Imipenem/cilastatin therapy of infections in cancer patients

Imipenem/cilastatin was administered during 153 febrile episodes occurring in cancer patients and the response rate was 68%. Considering only documented infections the response rate was 71%. Patients who received imipenem as initial therapy had a higher response rate than patients who received it after failing other antibiotics (77% versus 68%). The overall response rates for septicemias and pneumonias were 75% and 58%. Among the 57 gram-negative infections 77% responded, but the response rate was substantially higher if imipenem was used as initial therapy (94% versus 69%). The poorest response rate was observed when imipenem was given as secondary therapy for Pseudomonas infections (50%), but most of these patients had failed to respond to other appropriate antibiotics. The only serious side effect was seizures which occurred in ten patients, although eight of them had other predisposing factors. Imipenem appears to be a useful antibiotic for treatment of infections, even in neutropenic cancer patients.     

Mycobacterium tuberculosis and Mycobacterium avium inhibit IFN- gamma -induced gene expression by TLR2-dependent and independent pathways.

Mycobacteria-infected macrophages are poor responders to interferon-gamma (IFN-gamma), resulting in decreased expression of IFN-gamma-induced genes. In the present study, we examined the inhibition of IFN-gamma-induced gene expression by Mycobacterium tuberculosis and four different Mycobacterium avium strains in mouse RAW264.7 macrophages. Gamma-irradiated M. tuberculosis inhibited mRNA expression of a panel of six different IFN- gamma-induced genes. All four of the M. avium strains completely inhibited IFN-gamma-induced expression of MHC class II Aalpha and Ebeta mRNA. However, the Mac101 strain, which is serovar 1, inhibited IFN-gamma induction of IFN regulatory factor-1 (IRF-1) and guanylate-binding protein-1 (GBP-1) mRNA to a greater extent than the other M. avium strains, which are serovar 2. In this study, we also show that mycobacteria inhibit gene expression by both toll-like receptor 2 (TLR2)-dependent and independent pathways. The inhibition of IFN-gamma-induced gene expression by M. avium was reduced but not completely blocked in macrophages from TLR2(/) mice. IFN-gamma-induced gene expression was also inhibited by mycobacteria in RAW264.7 cells expressing dominantnegative TLR2 or myeloid differentiation factor 88 (MyD88), further indicating the existence of a pathway independent of TLR2 and MyD88. These data suggest that mycobacteria inhibit IFN-gamma-induced gene expression by multiple pathways involving both TLR2 and non-TLR receptors.     

Development of systemic lupus erythematosus in a patient on hemodialysis.

A case of systemic lupus erythematosus (SLE) that developed 2 years after beginning hemodialysis is reported. The patient had not been given any drug implicated in the production of SLE. She had been treated with deferoxamine, an in vitro inhibitory of DNA synthesis. The difficulty of the diagnosis is emphasized. Clinical improvement after prednisone treatment was impressive. SLE may appear even in patients receiving hemodialysis, despite immunological depression derived from chronic uremia.     

Interleukin-1 in alcoholic cirrhosis of the liver: the influence of nutrition.

Interleukin-1 (IL-1) is a cytokine produced by the macrophage-monocyte system that has important effects on immunological responses and inflammatory reactions. Several clinical studies have shown that severe protein energy malnutrition adversely effects cell-mediated immune responses and the functional state of macrophages. The objective of this study was to analyse IL-1 production by adherent cells stimulated in vitro with lipopolysaccharide B (LPS) from patients with alcoholic cirrhosis of the liver and its possible relationship with nutritional states. Forty-five patients with alcoholic cirrhosis and 28 healthy donors were investigated. A combined index of nine anthropometric and biochemical parameters was used to evaluate nutritional status of cirrhotic patients, allowing a distinction to be made between those patients with acceptable nutrition (group I: 40%), those with slight malnutrition (group II: 37.7%), and those with severe malnutrition (group III: 22.3%). IL-1 activity was significantly lower in the cirrhosis patients than in the controls (P less than 0.001). This activity also was significantly lower in samples obtained from cirrhotics with severe malnutrition than in those with acceptable nutrition (P less than 0.05); the combined index and the sole anthropometric index gave the same results, suggesting that malnutrition may play a role in the immunoregulatory disturbances in the pathogenesis of alcoholic liver disease.     

Dual action of prajmalium on the Ca currents in frog isolated cardiomyocytes

The effects of N-n-propylajmaline (prajmalium) on the Na and Ca currents of single frog atrial and ventricular cells were studied by means of the whole-cell patch-clamp technique. Prajmalium (10(-9) to 10(-6) M) depressed the Na current (INa) in a dose- and use-dependent manner. In the same range of concentrations, prajmalium induced a dual effect on the high (ICaL) and low (ICaT) threshold Ca currents (the latter being only present in atrial cells). At a low concentration (10(-9) M), prajmalium increased both Ca currents while at high concentrations (10(-6) M) it depressed them. Prajmalium appeared very potent on ICaT although this current is generally reported to be barely sensitive to agonists and drugs. The action of the drug was also accompanied by a shortening in the half-time of inactivation of the Ca currents and a slight hyperpolarizing shift of their availability curves. The increase in ICaL by prajmalium was not prevented by prazosin (10(-7) M) nor by propranolol (10(-6) M), and it was also observed after ICaL had been fully stimulated by isoproterenol (10(-7)M). Nifedipine (10(-6) M), however, was able to prevent or block the prajmalium-induced increase in ICaL. Some similarities between the actions of prajmalium and dihydropyridine agonists on Ca currents are discussed.     

Structure-activity relationships among di- and tetramine disulfides related to benextramine

The synthesis and irreversible alpha-blocking activity in the rat vas deferens of a series of tetra- and diamine disulfides 2-38, structural analogues of benextramine (BHC), are described. All compounds containing a central cystamine moiety displayed an irreversible alpha-adrenergic blockade at concentrations ranging from 10(-4) to 6 X 10(-6)M. Potency was increased in cystamines N,N'-disubstituted with 6-aminohexyl groups, especially when the outer nitrogen atoms bear arylalkyl substituents or are enclosed in a ring. However, N,N,N',N'-tetrasubstituted cystamines were poor blockers. Structural specificity in the outer portion of the tetramine disulfide is low, since many types of substituents gave rise to potent alpha-blockers. Even replacement of the outer amines with nonbasic ethers or amides was observed to maintain irreversible alpha-blockade.