Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery.

Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly transduce muscle cells. We tested the impact of preexisting AAV antibodies on microdystrophin expression following vascular delivery to nonhuman primates. Rhesus macaques were treated by isolated limb perfusion using a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of the three immune suppression groups: no immune suppression, prednisone, and triple immune suppression (prednisone, tacrolimus, and mycophenolate mofetil). The animals were analyzed for transgene expression at 3 or 6 months. Microdystrophin expression was visualized in AAV, rhesus serotype 74 sero-negative animals (mean: 48.0 ± 20.8%) that was attenuated in sero-positive animals (19.6 ± 18.7%). Immunosuppression did not affect transgene expression. Importantly, removal of AAV binding antibodies by plasmapheresis in AAV sero-positive animals resulted in high-level transduction (60.8 ± 18.0%), which is comparable with that of AAV sero-negative animals (53.7 ± 7.6%), whereas non-pheresed sero-positive animals demonstrated significantly lower transduction levels (10.1 ± 6.0%). These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV.

Comparison of methotrexate and cisplatin for patients with advanced squamous cell carcinoma of the head and neck region: a Southwest Oncology Group Study.

One hundred eligible patients with inoperable, locally advanced or metastatic squamous cell carcinoma of the head and neck region following prior therapy were randomized to receive im methotrexate (50 patients) or iv cisplatin (50 patients). Methotrexate produced a complete plus partial response rate of 16.0% and cisplatin produced a partial response rate of 8.0%, with median durations of response of 18 and 8 weeks, respectively. The corresponding median survival times were 20 and 18 weeks. Methotrexate responders survived 60 weeks, versus 17 weeks for nonresponders. The corresponding survival times for cisplatin-treated patients were 38 and 18 weeks. Good pretreatment performance status had a significantly positive effect on survival (P = 0.04), but prior therapy did not. Toxicity secondary to either agent occurred with the expected frequency. The two agents examined showed comparable antitumor activity in patients with squamous cell carcinoma of the head and neck who had not previously received chemotherapy.

Use of trimethoprim-sulfamethoxazole for treatment of infections in patients with cancer.

Trimethoprim-sulfamethoxazole (TMP-SMZ) was used alone and in combination with other antimicrobial agents as treatment for infections in patients with cancer. Patients who did not respond to previous treatment with combinations of antibiotics received TMP-SMZ orally or parenterally during a total of 127 episodes of infection. The combined response rate for these two routes of administration was 49%, and the individual rates were similar for both routes. Twenty-eight infections were treated with TMP-SMZ plus tobramycin, and 75% responded after treatment with other drugs had failed. Ticarcillin plus TMP-SMZ was used as initial therapy for presumed or proved infection during 276 episodes of fever. Of 102 documented infections, 77% responded. Toxicity from TMP-SMZ was minimal.

Intravenous trimethoprim-sulfamethoxazole alone or combined with tobramycin for infections in cancer patients.

A total of 120 episodes of infection in 113 cancer patients were treated with intravenous trimethoprim-sulfamethoxazole (TMP-SMX) alone (92 episodes) or with TMP-SMX plus continuous infusion tobramycin (28 episodes). The overall response rates were 47% and 75%, respectively. The majority of episodes had failed to respond to prior antibiotics. Pneumonia was the most common infection, and Klebsiella pneumoniae was the most common pathogen. TMP-SMX plus tobramycin cured 86% of episodes of septicemia and 76% of episodes of pneumonia, whereas TMP-SMX alone cured 20% and 42%, respectively. The initial neutrophil count did not appear critical in determining the outcome of infection. It was the change in the neutrophil count during the infection that appeared important. The outcome of infection was less favorable where abnormal renal and/or hepatic functions were documented. The sensitivity of the organism in vitro to TMP-SMX and/or tobramycin correlated well with the in vivo response. Intravenous TMP-SMX was well tolerated with a 4% incidence of reversible toxicity. A 15% incidence of renal toxicity was attributable to tobramycin. Intravenous TMP-SMX appears to be useful antimicrobial regimen for the therapy of infections caused by susceptible organisms in cancer patients.

Clinical evaluation of peptichemio.

Peptichemio is a peptide complex of m-L-phenylalanine mustard. A clinical evaluation of this agent was conducted in 116 patients, of whom 104 were evaluable for both toxicity and response. The majority of patients had solid tumors. The drug was administered iv daily for 3 days at doses of 20-75 mg/m2/day, with courses repeated at 3-4-week intervals. The optimal dose schedule appears to be 45 mg/m2/day for 3 days. The major side effects were cumulative myelotoxicity, phlebitis, and mild nausea and vomiting. No other major organ toxicity was observed. The partial remission rate was 7%. Most patients had received an alkylating agent as part of their previous therapy. There were seven partial responses and four less than partial responses achieved in patients with melanoma, lymphoma, and gastrointestinal, genitourinary, breast, and head and neck carcinomas. Responses lasted 4-36 weeks.

