Pentoxifylline decreases tumor necrosis factor expression and serum triglycerides in people with AIDS. NIAID AIDS Clinical Trials Group.

Tumor necrosis factor-alpha (TNF)-cachectin increases the expression of the human immunodeficiency virus (HIV), reverses the therapeutic efficacy of zidovudine (ZDV), and may contribute to the wasting syndrome. Pentoxifylline (Trental) decreases TNF activity; in cell culture, it decreases HIV replication and down-regulates expression of the HIV long terminal repeat (LTR). Therefore, pentoxifylline was administered to 25 patients with advanced AIDS in this AIDS Clinical Trial Group study (ACTG #160), the goal of which was to investigate the ability of the drug to decrease TNF expression and HIV replication in this patient population. One patient discontinued drug treatment because of toxicity. Data were analyzed on the 17 patients who completed the 8-week study treatment with pentoxifylline, 400 mg, thrice daily. The median pretreatment CD4+ lymphocyte count was 32 cells/mm3. Fasting serum triglycerides, which have previously been shown to correlate with levels of interferon-alpha and/or TNF, fell on average by 66 mg/dl (p = 0.06). TNF mRNA levels in peripheral blood mononuclear cells fell in 10 of 16 patients (p = 0.02). HIV load decreased and increased significantly in four and one patients, respectively, but did not change in the group as a whole. This study demonstrates the safety of pentoxifylline in AIDS patients and its ability to decrease triglycerides and TNF mRNA levels.

Spiro[isobenzofuran-1(3H),4'-piperidines]. 3. Diuretic and antihypertensive properties of compounds containing a sulfur attached to nitrogen.

The synthesis and antihypertensive and diuretic activity of several N-sulfur derivatives of 3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] are reported. Benzenesulfenamide 3 possessed marked, species-specific diuretic and antihypertensive activity in rats.

Carboxyarylindoles as nonsteroidal antiinflammatory agents.

An extensive series of carboxyarylindoles has been evaluated for antiinflammatory activity in the carrageenin paw edema assay. The requirements for optimal antiinflammatory activity in this series are relatively specific: a central pyrrole nucleus with (a) a 3-carboxy-4-hydroxyphenyl moiety substituted directly on the nitrogen, (b) a 2-phenyl group (R2) with a substituent of low electronegativity, (c) absence of a substituent in the 3 position (R3), and (d) a system fused across the 4,5 positions (X), which is lipophilic, quasiplanar, and does not interact sterically with the N-phenyl group. One derivative, 3-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5-dihydro-3H-benz[e]indole (42), has been selected for further study.

[(3-aryl-1,2-benzisoxazol-6-yl)oxy]acetic acids. A new diuretic series.

A series of [(3-aryl-1,2-benzisoxazol-6-yl)oxy]acetic acids was synthesized and tested for diuretic activity in saline-loaded mice and in conscious, water-loaded dogs. The structural requirements for good diuretic activity in both mice and dogs were found to be very specific. In summary, the compounds with the best diuretic activity (13i, 13q, and 13ff) were substituted with a 2-fluorophenyl group at the 3 position and chlorine or bromine at the 7 position. Compound 13ff, [(7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]acetic acid (HP 522), was found to be moderately uricosuric in chimpanzees and was selected for further development.

The in vitro antimicrobial activity of desacetylcefotaxime compared to other related beta-lactams.

Like all other cephalosporins that contain an acetyl side chain in the 3' position, cefotaxime (CTX) is partially desacetylated in vivo. Desacetylcefotaxime (des-CTX) possesses a broad antimicrobial spectrum and high beta-lactamase stability. With the exception of Pseudomonas aeruginosa, Morganella morganii, Bacteroides fragilis, and Staphylococcus aureus, most strains of other species tested usually had mean MICs of des-CTX lower than 1 microgram/ml. Its activity is generally lower than that of the parent compound. It was only against some strains of P. cepacia that des-CTX surpassed the activity of CTX. The activity of des-CTX markedly exceeds the activity of many therapeutically used cephalosporins. This is especially true for Haemophilus influenzae, Neisseria meningitidis, most species of Enterobacteriaceae, and streptococci other than Streptococcus faecalis.

