, and severe disorientation without focal neurological deficits.

Simultaneous primary infection with HIV and CMV in an 18-year-old woman led to an acute cytotoxic reaction, manifesting as pancytopenia, hepatitis, nephritis, perimyocarditis, and myositis. Within 14 days parameters indicating acute cell damage reverted to normal. Two weeks later transient alopecia totalis developed. Initially, HIV-antigen but no HIV antibodies were present. Within 3 weeks HIV-IgG antibodies appeared while HIV antigen disappeared. Anti-CMV-IgM was clearly and anti-CMV-IgG questionably positive; IgM persisted further, while IgG remained definitely undetectable. We speculate that a particular HIV-induced imbalance of the immune system led to a generalized severe cytotoxic reaction to a simultaneous infection with CMV.

Penicillin-binding proteins are the specific targets for the beta-lactam antibiotics. Recently it was observed that beta-lactam antibiotics also have targets in proliferating eukaryotic cells (1), one of which most likely is the replicative DNA polymerase alpha. Here we show that HIV-reverse transcriptase and human DNA polymerase alpha share amino acid sequence homologies to five bacterial penicillin-binding proteins.

In 3 of 15 consecutive patients receiving a human leukocyte antigen (HLA)-identical but major ABO incompatible bone marrow transplant (BMT), pure red cell aplasia (PRA) lasting 5 to 8 months was observed. Titers of the incompatible anti-A agglutinin before infusion of the red blood cell (RBC)-depleted BMT was very high in one, and in the usual range in two patients. Decrease of agglutinin titers during the first 4 weeks after BMT were comparable between PRA patients and those of ABO-incompatible BMT recipients with timely RBC recovery. However, in PRA patients, agglutinin titers rose again and remained elevated for 19 to 28 weeks. RBC engraftment and reticulocyte recovery ultimately occurred spontaneously and coincided with the decrease of agglutinin titers below 16. These observations indicate that PRA is antibody-dependent in this setting. Furthermore, it is conceivable that cyclosporine facilitates recipient-derived antibody synthesis after major ABO-incompatible BMT.

Seven cases of agranulocytosis and two of liver damage that were probably due to amodiaquine treatment were studied. In five cases agranulocytosis was combined with liver damage, and in one case of primary liver damage moderate neutropenia was present. Three patients died. High total doses or prolonged duration of treatment, or both, appear to favour the occurrence of these reactions. The clustering of five of the seven cases of agranulocytosis within six months in one medical centre indicates that the risk to benefit ratio of amodiaquine for malaria prophylaxis should be re-evaluated.

Several episodes of acute intravascular immune hemolysis in a 68 year old patient induced by (+)-cyanidanol-3 (Catergan) are reported. Clinical and serological criteria of the so-called immune-complex mechanism of immune drug-induced hemolysis were realised. The meaning of the additional marked affinity of the drug to the erythrocytic surface remains unclear. The patient's serum was cross-reactive with rutine but not with troxerutine.

Heat-induced radial segmentation (RS) of leucocyte nuclei in vitro (2 h at 41 degrees C) is a heretofore unknown phenomenon, accompanying inflammatory and necrotizing diseases. This phenomenon appears to be identical with the known oxalate-induced radial segmentation and is caused by contractile microfilaments and microtubuli radiating from the centriole. Preincubation of washed leucocytes from healthy donors with plasma of patients showing the phenomenon of RS did not induce RS and preincubation of washed RS-leucocytes with normal plasma did not suppress RS. RS, however, could be induced by intravenous endotoxin injection in a healthy volunteer and could be prevented in part by addition of Vincristine to the blood samples. The phenomenon corresponds to an incomplete, heat-inducible amitosis. The cause of the thermolability of the mitotic apparatus in various diseases remains unclear.

This is a case report on a nulliparous women, who developed the HELLP syndrome following intravenous tocolysis. Contrary to our expectations, neither schistocytes nor signs of intravasal coagulation were apparent; however, we found Fenoterol-associated anti-erythrocyte antibodies. However, the low titre of these antibodies does not explain the massive haemolysis. It is suggested, that these antibodies represent a causal factor in developing the HELLP syndrome.

Intravenous administration of a total dose of more than 200 million IU of penicillin-G led to sensitisation of lymphocytes and formation of specific anti-penicilloyl antibodies of the IgG class. These effects were prevented when the penicillin solution used was freshly prepared and given as a bolus rather than as a slow infusion. The causative antigens seem to be related not to penicilloylated high molecular weight impurities in the penicillin preparations, but to the degradation and/or transformation products of penicillin-G that form when the drug is in solution even if only for a few hours, and not only at room temperature but also at 4 degrees C. Thus penicillin solutions should be freshly prepared and administered from vials containing less than 10 million IU so that bolus doses can be given.

