P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma.

BACKGROUND: The response of adrenocortical carcinoma (ACC) to adjuvant chemotherapy has been disappointing with no significant impact on survival. The normal adrenal cortex has very high levels of P-glycoprotein, an energy-dependent efflux pump of a variety of structurally unrelated chemotherapeutic agents. P-glycoprotein has been implicated as a cause of multidrug resistance in a variety of neoplasms. The purpose of this study was to evaluate P-glycoprotein expression in ACC. METHODS: Eleven patients with ACC had paraffin-embedded tumor evaluated for P-glycoprotein expression. These were analyzed by immunohistochemistry assay with a battery of four anti-P-glycoprotein antibodies (MRK-16, JSB-1, UIC-2, MDR). RESULTS: All eleven cases showed intense, predominantly membrane immunoreactivity for P-glycoprotein. In 10 of the cases, most tumor cells were immunoreactive with at least three antibodies, and six of 11 cases were positive for all four antibodies. In this small series no correlation existed between P-glycoprotein expression and tumor grade, stage of disease, or survival. CONCLUSIONS: All 11 cases of ACC studied showed P-glycoprotein expression, which was similar to the normal adrenal cortex. This possible mechanism of multidrug resistance may help explain the significant chemoresistance seen in ACC.

Granular cell tumor of the biliary tree. A report of two cases and a review of the literature.

Granular cell tumors are relatively uncommon soft tissue tumors usually presenting in the skin and subcutaneous tissues or tongue, although many sites have been described. Two cases arising in the extrahepatic biliary tree are described, and the previously reported cases of this rare presentation are reviewed. These tumors may mimic sclerosing cholangitis and cholangiocarcinoma clinically, and occasionally histologically, in this relatively young group of patients. The histogenesis appears to be related to Schwann cells as in granular cell tumors of other sites, evidenced by histologic, immunohistochemical, and electron microscopic findings. Granular cell tumors, albeit rare, should be considered in the differential diagnosis of biliary tract disease in young patients, particularly black women, and are curable by surgical excision.

Comparison of cefoperazone and mezlocillin with imipenem as empiric therapy in febrile neutropenic cancer patients.

Seventy-eight patients with cancer experienced 88 episodes of fever while neutropenic and were randomly assigned to receive empiric antibiotic therapy with cefoperazone 2 g intravenously every 12 hours and mezlocillin 4 g intravenously every six hours or imipenem/cilastatin 500 mg intravenously over 30 to 60 minutes every six hours. Within 96 hours of starting antibiotic treatment, 24 patients (57 percent) treated with cefoperazone and mezlocillin and 34 patients (74 percent) receiving imipenem/cilastatin became afebrile. One half of the patients in each arm required changes in the antibiotic regimen because of side effects, persistent fever with a site suspicious for infection, resistant organisms, or breakthrough bacteremias. Forty patients (95 percent) receiving cefoperazone and mezlocillin and 43 patients (93 percent) receiving imipenem/cilastatin recovered from the neutropenic episode. Two patients in each regimen group died of their underlying disease. One patient in the imipenem/cilastatin arm died of Pseudomonas aeruginosa sepsis. Although the two regimens are comparable in efficacy, the incidence of side effects favored the cefoperazone and mezlocillin group. No seizures or bleeding were seen in either arm; however, 19 patients (41 percent) receiving imipenem/cilastatin required pretreatment antiemetic drugs for nausea.

Expression of Ia molecules by astrocytes during acute experimental allergic encephalomyelitis in the Lewis rat.

One question in the pathogenesis of experimental allergic encephalomyelitis (EAE) is whether antigen-presenting cells exist in the central nervous system which help induce the development of the disease. Since EAE is a delayed-type hypersensitivity condition, and since T cells require major histocompatibility complex (MHC)-restricted antigen presentation, it is presumed that if antigen presentation occurs in CNS tissue, the presenting cell should express surface Ia molecules. Using immunofluorescent double labeling, the possibility that astrocytes express surface Ia during EAE evolution in the Lewis rat was examined. Very rare Ia-positive astrocytes were found (less than 0.1% of the astrocytes), but only in the spinal cords of clinically ill animals. In addition, endothelial cell Ia positivity was noted prior to the onset of clinical disease. The immunological significance of such low numbers of astrocytes expressing Ia during EAE is uncertain.

Vancomycin therapy of severe staphylococcal infections.

Vancomycin, introduced clinically about 30 years ago, has been used widely over the past decade because of the increasing incidence of methicillin-resistant staphylococci. Its bactericidal action, high and prolonged blood levels, the lack of development of resistant strains, and decreased adverse reactions with the more purified preparation now available, make it an excellent agent for staphylococcal infections due to strains resistant to the beta-lactam antibiotics. Recent articles reviewing the efficacy of vancomycin are summarized.

