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Biomedical subjects

J G Gambertoglio

Publications and source records attributed to J G Gambertoglio.

At least 37 records · Page 2Linked to original sources
PubMed1996

Zidovudine phosphorylation after short-term and long-term therapy with zidovudine in patients infected with the human immunodeficiency virus.

BACKGROUND: Resistance of human immunodeficiency virus (HIV) to zidovudine (AZT) has been associated with mutations in the viral reverse transcriptase gene. However, recent studies suggest that host cellular factors such as a decreased thymidine kinase activity or an increased cellular P-glycoprotein expression may be important. This study compared concentrations of zidovudine monophosphate, zidovudine diphosphate, and zidovudine triphosphate with P-glycoprotein expression in peripheral blood mononuclear cells from patients receiving long-term (> 18 months) and short-term (< 2 months) zidovudine treatment. METHODS: Ten subjects in the short-term group and 11 subjects in the long-term group with CD4 counts between 300 and 500 received a single oral dose of zidovudine (200 mg) after a 24-hour washout period. Blood samples were collected at 0, 1, 2, 4, and 6 hours. Intracellular nucleotide concentrations were measured by a combined HPLC-radioimmunoassay method, and P-glycoprotein expression was determined by fluorescence activated cell sorting (FACS) analysis with use of the monoclonal mouse antibody MRK-16. RESULTS: Zidovudine monophosphate was the predominant compound, accounting for 73.4% +/- 7.1% (SD) of the total phosphates in the long-term treatment group and 74.2% +/- 15.0% (SD) in the short-term group. Zidovudine diphosphate accounted for 13.3% +/- 3.3% (SD) in the long-term group and 12.5% +/- 6.6% (SD) in the short-term group. Zidovudine triphosphate accounted for 13.4% +/- 4.1% (SD) in the long-term group and 13.5% +/- 8.3% (SD) in the short-term group. Mean peak concentrations for the active zidovudine triphosphate were 0.04 +/- 0.02 (SD) pmol/10(6) cells in both groups. Comparison of the individual zidovudine phosphate concentrations and P-glycoprotein expression revealed no significant difference in the two patient populations. CONCLUSIONS: These data suggest that intracellular phosphorylation does not change over time and that zidovudine does not select for P-glycoprotein expressing cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Protein binding of clindamycin in sera of patients with AIDS.

Patients with AIDS have altered pharmacokinetics of clindamycin compared with those of healthy control subjects. In an attempt to better understand these differences, we undertook a study of protein binding of clindamycin in sera of patients with AIDS. Fifteen patients with AIDS and 15 healthy volunteers were given a single 600-mg dose of clindamycin orally and intravenously, and serum samples were collected at three time points corresponding to high, midpoint, and low clindamycin concentrations. Protein binding was determined by ultrafiltration, and total and unbound clindamycin concentrations were measured with a gas chromatography assay. AIDS patients had alpha 1-acid glycoprotein values approximately twice those of healthy volunteers (mean +/- standard deviation, 103 +/- 27 versus 61 +/- 11 mg/dl; P = 0.001). Overall, serum protein binding levels were higher in AIDS patients (mean +/- standard deviation, 83 +/- 7 versus 78% +/- 8%; P = 0.0001), which is likely the result of increased alpha 1-acid glycoprotein levels in these patients. Total concentrations of clindamycin in plasma were significantly higher in AIDS patients at most time points studied, while unbound serum clindamycin concentrations did not differ among the groups at each sampling time after both oral and intravenous dosing. Increased protein binding may partly explain the altered pharmacokinetic disposition of clindamycin in AIDS patients; however, other factors cannot be excluded.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection.

Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of Pneumocystis carinii pneumonia in HIV-infected patients. To examine the pharmacokinetic interactions among these drugs, eight HIV-infected patients (26 to 43 years old) with a mean CD4 count of 524.4 +/- 405.7 cells per mm3 received zidovudine (200 mg), trimethoprim (200 mg), and dapsone (100 mg) as single agents and in two- and three-drug combinations. Blood and urine samples were collected at a specified time and analyzed for zidovudine, zidovudine-glucuronide, trimethoprim, dapsone, and monoacetyl-dapsone concentrations under single-dose and steady-state conditions. Zidovudine did not influence the pharmacokinetic disposition of dapsone or trimethoprim. Dapsone had no effect on the pharmacokinetic disposition of zidovudine. Trimethoprim significantly decreased the renal clearance of zidovudine by 58% (5.0 +/- 1.8 versus 2.1 +/- 0.5 ml/min/kg of body weight [P < 0.05]). There was a concurrent 54% decrease in the mean urinary recovery of zidovudine (11.7 +/- 3.5 versus 5.4 +/- 3.0 [P < 0.05]), and the metabolic ratio was decreased by 78% (0.32 +/- 0.4 versus 0.07 +/- 0.05 [P < 0.05]). The mean area under the concentration-time curve from 0 to 6 h of the zidovudine-glucuronide/ zidovudine ratio was unchanged. We conclude that zidovudine, trimethoprim, and dapsone can be coadministered to patients with AIDS without significant pharmacokinetic interaction. However, in AIDS patients with liver impairment and impaired glucuronidation, doses of zidovudine may need to be decreased.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Immunopharmacodynamic studies of cyclosporine in patients awaiting renal transplantation.