38% of penicillin-G in solution decays at 20 degrees C within 24 h, 50% at 37 degrees C and 66% within 3 h at 56 degrees C. These degraded penicillin-G solutions strongly inhibit growth and maturation of granulocytic stem cells in vitro. Inhibitory concentrations are in the range obtainable with high dose penicillin therapy in vivo. No cytotoxicity of degraded penicillin solutions on bone marrow cells was seen over 24 h. It is suggested that penicillin-G degradation products are responsible for severe granulocytopenia observed after high dose penicillin-G therapy.

Derivatives of beta-lactam antibiotics of the cephalosporin type at 0.02-1 mM concentrations interfered with in vitro replication of two DNA-containing viruses, herpes simplex I and vaccinia, but showed no effects on two RNA-viruses, lymphocytic choriomeningitis virus and vesicular stomatitis virus, or on cell viability. The exact structure of the active compounds remains unknown, but opening of the beta-lactam ring appears to be a prerequisite for their formation. Whereas cephalosporin derivatives were most active, no active products were obtained from penicillins and monobactams. The potential of these unexpected antiviral effects of widely used beta-lactam antibiotics remains subject of further study.

Based on the radioallergosorbent test (RAST), the authors have developed a series of assays to detect IgE and IgG antibodies against a number of frequently used drugs. In this system drugs bound covalently to cellulose paper are incubated with serum and washed; the hapten-specific IgE and IgG antibodies are then qualified and quantified by means of 125I-labelled anti-human IgE and IgG respectively. Thus far the sera of 1,228 patients have been analyzed following therapy with betalactam antibiotics, co-trimoxazole, salicylates, pyrazolones, flavonoids and tetrahydroisoquinoline. The induction of IgG antibodies is a frequent occurrence and that of IgE rare. Isolated high titers of IgE are associated mainly with anaphylactic reactions; in the presence of simultaneously raised IgG titers such side reactions are often absent. Highest IgG titers were found in patients with immune hemolysis after betalactam antibiotics, flavonoids and tetrahydroisoquinoline. In the other types of side reaction specific IgG titers were not significantly higher than in patients without side reactions. The estimation of circulating antibodies against drugs cannot yet be utilized diagnostically except in the rare cases of anaphylactic side reactions. However, the method described permits specific and sensitive detection of sensitization and is suited for scientific purposes.

Pretreatment blood smears of adult patients with acute lymphoblastic leukemia were examined for neoplastic cells showing nuclear radial segmentation (RS). RS was present in 6 of 7 patients with immunologically proven T-cell leukemia, but not in 11 patients whose leukemic cells lacked T-cell markers. Electron microscopic studies of neoplastic cells showed multiple nuclear indentations and abundant cytoplasmic microfilaments and microtubuli in connection with pericentriolar dense material. RS formation was decreased in 1 patient after chemotherapy with a vincristine-containing regimen, while the white cell count remained unchanged. Radial segmentation (RS) of leukocyte nuclei is a well-known phenomenon, which is observed ex vivo (Rieder cells), and can be induced in vitro. Convoluted or multilobulated nuclei in lymphoid neoplasms are similar to RS nuclei both with regard to their structure and their sensitivity to spindle-blocking drugs. We propose that the nuclear alterations observed in a variety of different T-cell neoplasms are identical with RS, and suggest that RS might be a morphological marker for subsets of lymphoproliferative disorders of T-cell origin.

Angiotensin I converting enzyme inhibition by captopril and enalapril may influence sodium and potassium homeostasis. In patients without cardiac failure and with normal renal function significant electrolyte disturbances rarely occur. We report on four patients who developed life-threatening electrolyte disturbances following treatment with enalapril for severe cardiac failure (NYHA-class II-IV). There were important concomitant factors in all four cases: in one case under additional medication with a thiazide diuretic and a nonsteroidal antiinflammatory, hyponatremia of 107 mmol/l occurred. In two further cases severe hyperkalemia of 7.4 and 7.3 mmol/l was observed in the presence of acute renal failure due to enalapril-induced hypotension and concomitant therapy with a nonsteroidal antiinflammatory drug respectively. In a fourth case the combination of enalapril with a potassium-sparing diuretic provoked severe hyperkalemia of 7.9 mmol/l.

During treatment with flavonoid drugs a number of patients developed adverse reactions such as fever, various skin eruptions and intravascular hemolysis. The appearance of flavonoid-specific IgE and IgG antibodies and its possible relation to the observed side effects was studied on a total of 168 individuals treated with flavonoid drugs: 71 patients received troxerutin (Venoruton) parenterally to improve tolerance of radiation therapy, 12 patients were treated intravenously with silymarin (Legalon) for amanita intoxication and 77 patients received various flavonoid drugs for other indications. Flavonoid treatment often induced specific IgG antibodies and less frequently IgE antibodies. After short treatment IgE antibodies were more frequently detected than after treatment of longer duration which nearly always induced IgG antibodies. Patients with hemolysis had the highest IgG titers. In cases with fever and skin eruptions no correlation with antibody titers became evident. Antibody production in patients undergoing radiation therapy appeared to be lower than in non-irradiated patients. Both the IgE and IgG antibody test show a remarkable cross-reactivity between four different flavonoids. Prospective studies will be necessary to decide whether or not this method for the detection of anti-flavonoid antibodies will be suitable for recognizing increased risk of side reactions upon reexposure to flavonoid drugs.

