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Biomedical subjects

B J Berger

Publications and source records attributed to B J Berger.

At least 37 records · Page 2Linked to original sources
PubMed1994

Properties of melarsamine hydrochloride (Cymelarsan) in aqueous solution.

The antitrypanosomal drug melarsamine hydrochloride (MelCy) (trade name, Cymelarsan) is a melamino-phenylarsine made by conjugation of one equivalent of melarsen oxide and two equivalents of cysteamine. Immediately after it was dissolved in water, the compound was found to exist as an equilibrium mixture containing MelCy (43%), MelCy which had lost one cysteamine moiety (MelCy -1; 24%), melarsen oxide (33%), and free cysteamine. Small amounts (< 1%) of the oxidation products derived from the last two components were also formed (cystamine and sodium melarsen). On incubation at room temperature, the MelCy content decreased steadily, with an associated increase in the melarsen oxide and sodium melarsen contents. After 5 days in solution at room temperature, 27% of the arsenical agent was MelCy, 14% was MelCy -1, 42% was melarsen oxide, and 17% was sodium melarsen. Since H2O2 production was detectable in MelCy or cysteamine solutions and the addition of small amounts of exogenous H2O2 readily converted the trivalent melarsen oxide to the pentavalent sodium melarsen, it is hypothesized that the nonenzymatic conversion of cysteamine to cystamine produced H2O2, which then oxidized melarsen oxide to sodium melarsen. Similar time course experiments showed that melarsonyl potassium and melarsoprol were more stable in solution.

Arsenicals↗
PubMed1994

Bacterial infections in HIV-infected patients.

Although the original opportunistic pathogens described in AIDS were protozoal and fungal organisms, bacterial infections are now recognized with increased prevalence and altered expression in patients with HIV infection. Especially since populations outside of North America and populations of i.v. drug abusers have been studied, bacterial infections have been shown to cause substantially increased morbidity and mortality both early and late in the course of HIV infection. Just as strategies have been developed for primary and secondary prophylaxis of classical HIV-related opportunistic infections, prevention of bacterial complications should be a high priority. Good hygiene and avoidance of unsterile needles in illicit drug use, tattooing, ear-piercing, or other cosmetic or ritual activities should be emphasized in patient education. Patients should be counseled to avoid uncooked or poorly cooked eggs and poultry and to avoid unpasteurized milk products. Pneumococcal vaccine is recommended for all HIV-seropositive patients and should be given as early as possible after recognition of HIV infection for maximal efficacy. Influenza vaccine is also recommended. It may have a role in preventing bacterial pneumonia secondary to influenza. Patient management should include regular dental care and nutritional evaluation. The use of intravenous or central catheters should be limited to essential therapies. When patients present with new febrile illness, a high index of suspicion for invasive bacterial disease is appropriate. The signs of serious bacterial infection in HIV-positive patients are subtle. Diagnostic evaluation should include cultures of blood and other relevant clinical specimens. Empiric antimicrobial therapy based on the clinical presentation may be life saving in patients with invasive bacterial disease complicating HIV infection.

AIDS-Related Opportunistic Infections↗
PubMed1993

Nosocomial outbreak of Klebsiella infection resistant to late-generation cephalosporins.

OBJECTIVE: To describe the epidemiology, antimicrobial susceptibility, and control of widespread ceftazidime-resistant Klebsiella pneumoniae infections in a North American hospital and circumstances that led to delayed detection. DESIGN: A 2-year epidemiologic, microbiologic, and clinical cohort study. SETTING: A 487-bed general hospital in New York City. PATIENTS AND CLINICAL ISOLATES: Patient records were reviewed retrospectively and prospectively. Isolates were obtained from the Clinical Microbiology Laboratory. RESULTS: Four hundred thirty-two isolates of ceftazidime-resistant Klebsiella pneumoniae were recovered during a 19-month study period. The peak incidence reached 17.3% of all Klebsiella isolates. One hundred fifty-five patients were colonized or infected, representing more than 70 per 1000 average daily census. Infections occurred in 39% of patients from whom ceftazidime-resistant Klebsiella was isolated. These included 14 bacteremias and 17 pulmonary infections among 52 infected patients. The outbreak coincided with increasing use of ceftazidime therapy for multiresistant Acinetobacter infections. Reduction in ceftazidime use and barrier precautions markedly reduced the incidence of colonization and infection. Ceftriaxone, ceftizoxime, cefotaxime, and cephamycins were inhibitory, but not bactericidal, against ceftazidime-resistant Klebsiella and appeared effective by routine disc diffusion tests. In contrast, imipenem provided consistent bactericidal activity. Preliminary studies indicated that the outbreak was caused by one or more plasmid-mediated beta lactamases. CONCLUSIONS: Nosocomial ceftazidime-resistant Klebsiella pneumoniae may be resistant to the bactericidal activity of all cephalosporins and cephamycins. Such isolates appear susceptible to cephalosporins other than ceftazidime by routine disc diffusion testing. Ineffective therapy, delayed detection of resistance, and epidemic spread are potential consequences. Imipenem provides consistent bactericidal activity. Ceftazidime restriction and barrier precautions for colonized and infected patients are effective control measures.

