Alteration by burn injury of the pharmacokinetics and pharmacodynamics of cimetidine in children

Summary We have studied the mechanisms of the increased dosage requirements of the H₂-receptor antagonist cimetidine in paediatric burned patients in a pharmacokinetic and pharmacodynamic study.Cimetidine (10–15 mg·kg^–1) was given to 21 burned children and multiple blood samples were obtained for determination of plasma cimetidine concentrations and pharmacokinetic analysis.The relation of gastric pH to plasma cimetidine concentrations was studied in five of these children who had nasogastric tubes. In an additional four patients the effects of cimetidine on gastric pH were studied during a continuous infusion of cimetidine, which maintained steady-state plasma cimetidine concentrations above 0.5 µg·ml^–1.The mean (SEM) clearance of cimetidine in burned children was 16.22 ml·kg^–1 and cimetidine half-life was 1.06 h. The cimetidine clearance and half-life values were significantly higher in burned children compared with our previously reported values for normal adult patients, 8.2 ml·min·kg^–1 and 2.21 h respectively.Endogenous creatinine clearance normalized to 70 kg in burned children was 190 ml·min^–1. In burned children 41% of the dose of intact cimetidine was excreted during 8 h of the study compared with 45% excretion during 24 h in healthy adult controls previously reported. The correlation coefficient between creatinine and cimetidine clearances was 0.93 (r ²=0.85).The plasma concentration of cimetidine needed to increase gastric pH to 4.0 was 1.0 µg·ml^–1, which contrasts with the value of >0.5 µg·ml^–1 required for adult burned patients.These findings support the hypothesis that the higher dosage requirements of cimetidine in burned children is due both to enhanced elimination kinetics and to alterations in target organ sensitivity, requiring higher than normal plasma concentrations for the desired effect. In burned children Cimetidine should be given in higher doses and/or more frequently.     

Increased drug cytotoxicity at reduced pH counteracts cyclophosphamide resistance in cultured rat mammary carcinoma cells

The sensitivity of a cyclophosphamide (CP)-resistant MIR rat mammary carcinoma cell variant (MIRCPr) in monolayer culture towards the cytotoxic effect of mafosfamide (an analogue of "activated" CP) was measured as a function of extracellular pH (pHe). An inverse correlation was found between cell survival and the H+ ion concentration in the culture medium. At pHe 7.4, the fraction of clonogenic MIRCPr cells exposed to mafosfamide (7.5 micrograms/ml) for 24 hr was 1 X 10(-1) in relation to untreated control cells. At pHe 6.2, however, this value was reduced to 3 X 10(-4), i.e., a value equal to that for the CP-sensitive parental MIR cells exposed to the same concentration of mafosfamide at pHe 7.4. Our data indicate complete compensation of CP resistance in MIRCPr cells at pHe 6.2. MIRCPr cells were not resistant to the cytotoxic effect of nornitrogen mustard. This suggests that resistance to CP in MIRCPr cells is due to enzymatic inactivation of the primary intermediates in CP bioactivation. The alkylating activity of nornitrogen mustard (and less so that of phosphoramide mustard) is strongly enhanced at low pH. In MIRCPr cells shifted to an acidic environment, therefore, a (putative) decrease in the intracellular concentration of alkylating CP metabolites may be counteracted by an enhancement of their alkylating activity (on a molar basis). By parenteral administration of glucose, the pH in malignant tumors of both animal and human origin can be lowered to values between 5.6-6.6. Our data suggest that an upshift of H+ ion concentration in malignant tissues may at least partially counteract CP resistance in cancer cells in vivo.     

Complement-opsonized HIV: the free rider on its way to infection

The complement system (C) is one of the main humoral components of innate immunity. Three major tasks of C against invading pathogens are: (i) lysis of pathogens by the formation of the membrane attack complex (MAC); (ii) opsonization of pathogens with complement fragments to favor phagocytosis; and (iii) attraction of inflammatory cells by chemotaxis. Like other particles, HIV activates C and becomes opsonized. To escape complement-mediated lysis, HIV has adopted various properties, which include the acquisition of HIV-associated molecules (HAMs) belonging to the family of complement regulators, such as CD46, CD55, CD59, and the interaction with humoral regulatory factors like factor H (fH). Opsonized virus may bind to complement receptor positive cells to infect them more efficiently or to remain bound on the surface of such cells. In the latter case HIV can be transmitted to cells susceptible for infection. This review discusses several aspects of C-HIV interactions and provides a model for the dynamics of this process.     