Antimicrobial spectrum of cefpirome combined with tazobactam against the Bacteroides fragilis group.

Cefpirome, a so-called fourth-generation cephalosporin, was tested alone and in combination with the sulfone beta-lactamase inhibitor, tazobactam, against 63 members of the Bacteroides fragilis group. The cefpirome MIC50 was only 64 micrograms/ml, but the MIC was reduced eightfold with tazobactam (2:1 ratio). The addition of tazobactam to cefpirome or the use of metronidazole as a codrug appear to be alternative choices to enhance the antianaerobic spectrum. Over 98% of strains had cefpirome-tazobactam MICs of less than or equal to 32 micrograms/ml.

Effect of blood product medium supplements on the activity of cefotaxime and other cephalosporins against Enterococcus faecalis.

The activities of cefotaxime and other aminothiazoyl oxime cephalosporins against Enterococcus faecalis were enhanced by addition of 5% sheep blood to Mueller-Hinton agar. This effect was not seen with aztreonam (aminothiazoyl oxime monobactam), cefotiam (aminothiazoyl, nonoxime), or other cephalosporins, and it was specific to the syn-configuration of the oxime moiety. Enhancement of cefotaxime activity was demonstrable against approximately 50% of 86 clinical isolates and could only be shown at low bacterial inocula. Human serum, serum alpha 1-, beta- and gamma-globulin fractions and albumin often antagonized or did not affect significantly the antimicrobial activity of cefotaxime, while the alpha 2-globulin fraction usually enhanced drug activity. The in vivo activity of cefotaxime against E. faecalis was examined in a rat peritoneal abscess model. The test organism was resistant to cefotaxime by standard methods (MIC greater than 128 micrograms/ml) but was inhibited by 1.0 microgram/ml when rat serum was presented in the medium. Cefotaxime reduced titers of bacteria within abscesses after 5 days of therapy (5.77 +/- 0.68 log10 CFU/g) in comparison with those in control animals (7.38 +/- 0.28 log10 CFU/g, p less than 0.05). Moxalactam, the in vitro activity of which was not augmented by serum, proved ineffective in the animal model. While these observations do not have direct therapeutic relevance, they offer a possible explanation for the relatively infrequent occurrence of enterococcal superinfection in patients treated with cefotaxime.

Absorption, distribution, metabolism, and excretion of furosemide in dogs and monkeys I: analytical methodology, metabolism, and urinary excretion.

35S-Furosemide was administered to beagle dogs and rhesus monkeys in an oral solution on a single and a 20 repeated 5-mg/kg/day dosing regimen. Following the single dose, 25.0% (dogs) and 24.0% (monkeys) of the dose were excreted in the urine in 24 hr. TLC analysis demonstrated that both species had similar excretory patterns; i.e., over 80% of the amount excreted in the urine was present as unchanged durosemide and the remainder was composed of a known metabolite, saluamine, and an as yet unidentified metabolite(s). The repetitive dosing regimen did not appear to alter significantly either the total amount recovered in the 24-hr urine or the excretion pattern. Studies in dogs showed that only 50-60% of furosemide was absorbed from oral solution. A significant biliary secretion elimination pathway for furosemide also was observed.

New pharmacological studies with pentoxifylline.

