Clinical impact of in vitro data with newer quinolones.
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Antacids↗
Biomedical subjects
J T Smith
Publications and source records attributed to J T Smith.
The histology of a failed shelf procedure.
Clinical, radiographic and histologic findings are reported in a patient who underwent a hip shelf procedure 24 years previously. While the histologic observations confirm the presence of metaplasia of the surgically formed articular surface to fibrocartilage, there are superadded degenerative changes morphologically similar to those seen in degenerative arthritis.
Adult↗
Gain of antibiotic sensitivity accompanying emergence of clinical ciprofloxacin resistance.
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Aminoglycosides↗
Bactericidal mechanisms of ofloxacin.
Ciprofloxacin and ofloxacin are known to exert a second bactericidal mechanism (termed B) against Escherichia coli which functions even when protein synthesis is inhibited by chloramphenicol or when RNA synthesis is inhibited by rifampicin. However, the bactericidal activity of ciprofloxacin against a coagulase-negative staphylococcus (Staphylococcus warneri) was found to be abolished by chloramphenicol so the 4-quinolone does not exert mechanism B against this species. On the other hand, ofloxacin did exhibit mechanism B against S. warneri because the drug remained bactericidal in the presence of chloramphenicol. When S. aureus was investigated results similar to those observed in S. warneri were obtained throughout the range of clinically achievable concentrations of ofloxacin and ciprofloxacin. Ofloxacin seems to exhibit mechanism B against the staphylococci while ciprofloxacin does not. This may explain why ciprofloxacin is more potent than ofloxacin against Gram-negative bacteria but against staphylococci both drugs are equipotent.
Chloramphenicol↗
Simultaneous fractures of the distal radius and scaphoid.
Simultaneous fractures of the distal radius and scaphoid are uncommon injuries for which the treatment is controversial. Nine patients with these fractures are presented. Five patients were available for long-term followup. In the series, there were five Colles and four Smith's fractures of the distal radius. All scaphoid fractures occurred at the anatomic waist. All injuries resulted from falls of considerable force producing hyperextension at the wrist. The ages of the patients ranged from 21 to 90 years (median, 34). All fractures were placed in a thumb spica cast with the wrist in neutral position. Five fractures required a second reduction of the radius and were placed in external skeletal fixation. No scaphoid fracture was displaced by this treatment, and all scaphoid fractures progressed to union. The principal deformity at followup was an average 16 degrees loss of volar tilt. Residual pain or functional disability was not noted. We conclude that these fractures can be successfully treated by reduction of the radius and immobilization by whatever means necessary to maintain an acceptable position. Scaphoid reduction and healing seemed unaffected by the method of treatment used to treat the distal radius fracture in this series.
Adult↗
Albuterol has no effect on diaphragmatic fatigue in humans.
Diaphragmatic fatigue may play an important role in precipitating acute respiratory failure. Pharmacologically, theophylline and beta-2 agonists have been used to improve diaphragmatic contractility. We designed experiments to study the effects of albuterol, a beta-2 agonist, on diaphragmatic fatigue in humans. In 5 normal subjects, fatigue was induced by breathing through an inspiratory resistance. Studies were done at 2 levels of diaphragmatic tension-time index (TTdi) of 0.25 and 0.30. At each TTdi, either placebo or albuterol (4 mg three times daily) was taken for 3 days. All subjects experienced side effects of sympathetic stimulation. Albuterol did not significantly increase the strength of the fresh diaphragm. With a TTdi of 0.25, values for mean endurance time were 649 +/- 250 (mean +/- SE) and 552 +/- 161 s, respectively, in placebo and albuterol runs. Respective values for TTdi of 0.30 were 109 +/- 14 and 143 +/- 27 s. During recovery, the mean values for the time needed for maximal transdiaphragmatic pressure (Pdimax) to reach 90% of the prefatigue Pdimax were 891 +/- 370 and 1043 +/- 394 s, respectively, for placebo and albuterol runs (TTdi = 0.25). Respective values for TTdi of 0.30 were 219 +/- 57 and 231 +/- 108 s. We conclude that, in humans, albuterol has no significant effect on the strength of the fresh or fatigued diaphragm, diaphragm endurance time, or the recovery of Pdimax from fatigue.