Aged↗
PubMed1993

Cytochrome P450 in trypanosomatids.

Post-mitochondrial supernatant extracts prepared from bloodstream forms of Trypanosoma brucei brucei, T. cruzi epimastigotes, Leishmania donovani promastigotes and Crithidia fasciculata have been found to catalyse cytochrome P450-dependent reactions. Appreciable ethoxycoumarin deethylase and ethoxyresorufin deethylase activities were found in all of the above trypanosomatids, with T. cruzi epimastigotes having the highest activity (57.1 and 10.7 pmol/min/mg protein, respectively). In all four species these reactions were inhibited by the cytochrome P450 inhibitors carbon monoxide, proadifen and metyrapone. In contrast to rat liver microsomes, the trypanosomatid extracts showed no detectable pentoxyresorufin depentylase or pentamidine hydroxylase activity. Both C. fasciculata and T. b. brucei post-mitochondrial supernatants showed carbon monoxide difference spectra consistent with the presence of cytochrome P450 (9.6 and 6.3 pmol/mg protein, respectively). An additional hemoprotein which gave a carbon monoxide difference peak at 420 nm was also detected in C. fasciculata and T. b. brucei microsomes and C. fasciculata mitochondria. Subcellular fractionation of both early and late log C. fasciculata showed that the ethoxycoumarin deethylase activity was enriched in the microsomal fraction.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1993

Polyamine and pentamidine metabolism in African trypanosomes.

A pentamidine-resistant line of bloodstream Trypanosoma brucei brucei (S427/118) has been developed by stepwise selection in axenic culture in vitro. After 57 days of selection, the resistant line (S427/118/PR32) was able to grow normally in 32 ng/ml (54 pM) pentamidine with an IC50 value of 105 ng/ml (177 pM), which is 26-times higher than that of the parental strain. Post-mitochondrial supernatant extracts of both strains were unable to metabolize [3H]pentamidine, whereas under identical conditions rat liver microsomes were able to convert > 5% of the drug to hydroxylation products. Thus metabolic conversion of pentamidine does not appear to be involved in either the mode of action of or resistance to pentamidine. Pentamidine-sensitive trypanosomes exposed for 4 h in vivo to therapeutic doses of pentamidine (4 mg/kg) did not show any significant changes in either polyamine-, thiol- or S-adenosylmethionine metabolites, indicating that inhibition of S-adenosylmethionine decarboxylase is not involved in the trypanocidal action of the drug. However, a marked increase in basic amino acid content was noted. In particular, lysine content was increased 13-fold following exposure to pentamidine.

Animals↗
PubMed1993

Effect of sulbactam on infections caused by imipenem-resistant Acinetobacter calcoaceticus biotype anitratus.

A recent outbreak of multiresistant strains of Acinetobacter calcoaceticus biotype anitratus was observed mostly, but not exclusively, in the surgical intensive care unit in our hospital. Disk diffusion and microdilution susceptibility studies demonstrated resistance to imipenem, all aminoglycosides, and all individual beta-lactam antibiotics. Only ampicillin plus sulbactam, cefoperazone plus sulbactam, and polymyxin produced zone sizes and MICs in the susceptible ranges. Determination of MICs and MBCs demonstrated that sulbactam was the antimicrobial agent responsible for the killing of these organisms. Nine of 10 patients who were infected with imipenem-resistant Acinetobacter strains and received ampicillin plus sulbactam for > 3 days improved clinically, and in many cases organisms were eradicated from the site of isolation.