Polymorphonuclear (PMN) overactivation plays a critical role in microcirculation as well as in conditions such as multiorgan failure (MOF). Pentoxifylline has been shown to prevent PMN activation by endotoxin and cytokines such as TNF alpha and IL-1. In addition, MOF induced by IL-2 in animals can be prevented by pentoxifylline. The present studies evaluated two aspects of PMN activation and pentoxifylline interaction. The first was the time sequence for pentoxifylline prevention of TNF alpha activation and the second was the activity of pentoxifylline on amphotericin B activation of PMNs. TNF alpha activation of PMNs is blocked by pentoxifylline when cells are exposed to pentoxifylline prior to TNF alpha or after TNF alpha. Amphotericin B activation of PMNs was demonstrated by a decreased chemotaxis, increased chemiluminescence, and increased PMN spreading. In all conditions, pentoxifylline decreased amphotericin B activation of PMNs. These results suggest that pentoxifylline can reverse cytokine activation of PMNs and that pentoxifylline may alter some of the toxic effects of amphotericin.

Levels of cefotaxime in body fluids and tissues: a review.

Cefotaxime is a third-generation cephalosporin with a broad spectrum of activity. Concentrations of cefotaxime in serum and urine are sufficient for clinical efficacy. This report reviews the available data on the penetration of cefotaxime into other body fluids and tissues. Therapeutic doses of cefotaxime result in significant levels in bile (20 micrograms/ml), in cerebrospinal fluid of patients with meningitis (5-10 micrograms/ml), in pleural fluid (2-7 micrograms/ml), and in otitis media exudate (2-10 micrograms/ml). Lower levels of cefotaxime are obtained in uninflamed aqueous humor (1 microgram/ml), in breast milk (0.1-0.5 microgram/ml), and in cerebrospinal fluid of patients without meningitis (0.2 microgram/ml). Cefotaxime levels in tissues are generally well within the range required for clinical efficacy--i.e., 2-5 micrograms/g, with some higher levels reported in testis, prostate, ureter, skin, and gallbladder wall. Drug levels of less than 2 micrograms/g have been reported in fat, muscle, and uterus. All body fluids and tissues, including bone and skin, are penetrated easily by therapeutic doses of cefotaxime.

Production of hypoprothrombinaemia by cefazolin and 2-methyl-1,3,4-thiadiazole-5-thiol in the rat.

Recent findings have suggested that the 1-methyltetrazole-5-thiol (MTT) group contained in several beta-lactam antibiotics may be responsible for the hypoprothrombinaemia associated with these drugs. In order to determine if the hypoprothrombinaemia associated with cefazolin is due to the presence of the structurally related 2-methyl-1,3,4,-thiadiazole-5-thiol (MTD) group which it possesses, the ability of MTD and cefazolin to produce hypoprothrombinaemia in rats was examined. Female rats maintained on a vitamin K-deficient diet for ten days developed hypoprothrombinaemia after the intravenous administration of cefazolin for two subsequent days. Hypoprothrombinaemia was also produced by the oral administration to vitamin K-deficient rats of either cefazolin or MTD, while the oral administration of cefotaxime, which does not contain a thiol group, had no effect. In a rat liver microsomal system, MTD was found to be a much more potent inhibitor than cefazolin of the vitamin K-dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid. These results suggest that the hypoprothrombinaemia associated with cefazolin may be due to the MTD group.

Criteria for testing the susceptibility of Streptococcus pneumoniae to cefotaxime and its desacetyl metabolite using 1 microgram or 30 micrograms cefotaxime disks.

In vitro susceptibility tests were performed with 350 selected strains of Streptococcus pneumoniae to evaluate disk diffusion tests with 30 micrograms and 1 microgram cefotaxime disks. Zones were compared to MICs of cefotaxime with and without its desacetyl metabolite. Cefotaxime was two to eight times more active than desacetyl cefotaxime, but the two compounds were additive when combined in vitro. For 30 micrograms disks, zone size breakpoints were < or = 27 mm, 28-30 mm and > or = 31 mm for resistant, intermediate and susceptible, respectively. For 1 microgram disks, those zone size criteria were reduced to < or = 13 mm, 14-16 mm and > or = 17 mm. The 30 micrograms disk that is currently available for testing other species can be used for testing pneumococci; however, the 1 microgram disk has some important advantages.