Adult↗
Herpes zoster oticus: treatment with intravenous acyclovir.
Herpes zoster oticus generally has a poor prognosis, leaving many patients with permanent facial nerve dysfunction. This preliminary report describes results in seven patients treated for zoster; all were given intravenous acyclovir. Patients were infused with 10 mg/kg every 8 hours over a 7-day hospitalization period. Five of the seven patients showed some return of facial function at the time of discharge. At follow-up, 4 patients had achieved a House grade I result, 1 patient a grade II, and 2 patients a grade III. Reasons for the differences in final results are discussed, along with a recommended regimen for treatment.
Acyclovir↗
The anemia of sarcoidosis.
Anemia and leukopenia have been reported in sarcoidosis. In order to characterize the prevalence and association with disease activity, 75 patients with active pulmonary sarcoidosis were studied. One or more hematologic abnormalities were identified in 87% of patients studied. Anemia was present in 21 patients (28%), and bone marrow examination in 17 anemic patients revealed noncaseating granulomas in 9 patients and absent iron stores in 8 patients. The bone marrow aspirates did not show characteristics seen in other anemias of chronic disease, such as tuberculosis. In the majority of unexplained anemia cases, hemoglobin levels normalized with prednisone treatment. Forty-one of 75 patients (55%) had lymphopenia. Anemia found in patients with active sarcoidosis was associated with noncaseating granulomas in the bone marrow and an improvement with steroid therapy.
Adult↗
Aspiration after percutaneous gastrostomy. Assessment by Tc-99m labeling of the enteral feed.
Aspiration pneumonia, a recognized complication of enteral feeding via a nasogastric tube, is considered uncommon with percutaneously placed gastrostomy tube feeding. We report aspiration pneumonia during enteral alimentation in a neurologically compromised but conscious patient. Aspiration continued despite changing the route of enteral feeding from nasogastric to percutaneous gastrostomy. Quantitative scintigraphic studies with Tc-99m-labeled enteral infusion demonstrated frequent episodes of gastroesophageal reflux and aspiration of gastric contents, which increased when the infusion rate was speeded up for nutritional replacement. Gastric retention also occurred at the higher infusion rate. Thus, percutaneous gastrostomy may not decrease the frequency of aspiration in patients at risk.
Adult↗
Down-regulation of rat liver beta-adrenergic receptors by cysteine.
Down-regulation of hepatic beta-adrenergic receptors was indicated by a 56% decrease in the specific activity of 125I-iodocyanopindolol bound to rat liver membrane preparations from rats fed diets containing 15% of casein supplemented with cysteine, instead of methionine or unsupplemented. Down-regulation of hepatic beta-adrenergic receptors by cysteine appears to be mediated through an effect of cysteine on the tissue concentration of S-adenosyl methionine (SAM). The liver tissue concentration of SAM in rats fed cysteine-supplemented diets decreased 53% compared to those fed diets supplemented with methionine. The decrease in liver SAM in rats fed the diet supplemented with cysteine appears to reflect a non-competitive inhibition of methionine adenosyl-transferase by cysteine. Lineweaver-Burk plots demonstrated a dose-related Vmax response to cysteine but did not change the apparent Km at any concentration tested.
Animals↗
[Mechanism of action of quinolones].
How do the quinolones inhibit bacteria? The chromosome of bacteria is composed of helical double-stranded DNA and contains 60 to 70 spatial regions of organisation, termed domains of supercoiling. Each domain is about 20 mu long, attached to an RNA core and is organised by supercoiling which occurs quite independently of the DNA coiling in any other domain. Supercoiling is controlled by the enzyme DNA gyrase, which introduces transient breaks into both DNA strands of each domain, removes about 400 turns from its DNA helix, then reseals the DNA so locking in the supercoiling. This supercoiled state is essential to the well-being of bacteria as it enables them to accommodate their chromosome (1300 mu long) within the confines of their cell envelope (2 mu X 1 mu). The target site of action of the quinolone antibacterial agents is DNA gyrase and its inhibition by them sets off a complex series of events which ultimately causes bacteria to die. However, the bactericidal action of nalidixic acid and most other quinolones can be abolished if protein synthesis is inhibited by chloramphenicol, and perhaps not surprisingly the same is true if RNA synthesis is inhibited by rifampicin. With ofloxacin and ciprofloxacin the situation is more complicated because protein or RNA synthesis inhibition does not completely abolish their bactericidal effects. Hence ofloxacin and ciprofloxacin exhibit a qualitative difference from most other quinolone antibacterial agents in that they possess an additional mechanism of killing bacteria that is not possessed by the older, lesser active drugs. How can these quinolones kill bacteria without harming man? Mammalian cells possess an enzyme which resembles bacterial DNA gyrase in that it cuts double-stranded DNA in a similar manner. However, the mammalian enzyme does not possess any supercoiling action nor is it susceptible to inhibition by the quinolone antibacterials, which can hence be used to inhibit bacteria in man without harm to the latter.