Vancomycin therapy in severe staphylococcal infections.

Vancomycin was developed in the 1950s, when available therapy for severe staphylococcal infections was unsatisfactory. Early clinical experiences with vancomycin indicated a cure rate of 70%. The introduction of beta-lactamase-resistant penicillins and cephalosporins, which have a lower potential for toxicity, resulted in limited use of vancomycin. The current renewal of interest in vancomycin for treatment of severe staphylococcal infections stems primarily from the efficacy of this drug against methicillin-resistant pathogens and its utility in a number of unique clinical situations. In addition, the development of more purified preparations of vancomycin has lowered the frequency of adverse side effects.

Pharmacokinetics of fosfomycin.

Fosfomycin, an antibiotic discovered in Spain, has a unique chemical structure and pharmacologic features that are promising for clinical therapy. It is only partially absorbed orally, with relatively low blood levels. Intramuscularly, however, absorption is complete with peak blood levels 3-5 times as high as orally, and rapid intravenous injections give serum concentrations almost twice as high as intramuscularly. Some accumulation occurs with all three routes, and concentrations in excess of 1,000 mug/ml are consistently obtained in the urine with parenteral doses every 6 h. The serum half-life is 1.5-2 h, urinary excretion is by glomerular filtration, the antibiotic is not bound to serum proteins, and the volume of distribution is large. Diffusion into tissues and body fluids is good. Thus, the pharmacologic characteristics of fosfomycin along with its low toxicity make it comparable in these respects to other well-established antibiotics.

Clinical pharmacology of amikacin and kanamycin.

During and after a 4-hr intravenous infusion of amikacin and kanamycin in a cross-over study in healthy adult male volunteers, average concentrations of drug in serum were similar, with half-lives of approximately 2 hr. Apparent volumes of distribution at the steady state averaged 30% of body weight, and the rate of renal clearance was less than the rate of creatinine clearance (83 vs. 120 ml/min), a finding that indicates tubular reabsorption. The rate of serum clearance was greater than the rate of renal clearance (100 vs 83 ml/min). Urinary excretion in 24 hr averaged 94% of the dose, and there was no binding of serum proteins. In another cross-over study, volunteers received single intramuscular injections of these antibiotics. Peak concentrations of drug in serum after 45 min to 2 hr averaged 19.9 and 19.0 mug/ml for amikacin and kanamycin, respectively. Serum half-lives between 4 and 8 hr after administration of drug were 2 hr, and an average of 94% of the dose was recovered in the urine in 24 hr. Thus, the pharmacologic properties of amikacin and kanamycin were virtually identical.

Relative inactivation by Staphylococcus aureus of eight cephalosporin antibiotics.

These studies extend the recent observation that cefazolin is inactivated to a greater extent than cephaloridine by some strains of penicillinase-producing Staphylococcus aureus, whereas cephalothin undergoes little if any inactivation. In Mueller-Hinton broth (inoculum, 3 x 10(6)) 100 recently isolated strains had minimal inhibitory concentrations (MICs) 2 mug/ml and 10% (designated "resistant" strains) were >8 mug/ml for cephaloridine but remained

Clinical pharmacology of cefamandole as compared with cephalothin.

We compared the pharmacology of cefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 mug/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 mug/ml for cefamandole and 18.2 mug/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 mug/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average t((1/2)) as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m(2)), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m(2)). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m(2), respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.

Bioassay of metronidazole with either anaerobic or aerobic incubation.

In a bioassay for metronidazole, a modified agar well diffusion technique was used. Two clostridial species were used as the test organisms, and, with minor variations, the method was as effective with aerobic as with anaerobic incubation. Serum and urine levels of 0.25-128 mug/ml were measurable by this method without dilution of the specimens being assayed. The principal acid and alcohol metabolites of metronidazole were found to possess only approximately 5% and 30%, respectively, of the activity of the parent compound.

Unique bactericidal action of metronidazole against Bacteroides fragilis and Clostridium perfringens.

The comparative bactericidal activity of penicillin G, carbenicillin, clindamycin, and metronidazole against eight susceptible strains of Bacteroides fragilis and four strains of Clostridium perfringens was determined by performing colony counts anaerobically of cultures incubated in brucella broth. With the B. fragilis strains, there was a lag phase of growth of approximately 8 h, during which time metronidazole did not reduce the colony counts. However, within 4 h of the onset of exponential growth, metronidazole caused an abrupt decrease in counts to less than 100 colonies per ml in all strains tested. Moreover, in two strains in which the bactericidal rate was followed hourly, a 3- to 6-log decrease occurred over 1 h or less. In contrast, penicillin G and carbenicillin caused a gradual decline in colony counts from the start of approximately 1 log for each 8-h interval and were bactericidal for all strains tested. Clindamycin demonstrated the slowest bactericidal activity and for 25% of the strains was only bacteriostatic. With the C. perfringens strains, after a lag phase of 4 h, an abrupt decrease in colony counts also occurred with metronidazole, whereas penicillin and clindamycin again demonstrated more gradual killing effects. These studies showed a unique, time-related bactericidal action of metronidazole as compared with the other three antimicrobial agents.