Acinetobacter Infections↗
PubMed1993

Midazolam enhances anterograde but not retrograde amnesia in pediatric patients.

BACKGROUND: Midazolam sedation has been shown to diminish recall of one to four cards shown prior to induction of general anesthesia in pediatric patients. This promising but limited finding prompted us to investigate the effect of midazolam sedation on retrograde and anterograde recall and recognition in children scheduled for elective surgery. METHODS: Forty patients aged 4-10 yr were randomized using a double-blind study design to receive either 0.2 mg/kg intranasal midazolam or 0.2 ml/5 kg placebo (distilled water) using a Devilbiss #286 atomizer. To assess postoperative memory of preoperative events, recall and recognition tasks were performed using a series of picture cards designed for this purpose. Retrograde amnesia was measured by postoperative recall and recognition of cards shown prior to midazolam/placebo administration, and anterograde amnesia was measured by postoperative recall and recognition of cards shown during the interval between midazolam/placebo administration and induction of general anesthesia. RESULTS: Compared to placebo, the midazolam group experienced a significant postoperative reduction in ability to both recall (P < .003) and recognize (P < .001) cards shown subsequent to midazolam/placebo administration (anterograde amnesia). In distinction, there was no difference between groups in postoperative ability to recall or recognize cards shown prior to midazolam/placebo administration (retrograde amnesia). CONCLUSIONS: These results support and extend the inference that midazolam diminishes anterograde recall. In addition, our findings indicate that midazolam diminishes anterograde recognition, thereby providing partial anterograde amnesia without affecting retrograde memory in pediatric patients.

Amnesia↗
PubMed1992

Interactions between immunity and chemotherapy in the treatment of the trypanosomiases and leishmaniases.

The immune status of a host infected with Trypanosoma spp. or Leishmania spp. can play an important role in successful chemotherapy. In animal models, treatment of African trypanosomiasis with difluoromethylornithine or melarsoprol requires an appropriate antibody-mediated immune response. An intact immune system is also necessary for rapid clearance of trypanosomes from the bloodstream following treatment with suramin or quinapyramine. Similarly, an efficient cell-mediated immune responses is required for maximal efficacy of pentavalent antimonials in the treatment of leishmaniasis. However, the potential relationship between parasite-induced or acquired immunosuppression and effective chemotherapy has been poorly studied. Macrophages which have been activated by bacterial cell wall components or gamma-interferon are known to display increased activity against Leishmania donovani or Trypanosoma cruzi. In experimental and clinical visceral leishmaniasis, use of macrophage activators together with pentavalent antimonials has lowered the dose of antimony required to cure the infection.

Animals↗
PubMed1992

Primary and secondary metabolism of pentamidine by rats.

The antiprotozoal drug pentamidine [1,5-bis(4'-amidinophenoxy)pentane] has been previously shown to be metabolized by rat liver microsomes, and five of the seven putative primary metabolites have been identified. With the synthesis and identification of 5-(4'-amidinophenoxy)pentanoic acid and 5-(4'-amidinophenoxy)-1-pentanol as the remaining two metabolites, the primary metabolism of pentamidine in rats appears fully characterized. Use of [14C]pentamidine with rat liver microsomes confirms this conclusion, since no unidentified radioactive peaks were detected by high-performance liquid chromatography (HPLC). Isolated, perfused rat livers were used with [14C]pentamidine to identify secondary metabolites. Only two novel radioactive peaks were detected by HPLC analysis of perfused liver samples. The treatment of liver samples with sulfatase or beta-glucuronidase resulted in the reduction or elimination of these peaks and gave rise to peaks identified as para-hydroxybenzamidine and 5-(4'-amidinophenoxy)pentanoic acid. It was concluded from these results that only these two primary metabolites were conjugated with sulfate or glucuronic acid. After 4 h of incubation in the perfused liver system, approximately 15% of the recovered radiolabel was pentamidine. These results suggest that pentamidine metabolism can be rapid and extensive in rats.