Anti-Bacterial Agents↗
[Effect of pH value and magnesium on the antibacterial activity of quinolone preparations].
The activity of ten different 4-quinolone antibacterial agents against Escherichia coli KL16 was investigated at four pH values between 5.6 and 8.3, which is the pH range of urine. It was found that pH affected the minimum inhibitory concentrations of all the drugs, but the nature of the substituent at the C7 position of each 4-quinolone governed how its activity was altered by the hydrogen ion concentration. When a 4-quinolone possessed a piperazine group at its C7 position its activity became progressively less as the pH fell. However, all drugs that lacked a C7 piperazine, irrespective of the nature of their substituent at this position, exhibited a progressive increase in activity as the pH was reduced. In addition it was found that, excepting cinoxacin, a urinary concentration of magnesium generally caused a further antagonism of the activity of the nine other 4-quinolone antibacterials at all pH values tested.
Anti-Bacterial Agents↗
Effect of pyridoxine deficiency on phospholipid methylation in rat liver microsomes.
The effect of altered methionine metabolism during pyridoxine deficiency on the activity of phosphatidylethanolamine methyltransferase (EC 2.1.1.17) and the levels of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) has been evaluated in rat liver microsomes. Animals fed a pyridoxine-deficient diet for 7 wk displayed a fivefold increase in the hepatic tissue level of S-adenosylhomocysteine when compared to either control or pair-fed animal counterparts. When PE methyltransferase was assayed in vitro, a significant increase in specific activity was observed using enzyme preparations from either pair-fed or pyridoxine-deficient rats. On the other hand, phospholipid levels did not conform to the measured enzyme activity. The level of PC in microsomes from either pyridoxine-deficient or pair-fed animal groups was significantly lower than that determined for the control group of rodents. However, the level of PC was noticeably lower in microsomes from pyridoxine-deficient animals than that from pair-fed animals, which received 45% of the feed intake of the control animals. In addition, the level of PE in microsomes from pair-fed and pyridoxine-deficient animals was significantly higher than that analyzed from the control animals, further confirming decreased methylation of substrate to product. It is concluded that pyridoxine deficiency may alter the methylation of phospholipid in the endoplasmic reticulum above and beyond that produced by feed restriction alone.
Adenosine↗
The mode of action of 4-quinolones and possible mechanisms of resistance.
Supercoiling of bacterial DNA, mediated by DNA gyrase, is essential to enable bacteria to accommodate their very long chromosomes within the cell envelope. Bacterial DNA gyrase, unlike the comparable mammalian enzyme, is susceptible to 4-quinolone antimicrobials. All 4-quinolones share this action, but ciprofloxacin, norfloxacin and ofloxacin possess an additional killing mechanism which vastly increases their potency. The occurrence of this second mechanism may also explain the lower frequencies (in populations of Escherichia coli KL 16) of mutants resistant to these three quinolones (less than 10(-12)) compared with other quinolones (10(-10)-10(-8)). No mutant was encountered that was resistant to peak serum concentrations of ciprofloxacin, norfloxacin or ofloxacin, or resistant to attainable urine concentrations of these or of acrosoxacin, flumequine, enoxacin, oxolinic acid or pipemidic acid. Mutational resistance may not necessarily lead to therapeutic resistance to 4-quinolones in E. coli.
Anti-Bacterial Agents↗
Creatine metabolism in the pyridoxine-deficient rat.