Clinical pharmacology of intravenously administered trimethoprim-sulfamethoxazole.

Pharmacokinetic studies of intravenously administered trimethoprim-sulfamethoxazole (TMP-SMX) were conducted in 11 patients with cancer while they received therapy with this drug combination for infection. Each patient received 160 mg of TMP and 800 mg of SMX every 8 h. The highest plasma concentrations of both agents were attained at the end of a 1-h infusion period, and the levels were maintained above 38 mug of free SMX and 2 mug of TMP per ml for 2 to 4 h on day 1. On day 4, these concentrations were exceeded at all time intervals of blood sampling. High concentrations of TMP and free SMX were recovered in the urine during the 8-h period. The plasma half-lives of TMP and free SMX, as determined during the first 8-h period, were 7.6 and 8.6 h, respectively. Compared with SMX, TMP had an approximately 2.5 times higher volume of distribution. This drug combination was well tolerated by the patients and unaccompanied by drug-related toxicity.

Escherichia coli bacteremia in patients with malignant diseases.

Of 142 episodes of Escherichia coli bacteremia that were reviewed, appropriate antibiotics were administered during 98 episodes diagnosed premortem and 74 episodes (71%) responded. The highest cure rates were observed when the portals of entry were the urinary tract and soft tissues. Administration of adrenal corticosteroids did not affect the outcome of these patients. The patients' neutrophil counts at the onset and during infection were important factors in predicting survival. Septic shock occurred in 13% of all episodes, and only 11% of these patients responded. Of those patients who died, 63% died within the first 24 hours. Aminoglycosides, cephalosporins, and semisynthetic penicillins used alone or in combination offered optimal coverage.

Phase I study of hycanthone.

Hycanthone was given to 15 patients with metastatic cancer in order to determine the maximum tolerable dose. The drug was administered in 5-day courses at 3-week intervals. The starting dose was 30 mg/m2/day and the highest dose level reached was 90 mg/m2/day. The most common (13 patients) side effect was nausea and/or vomiting. The dose-limiting toxicity was toxic hepatitis manifested as elevation in serum transaminases in eight of 15 patients and an increase in serum bilirubin in three patients. Hepatotoxicity was dose-related and was observed in two of 25 courses given at the dose level of less than or equal to 70 mg/m2 compared to seven of nine courses given at the dose level of greater than or equal to 80 mg/m2. Because of an unacceptable incidence of hepatotoxicity at higher doses, 70 mg/m2/day x 5 appears to be a safe dose for phase II studies.

Sulfamethoxazole-trimethoprim for infections in cancer patients.

A combination of sulfamethoxazole and trimethoprim (Bactrim) was given orally to 35 cancer pattients with infections. Thirty-two patients did not respond to an initial antibiotic regimen that consisted primarily of carbenicillin disodium and an aminoglycoside. There were 18 single-organism, Gram-negative infections. The overall cure rate was 54%. The most common infection was pneumonia (47% responded to treatment). Eighty precent of the cases of septicemia were cured. The most common infecting organism was Klebsiella pneumoniae (45% with this infection responded). Eight cases of infection of unknown origin occurred (63% responded to treatment). Overall, 47% of the patients whose neutrophil count remained unchanged or decreased responded, while 61% of those whose neutrophil count remained unchanged or increased responded. There was no close correlation between the minimum inhibitory concentrations and the clinical responses. Sulfamethoxazole-trimethoprim orally is a well tolerated and effective form of antimicrobial therapy.

Observations in man on some pharmacologic features of cefamandole.

Comparative studies of cefamandole and cephalothin were carried out in 32 cancer patients. After rapid intravenous injection of 1 gm cefamandole or cephalothin, the peak mean serum concentrations in 11 patients achieved at 0.25 hr were 103.4 mcg/ml and 56.7 mcg/ml, respectively. Except at 6 hr, the serum concentration of cefamandole was higher (p less than 0.05) at all times. The terminal half-lives (t 1/2) were similar, being 1.2 hr for cefamandole and 1.0 hr for cephalothin. Cefamandole, 1 gm intramuscularly, induced a peak mean serum concentration of 26.6 mcg/ml at 1 hr, with a slow decay. Intermittent cefamandole (2 gm intravenously every 6 hr) induced very high mean serum concentrations (7 patients), but at 4 hr the concentrations were similar to those after 1 gm intravenously. Per cent of urinary excretion was similar for both drugs regardless of dose and mode of administration. Continuous-infusion cefamandole or cephalothin (2 gm loading followed by 2 gm every 6 hr) in 14 patients showed consistently higher serum concentrations for cefamandole (p less than 0.05) over a 5-day period. There was no evidence of drug accumulation in the multiple-dose studies. Both the single- and multiple-dose schedules were well tolerated.