Serum samples from 41 patients who developed adverse reactions during therapy with nomifensine were screened by RAST-based immunoassay for specific IgE and IgG antibodies against nomifensine and three of its metabolites. The results were compared with those of 10 patients without side effects and with 8 non-treated controls. Nomifensine-specific IgE antibodies were found in none of the subjects. However, all patients treated with nomifensine (with and without side effects) had specific IgG antibodies. The antibody cross-reacted in all cases with the metabolites. The titers did not discriminate clearly between the different side reactions and only partially between the presence or absence of a side reaction. The finding of specific anti-drug IgG antibodies warrants more detailed investigation of immunological mechanisms, to determine the clinical relevance of these antibodies and identify patients at risk for serious side effects.

Benzodiazepines are the most frequently prescribed drugs in the Western world. About 3% of the adult Swiss population regularly use benzodiazepines for the treatment of anxiety states or for induction of sleep. All benzodiazepine agonists available exert qualitatively similar pharmacodynamic actions. They commonly activate central GABAergic neuroinhibition, thereby inducing anxiolysis, sedation/hypnosis, anticonvulsion and muscle relaxation. However, various derivatives differ in their physicochemical and pharmacokinetic properties such as lipophilicity, rate of gastrointestinal absorption, hepatic biotransformation and elimination half life. These differences among individual substances can be used clinically to optimize therapy for the individual patient. For example, the elimination half life greatly influences the frequency, intensity and type of adverse reactions such as hangover, rebound insomnia, development of tolerance and dependence as well as withdrawal symptoms. It is estimated that "low-dose dependency" develops in as many as 30 to 45% of chronically treated patients. Low-dose dependency is mainly characterized by the appearance of withdrawal symptoms after cessation of therapy. Since management of the withdrawal state is difficult and especially troublesome for the patient it is best to prevent the development of benzodiazepine dependence by prescribing these drugs less and restricting them to short-term use (7-14 days).

beta-Lactam antibiotics can induce severe neutropenia by a hitherto unknown mechanism. Fifty cases of beta-lactam antibiotic-induced neutropenia (less than 1,000 neutrophils/mm3) from 17 hospitals were analyzed and compared with 140 literature cases. The incidence of neutropenia was 5%-greater than 15% in patients treated for greater than or equal to 10 days with large doses of any beta-lactam antibiotic but less than 0.1% with shorter duration of therapy. In greater than 95% of cases recovery occurred between one to seven days after withdrawal of beta-lactam antibiotics. Bone marrow aspirates were characterized by a lack of well-differentiated myeloid elements in the presence of numerous immature granulocyte precursors. Nine penicillins and eight cephalosporins inhibited in vitro granulopoiesis in a dose-dependent manner. There was a good correlation between the inhibitory capacity of beta-lactam antibiotics in vitro and the doses inducing neutropenia in vivo. These observations may be relevant for therapy in the granulocytopenic patient.

Clinical and serological data in 5 cases of autoimmune hemolysis following therapy with Catergen are reported and compared to the data in similar literature reports. The main argument in favour of Catergen as causative agent in our 5 cases was rapid remission of hemolysis within 2 1/2 to 10 weeks of withdrawing Catergen treatment. Besides causing hemolysis mediated by drug dependent antibodies, long term treatment with Catergen may induce formation of IgG autoantibodies against red blood cells with or without overt hemolysis.

Radial segmentation (RS) of leukocyte nuclei has been observed, for example, in leukemias (Rieder cells). In 6 of 8 patients with T-ALL, RS of neoplastic cells was found in the peripheral blood, whereas in 14 patients with non-T-ALL no RS cells were present. RS may be a morphologic marker for certain T-cell neoplasms, and with regard to ultrastructure it seems to be identical to heat-induced RS of non-neoplastic cells.

Severe hemolysis occurred in a 51-year-old female after a 17-day course of intravenous amoxicillin. A strongly positive direct antiglobulin test (anti-IgG titer 1:2,000) ensued which disappeared after withdrawal of the drug. Both the patient's serum and eluate obtained from the patient's red cells contained an IgG antibody which reacted with red blood cells coated in vitro with amoxicillin, but not with uncoated cells. In addition, high-titer antipenicillin, antiampicillin and antiamoxicillin IgG antibodies could be demonstrated in her serum by a RAST-based solid-phase radioimmunoassay. The patient's hemolysis gradually subsided within 1 week after discontinuing the drug. This is the first report of amoxicillin-induced immune hemolytic anemia.