Ticarcillin vs carbenicillin: clinical pharmacokinetics.

The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were compared to those of carbenicillin in 12 healthy volunteers. Following an intravenous infusion of 2 gm in 5 min, there was a lower average serum level for ticarcillin (218 mug/ml) than for carbenicillin (301 mug/ml), but after 2 hr the differences were not significant. The biologic half-life of ticarcillin was slightly longer than that of carbenicillin (72 and 65 min, P smaller than 0.01) and its volume of distribution was larger (15.7 and 12.3 l, P smaller than 0.01). Eighty-six per cent of the dose of ticarcillin and 99 percent of the dose of carbenicillin was recovered in the urine in 24 hr. Similar but much less marked blood level differences were noted with 2 gm, 30-min infusions. An intravenous infusion of 1 gm/hr gave average steady-state blood levels of about 124 mug/ml for both antibiotics. Probenecid, administered 1 hr before the infusion, caused significant and similar increases in blood levels, half-lives, and volumes of distribution of the 2 antibiotics. Protein binding in 100 percent human serum was 50 percent and 65 percent for carbenicillin and ticarcillin, respectively. These relatively small but definite differences in the pharmacokinetics of ticarcillin and carbenicillin are not likely to be of clinical significance.

Human pharmacokinetics of BL-P1654 compared with ampicillin.

BL-P1654 is a new ureido-penicillin which has significant activity against both pseudomonas and klebsiella. Its pharmacokinetics were evaluated in five studies in four healthy adult male volunteers after 1-g doses given as: 5- and 30-min intravenous infusions, a 30-min infusion 1 h after the oral administration of 1 g of probenecid, and an intramuscular injection. For comparison, volunteers also received a 30-min infusion of 1 g of ampicillin. Serum levels of the antibiotic were found to fit a two-compartment open model using a Burroughs-5500 computer. After a 30-min infusion, peak serum levels of BL-P1654 (72.8 mug/ml [standard deviation] +/- 5.9) were 50% greater than those of ampicillin (53.6 +/- 8.9). Six hours later, the relative difference was even greater (4.58 +/- 0.25 versus 0.35 +/- 0.09). At 75 min after the 1-g intramuscular injection of BL-P1654, peak serum levels averaged 28.4 +/- 10.3 mug/ml. The half-life of BL-P1654 (2.04 h) was significantly longer than for ampicillin (1.15 h), and the renal clearances of BL-P1654 and ampicillin were 79 versus 244 ml/min per 1.73 m(2), respectively. Probenecid produced no significant change in blood levels, volume of distribution, half-life, or renal clearance, indicating that there is no net tubular secretion of this antibiotic.

Pharmacokinetics of metronidazole as determined by bioassay.

The pharmacokinetics of metronidazole, a drug effective in vitro against most anaerobic bacteria and promising in treating anaerobic infections, are described. Serum and urine levels after single and multiple doses in 10 adult male volunteers were measured by an agar well diffusion bioassay using clostridial species as the test organisms under anaerobic conditions. Peak serum levels averaged 11.5 mug/ml and 6.2 mug/ml after single 500-mg and 250-mg doses, respectively. Renal clearance was only 10.2 ml/min per 1.73 m(2), and less than 20% of the administered dose was recovered in the urine as active drug in 24 h. The average serum half-life was 8.7 h, and there was no protein binding as determined by an ultrafiltration method. With multiple doses of metronidazole (500 mg four times a day and 250 mg three times a day), blood levels increased progressively for the first few doses and then leveled off, with no significant accumulation occurring between 3 and 7 days. On 250 mg three times a day, serum levels just before the 8 a.m. dose (12 h after the preceding dose) on the third day averaged 3.9 mug/ml, and before the 8 p.m. dose, 5.7 mug/ml. For the higher, 500-mg dose (four times a day) regimen, the corresponding minimum serum levels were 13.1 mug/ml at 8 a.m. and 21.3 mug/ml at 8 p.m. Peak levels would have been about 10 mug/ml higher, and since the minimum inhibitory concentrations of most anaerobes including Bacteroides fragilis are less than 6 mug/ml, these concentrations should be highly effective therapeutically, even for severe infections.