Creatine metabolism was studied in rats fed a pyridoxine-deficient diet for 6-7 wk. Indirect evidence had suggested that creatine levels may be low in these animals, since their livers accumulate a competitive inhibitor of creatine biosynthesis (S-adenosylhomocysteine), and they develop muscle signs suggestive of abnormal creatine metabolism. In contrast, however, the concentration of creatine in both liver and skeletal muscle of pyridoxine-deficient rats was higher than in pair-fed control rats. Pair-fed control rats also had higher creatine levels in liver and skeletal muscle than ad libitum-fed control rats, whose feed intake was about double that of the pair-fed control rats. Thus, feed restriction also increased the tissue creatine levels, and this effect was augmented slightly by pyridoxine deficiency. These changes could not be explained by the results of in vitro measurement of the enzymes of creatine biosynthesis. The activity of guanidoacetate methyltransferase in liver did not differ significantly among the three groups of animals. Kidney arginine-glycine transamidinase activity was noticeably lower in the pyridoxine-deficient rats than in pair-fed control rats and lower in pair-fed control rats than in ad libitum-fed control rats. Since creatinine excretion did not differ significantly among the three animal groups, the results suggest that decreased turnover of creatine may occur during pyridoxine deficiency above and beyond that of an apparent feed restriction alone.
Amidinotransferases↗
Frequency and expression of mutational resistance to the 4-quinolone antibacterials.
The frequency with which Escherichia coli mutated to resist a series of ten 4-quinolone antibacterials was studied. It was found that the mutation frequency could not be predicted from the potency of the drugs against sensitive bacteria. The mutation rates were lowest with ofloxacin, norfloxacin and ciprofloxacin. No mutants were observed with ofloxacin while less mutants were observed with norfloxacin than with ciprofloxacin, despite the latter possessing greatest activity against susceptible bacteria. The mutation frequencies observed with nalidixic acid, cinoxacin, pipemidic acid, flumequine, rosoxacin, oxolinic acid, and enoxacin were much higher than those observed with the three 4-quinolones mentioned earlier. When the sensitivities of the mutants to 4-quinolones were investigated, it was again found that the potency of each 4-quinolone against sensitive bacteria did not correlate with the levels of resistance of mutants to that drug. However, when the relative activities of the 4-quinolones against the mutants were investigated, it was found that no mutant isolated resisted a concentration exceeding the peak serum levels of ciprofloxacin, norfloxacin or ofloxacin. Although some mutants exhibited more resistance than the maximum attainable serum levels of the other 4-quinolones, the sensitivity of all the mutants fell well within the urine levels of pipemidic acid, flumequine, rosoxacin, oxolinic acid, enoxacin, norfloxacin, ofloxacin, and ciprofloxacin.
4-Quinolones↗
Effect of S-adenosylhomocysteine on sulfhydryl xenobiotic transmethylases in rat liver.
Rat liver cytosolic thiopurine methyltransferase and microsomal thiol methyltransferase were each found to be subject to control by the absolute molar ratio of S-adenosylmethionine to S-adenosylhomocysteine using cell-free enzyme preparations. As this ratio was lowered, inhibition of both sulfhydryl xenobiotic transmethylases occurred. On the other hand, when the ratio was decreased in vivo by the administration of D,L-homocysteine thiolactone to animals, this alteration was accompanied by an inhibition of only thiopurine methyltransferase activity. Thiol methyltransferase activity was not significantly affected after drug treatment, which would suggest that there is a compartmentalization of S-adenosylhomocysteine in the intact hepatocyte.
Animals↗
Glutathione: an endogenous substrate for thiopurine methyltransferase?
An investigation was initiated to determine if glutathione is an endogenous substrate for thiopurine methyltransferase. Glutathione, as well as S-methylglutathione, were each capable of inhibiting the enzyme in a concentration-dependent manner, which suggested competitive and product inhibition, respectively. However, radiochromatography revealed that S-methylation of glutathione is not a catalytic activity of this sulfhydryl transmethylase. Subsequent experiments indicated that the inhibitory effects of both glutathione and S-methylglutathione on thiopurine methyltransferase may be due to their acidic natures, changing the reaction mixture pH away from the optimal range for the enzyme.
Animals↗