In vitro activities of cefotaxime, ceftriaxone, ceftazidime, cefpirome, and penicillin against Streptococcus pneumoniae isolates.

The in vitro activities of four extended-spectrum cephalosporins and benzyl penicillin were evaluated against 698 clinical isolates of Streptococcus pneumoniae, including 130 (19%) penicillin-intermediate and 84 (12%) penicillin-resistant strains. Cefotaxime and ceftriaxone were essentially identical in their antipneumococcal activities: both were active against penicillin-susceptible strains and most penicillin-intermediate strains. Cefpirome was twice as potent as cefotaxime and ceftriaxone against penicillin-resistant strains. Ceftazidime was 8- to 16-fold less active than cefotaxime and ceftriaxone against S. pneumoniae in vitro, and thus, its spectrum included only penicillin-susceptible strains.

In vitro evaluation of pyridine-2-azo-p-dimethylaniline cephalosporin, a new diagnostic chromogenic reagent, and comparison with nitrocefin, cephacetrile, and other beta-lactam compounds.

Pyridine-2-azo-p-dimethylanaline cephalosporin (PADAC), a chromogenic reagent which is purple and changes to yellow upon cleavage of its beta-lactam ring, was evaluated in comparison with other chromogenic cephalosporins. PADAC exhibited little antimicrobial activity against gram-negative bacteria, but did have good activity (minimum inhibitory concentration, 0.12 to 0.5 microgram/ml) against Staphylococcus aureus, a quality comparable to nitrocefin. Nitrocefin, however, demonstrated an unexpected and uniquely potent activity against Streptococcus faecalis (minimum inhibitory concentration, less than or equal to 0.06 to 0.12 microgram/ml) The relative hydrolysis rate of PADAC when subjected to six different beta-lactamases was substantially greater than that of cephacetrile, but less than that of nitrocefin. The relative hydrolysis rates of PADAC and nitrocefin were comparable with type IIIa beta lactamase and the derived from Bacillus cereus. The inhibition of beta-lactamase hydrolysis of the chromogenic cephalosporin substrates by six enzyme-stable inhibitors was generally greater with PADAC than with nitrocefin. Unlike nitrocefin, PADAC mixed with 50% human serum or various broth culture media showed no evidence of color change or degradation over several hours. The subsequent enzyme hydrolysis rates of such mixtures were the same as in phosphate buffer. Beta-lactamase-containing bacterial suspensions and clinical specimens containing such bacteria produced positive visual and spectrophotometric color changes when mixed with PADAC or nitrocefin. Although color changes occurred more slowly with PADAC than with nitrocefin, PADAC was not adversely influenced (non-enzyme-related color change) by the protein content of specimens. PADAC appears to be a promising alternative for beta-lactamase diagnostic testing in the clinical and research microbiology laboratory.

Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats.

To determine whether the hypoprothrombinemia associated with antibiotics containing a 1-methyl-5-thiotetrazole (MTT) group is a result of the presence of the MTT group, rats were maintained on a vitamin K-deficient diet for 10 days and then received either intravenous moxalactam or cefotaxime or oral MTT for two additional days. MTT and moxalactam, which contains the MTT group, prolonged prothrombin time. Cefotaxime, which lacks the MTT group, had no effect.

Chronic Pseudomonas aeruginosa endobronchitis in rhesus monkeys: I. Effects of pentoxifylline on neutrophil influx.

Host defense abnormalities in cystic fibrosis (CF) against Pseudomonas aeruginosa (PA) lead to excessive neutrophil influx into the infected lungs, resulting in pulmonary complications. We have developed a rhesus monkey model of chronic PA endobronchitis by intrabronchial instillation of PA-embedded agar beads, utilizing flexible fiberoptic bronchoscopy. Treatment of infected monkeys with pentoxifylline suppressed neutrophil influx and ameliorated pulmonary damage. The results suggest a method by which neutrophil influx and pulmonary damage in CF patients can be managed or prevented.

Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline.

Inflammatory cytokines, including interleukin-1 and tumor necrosis factor, are produced by monocytes and macrophages in response to microorganisms and microbial products such as endotoxins. The cytokines stimulate neutrophil adherence, degranulation, and superoxide production but inhibit neutrophil migration. We studied the modulation of cytokine-induced neutrophil activation by pentoxifylline and its principle metabolites. Lipopolysaccharide-stimulated mononuclear-leukocyte-conditioned medium containing inflammatory cytokines, purified human interleukin-1, or recombinant human tumor necrosis factor increased neutrophil adherence to nylon fiber, primed neutrophils for increased superoxide production in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), increased neutrophil lysozyme release stimulated by FMLP, and decreased directed migration of neutrophils to FMLP. Pentoxifylline and its principle metabolites at or near therapeutically achievable levels were able to counteract these effects. Pentoxifylline inhibited the increase in free intracellular calcium in polymorphonuclear leukocytes stimulated by FMLP and increased binding of FMLP to neutrophils at 37 degrees C but not at 4 degrees C. By blocking the inflammatory action of interleukin-1 and tumor necrosis factor on neutrophils, pentoxifylline may diminish the tissue damage caused by neutrophils in such conditions as septic shock, adult respiratory distress syndrome, cardiopulmonary bypass lung damage, and myocardial reperfusion injury.

Chronic Pseudomonas aeruginosa endobronchitis in rhesus monkeys: II. A histopathologic analysis.

We have recently established a rhesus monkey model of chronic Pseudomonas aeruginosa (PA) endobronchitis by bronchoscopic instillation of PA-embedded agar beads. All experimental animals developed chronic neutrophilic endobronchitis similar to chronic PA endobronchitis in cystic fibrosis (CF). Histopathologic studies further confirmed similarities to chronic PA endobronchitis in CF, including marked peribronchial inflammation, epithelial damage, presence of degraded cilia and ciliary abnormalities, appearance of PA bacterial clusters, mucosal hyperplasia, goblet cell hypertrophy/hypersecretion, airway obstruction, alveolar abnormalities, bronchiectasis, and fibrosis.

Effects of pentoxifylline on sputum neutrophil elastase and pulmonary function in patients with cystic fibrosis: preliminary observations.

High concentrations of free human neutrophil elastase in bronchial epithelial fluid are believed to be a major factor in the evolution of pulmonary injury in cystic fibrosis (CF). To test this hypothesis, we studied pentoxifylline, a compound that inhibits tumor necrosis factor alpha transcription and its stimulatory effect on polymorphonuclear neutrophils, in patients with CF who had chronic Pseudomonas bronchitis. Subjects older than 11 years of age randomly received placebo or pentoxifylline (1600 mg/day) orally, in a double-blind fashion, for 6 months. Pulmonary function and sputum elastase concentrations were determined before therapy and bimonthly during therapy; compliance was determined by measuring serum drug concentrations. Of the 16 patients who completed the study, 9 received pentoxifylline. The sputum elastase concentrations among placebo recipients were significantly increased from baseline at 4 and 6 months (F = 3.44; p < 0.05); the values remained unchanged in the treatment group. The mean forced vital capacity for the placebo group decreased from 59.2% +/- 15.4% predicted at baseline to 52.0% +/- 12.9% predicted at 6 months; the values in the treatment group remained largely unchanged. The forced vital capacity improved between baseline and 6 months for four of nine pentoxifylline recipients and none of the seven control patients (p = 0.09). During the study, four of seven placebo recipients experienced a significant pulmonary exacerbation compared with one of nine treated patients (p = 0.077). These findings support the hypothesis that polymorphonuclear neutrophil elastase is a factor in the evolution of CF lung disease; further studies are needed to define the role of pentoxifylline in the treatment of CF.