Quartz glass pipette puller operating with a regulated oxy-hydrogen burner

Quartz glass electrodes are superior to conventional glass electrodes for low-noise recording. They have better electrical characteristics and hydrophobic surfaces which resist creeping of salt solutions. We used oxy-hydrogen heating with program-controlled gas pressure to melt quartz glass capillaries. Usually, the relative wall thickness (the quotient of the outer and inner diameters do/di) of capillaries is, at best, maintained up to the electrode tip. If tips with thicker walls can be produced, coating and other surface treatments can be avoided. We found that programmed heating periods without pull allowed an fivefold increase of do/di in the tip region. Since do/di is inversely proportional to input capacity, the recording noise was minimized and became insignificant relative to amplifier and holder noise. A sample patch-clamp recording is shown.     

Der Einfluß von N1-n-Butylbiguanid auf das Verhalten der Unveresterten Fettsäuren (UFS) bei Normalpersonen und bei Diabetikern und am epididymalen Fettgewebe der Ratte

Zusammenfassung Das Verhalten der Unveresterten Fettsäuren an Gesunden und Diabetikern und am epididymalen Fettgewebe der Ratte unter N₁-n-Butylbiguanid wurde untersucht. Normalpersonen mit und ohne Biguanid reagieren bei Blutzuckerabfall mit einem Anstieg der UFS, der unter Biguanid signifikant höher ist. Diabetiker zeigen einen geringfügigen Abfall der UFS nach Biguanid. Unter Biguanidkonzentrationen, die der therapeutischen Serumkonzentration entsprechen (5/ml), werden vom Fettgewebe in Gegenwart von Glucose vermehrt UFS utilisiert. Bei hohen Konzentrationen (100 bis 1000/ml) tritt ein Wirkungsumschlag ein, die Fettsäureutilisation wird gehemmt.Teile dieser Arbeit sind in den Dissertationen vonM. L'age undJ. Stehr enthalten.     

CD1 assembly and the formation of CD1-antigen complexes

The CD1 antigen presentation system presents lipid antigens to effector T cells, which have diverse roles in antimicrobial responses, antitumor immunity and in regulating the balance between tolerance and autoimmunity. The trafficking of CD1 molecules and lipid antigens facilitates their intersection and binding in specific intracellular compartments. Recent studies have now identified unexpected accessory molecules that are critical to CD1 assembly and lipid loading. The atomic structures of CD1-antigen complexes have defined both the orientation of polar headgroups between the alpha1 and alpha2 helices of CD1 and the manner in which distinct CD1 isoforms bind a range of lipids that have different lengths and numbers of hydrocarbon chains.     

Protein expression of MMP-13, uPA, and PAI-1 in pseudocapsular and interface tissue around implants of loose artificial hip joints and in osteoarthritis

Matrix metalloproteinase 13 (MMP-13), urokinase type plasminogen activator (uPA), and plasminogen activator inhibitor type-1 (PAI-1) have been reported to be involved in aseptic loosening of artificial hip joints. This study for the first time presents the protein levels of all of these factors in synovial-like interfaces between bone and prosthesis and in pseudocapsular tissues surrounding the artificial joint in patients with aseptic loosening (n=17) measured by ELISA. No differences were observed in the antigen expression of MMP-13, uPA, and PAI-1, comparing interface and pseudocapsular tissue. Also, no significant correlation between the protein expression of these factors and years from arthroplasty to revision or to type of fixation (cemented vs. cementless) was observed. As control, MMP-13, uPA, and PAI-1 antigen levels were also determined in the synovium of patients with osteoarthritis (n=10). Yet, the antigen levels of MMP-13, uPA, and PAI-1 in tissue specimens from patients with aseptic loosening of artificial hip joints were significantly higher compared to their expression in synovial capsular tissues obtained from patients with osteoarthritis. In conclusion, this study shows that elevated protein levels of uPA, PAI-1, and MMP-13 in periprosthetic pseudocapsular and interface tissues from patients after total hip replacement due to aseptic loosening seem not to be associated with the patient outcome.     

September 2002: 24-year-old female with a 6-month history of seizures

The September 2002 COM. A 24-year-old female presented with a history of 3 generalized seizures, the first of which had occurred 6 months before admission. Her neurological examination was normal, but upon admission her MRI showed a small cystic lesion in the left parieto-occipital region. The lesion was hyper-intense on T-2 weighted images and did not show contrast enhancment. At surgery, the tumor was found to be deep to the cortex and was a cyst with amber fluid surrounded by gliotic brain. Microscopically, the tumor was well-demarcated from the surrounding tissues, which showed reactive changes, including Rosenthal fibers. The tumor was composed of GFAP-positive glial cells, which were arranged in a pseudopapillary fashion around blood vessels. In between, the tumor cells were positive for neuronal markers. The diagnosis was papillary glioneuronal tumor (PGNT), a relatively recently described lesion that may be a variant of ganglioglioma. The current literature on PGNTs is reviewed.