Animals↗
PubMed1991

Hydroxylation of pentamidine by rat liver microsomes.

The antiprotozoal/antifungal drug pentamidine [1,5-bis(4-amidinophenoxy)pentane] has been recently shown to be metabolized by rat liver fractions to at least six putative metabolites as detected by high-performance liquid chromatography. Two minor metabolites have been previously identified as N-hydroxypentamidine and N,N'-dihydroxypentamidine. In this study, the two major microsomal metabolites have been identified as the 2-pentanol and 3-pentanol analogs of pentamidine [1,5-di(4-amidinophenoxy)-2-pentanol; and 1,5-bis(4-amidinophenoxy)-3-pentanol]. As well, a seventh putative metabolite has been discovered and identified as para-hydroxybenzamidine, a fragment of the original drug. Whereas the cytochromes P-450 have been demonstrated as the enzyme system responsible for pentamidine metabolism, hydroxylation of the drug was not inducible by phenobarbital, beta-naphthoflavone, clofibrate, isosafrole, pregnenolone-16 alpha-carbonitrile, ethanol or pentamidine pretreatment of rats. The kinetics of the production of the two major microsomal metabolites has been determined as Km = 56 +/- 19 microM and Vmax = 126 +/- 21 pmol/min/mg microsomal protein for the 2-pentanol analog, and Km = 28 +/- 0.28 microM and Vmax = 195 +/- 2.4 pmol/min/mg microsomal protein for the 3-pentanol analog. Therefore, the mixed-function oxidases readily convert pentamidine to hydroxylated metabolites, but exactly which isozyme(s) of cytochrome P-450 is responsible is not clear.

Animals↗
PubMed1990

Metabolic N-hydroxylation of pentamidine in vitro.

By using high-performance liquid chromatography, the in vitro conversion of pentamidine to the corresponding amidoximes (N-hydroxypentamidine and N,N'-dihydroxypentamidine) was studied in supernatants of rat liver homogenate centrifuged at 9,000 x g. The presence of the two amidoxime peaks in chromatograms was confirmed by liquid secondary ion mass spectrometry and by unequivocal synthesis of the suspected metabolites. The metabolic reactions were found to be catalyzed by the cytochrome P-450 system (mixed-function oxidases). The formation of the monohydroxylated product was found to have a Km of 0.48 mM and a Vmax of 29.50 pmol/min per mg of protein, while the dihydroxylated metabolite had a Km of 0.73 mM and a Vmax of 4.10 pmol/min per mg of protein. N,N'-Dihydroxypentamidine was found to have highly reduced antiprotozoal activity in vitro relative to that of pentamidine, and neither of the hydroxylated metabolites nor pentamidine was found to be significantly mutagenic by the Ames test. Contrary to previous reports, pentamidine is readily metabolized to at least two hydroxylated products, and this conversion may be relevant to the clinical use of the compound and to future drug design.

Animals↗
PubMed1989

High-performance liquid chromatographic method for the quantification of several diamidine compounds with potential chemotherapeutic value.

A high-performance liquid chromatographic method has been developed for the detection and quantification of pentamidine and pentamidine analogues of chemotherapeutic value in order to measure their concentration in physiological fluids. The compounds were extracted from urine over octadecyl solid-phase extraction columns, followed by chromatographic separation with an octadecyl reversed-phase column. For the mobile phase, a gradient of 31.5-37.5% acetonitrile in water, with sodium heptanesulfonate and tetramethylammonium chloride as ion modifiers, was used. This method was used to reliably detect levels as low as 341 ng/ml without concentration of the compounds during the solid-phase extraction. The assay was used to determine the effectiveness of several solid-phase extraction columns for isolating the compounds of interest and to quantify the amount of pentamidine and its analogues contained in the urine of dosed rats.

Animals↗
PubMed1989

Snake venom components and their cross-reactivity: a review.

Snake venoms are complex mixtures of organic and inorganic compounds, many of which display biological activity. It has been demonstrated that antisera raised against whole venom or a single purified venom protein from one species of snake will react with proteins in the venom of other species. This cross-reactivity between species may have applications in determining snake phylogeny, but recent studies on the variation of venom components within a species make these evolutionary conclusions questionable.

Amino Acid Oxidoreductases↗