The immunopharmacodynamics of cyclosporine were investigated in eight hemodialysis patients awaiting renal transplantation. Cyclosporine was administered orally (10 mg/kg) and intravenously (4 mg/kg), with both administrations separated by at least one week. Plasma samples were processed at 37 degrees C and analyzed for specific cyclosporine and its four major metabolites (AM1, AM1c, AM9, and AM4N) using high-performance liquid chromatography. In addition, the in vitro immunosuppressive activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferation stimulated with phytohemagglutinin. The relationships between concentration and effect of cyclosporine versus time were noted. These results suggest that unchanged cyclosporine concentrations in plasma correlate with mitogen-induced lymphocyte suppression yielding significant immunosuppressant activity of cyclosporine. Control studies with plasma from healthy volunteers spiked with cyclosporine in the concentration range of 0-10,000 ng/mL were developed. A sigmoidal Emax model was fitted to the effect versus plasma concentration data. The ratio of effect versus predicted effect were calculated for intravenous cyclosporine dosing. There was a good correlation between the observed and predicted inhibitory effect.

Administration, Oral↗
PubMed1995

Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS-related cytomegalovirus retinitis.

INTRODUCTION: The use of foscarnet and ganciclovir as a combination treatment for cytomegalovirus retinitis is increasing because of limitations associated with single agent therapy. METHODS: The pharmacokinetics of foscarnet and ganciclovir were determined in 13 patients receiving either concomitant therapy (regimen A) or daily alternating therapy (regimen B) for maintenance of cytomegalovirus disease. For regimen A, 60 mg/kg intravenous foscarnet and 3.75 mg/kg ganciclovir were sequentially administered daily; for regimen B, 120 mg/kg foscarnet and 6 mg/kg ganciclovir were administered on alternating days. For both regimens, serial blood sampling for pharmacokinetic analysis was performed for each drug alone (day 1 or 2) and after 2 weeks of combination therapy. Plasma samples for foscarnet and ganciclovir analysis were performed by means of high-performance liquid chromatography. Pharmacokinetic analysis was performed with noncompartmental methods. RESULTS: For regimen A, the plasma clearance (CL) of foscarnet did not change in the presence of ganciclovir, averaging 0.12 +/- 0.08 and 0.11 +/- 0.02 L/hr/kg on study days 2 and 14, respectively (p = 0.34). The volume of distribution (VSS) and mean residence time (MRT) also did not change significantly. CL and MRT of foscarnet did not change for regimen B, although a slight increase in VSS was observed before (0.38 +/- 0.05 L/kg) and after (0.46 +/- 0.07 L/kg) alternating therapy (p = 0.03). Ganciclovir CL did not change for either regimen, with mean values of 0.21 +/- 0.10 and 0.25 +/- 0.10 L/hr/kg (regimen A, p = 0.17) and 0.32 +/- 0.10 and 0.34 +/- 0.11 L/hr/kg (regimen B, p = 0.24). MRT and VSS were also not significantly different. CONCLUSION: These plasma data suggest that further dosage adjustments are unnecessary for or alternating maintenance therapy.

AIDS-Related Opportunistic Infections↗
PubMed1995

Determination of ticarcillin in human plasma and in urine by reversed-phase LC.

A liquid chromatographic assay for ticarcillin (ticar.) in plasma and urine is described. For analysis, the internal standard cefoperazone (cfp) is dissolved in acetonitrile, which is used for precipitating the protein. The supernatant is evaporated, reconstituted in running mobile phase and injected directly onto the reversed-phase C18 column, with detection at 205 nm. The mobile phase is composed of water-acetonitrile-o-phosphoric acid-tetramethylammonium chloride (TMA). Coefficients of variation for reproducibility were in the range of 2.2-15.5% for extra-low, low, medium and high controls. Limits of detection were 0.5 microgram ml-1 for plasma and 1 microgram ml-1 for urine. No interference from other cephalosporins or other antibiotics was noted. This liquid chromatographic assay is simple, accurate, requires no extraction and overcomes previous problems related to the drug's peak splitting due to isomerization.

Calibration↗
PubMed1995

Roxithromycin disposition in patients on continuous ambulatory peritoneal dialysis.

Roxithromycin is a macrolide antibiotic with a spectrum of activity similar to erythromycin. Roxithromycin has been shown to have a favourable pharmacokinetic profile with more reliable absorption and higher, prolonged plasma and tissue concentrations compared with erythromycin. The pharmacokinetics and dialysis clearance of roxithromycin were studied in twelve patients with end-stage renal disease on continuous ambulatory perionteal dialysis. Following a single 300 mg oral dose, multiple blood, dialysate and urine samples were collected over 48 h and assayed for roxithromycin by a microbiological method. Peak plasma concentrations were attained between 0.5 and 5 h, and ranged from 2.3 to 6.8 mg/L. The mean elimination half-life was 20.6 +/- 8.7 h, compared with 10 to 14 h previously reported in healthy volunteers given a single 300 mg dose. Plasma clearance relative to bioavailability (Clp/F) ranged from 37.3 to 118.3 mL/min. The percentage of the dose recovered in the dialysate and net dialysis clearance were low, ranging from 1.0 to 3.1% and 0.9 to 1.8 mL/min, respectively. Only 1% of the dose was recovered in the urine. These results demonstrate that roxithromycin is not substantially removed by continuous ambulatory peritoneal dialysis, and its elimination is prolonged in renal failure, possibly due to impaired nonrenal elimination.

Adult↗
PubMed1994

Paired ion reversed-phase HPLC assay for the determination of iothalamic acid and para aminohippuric acid in urine.

A paired ion reversed-phase high performance liquid chromatographic method for simultaneous determination of iothalamic acid (Io) and para aminohippuric acid (PAH) in urine is described. The method uses a single internal standard for both drugs. The only sample preparation required is dilution of urine (1:100 or 1:500) with deionized water. The internal standard is added to a small aliquot of the diluted specimen and injected. For HPLC, a C8 column and a mobile phase consisting of potassium phosphate buffer with dodecyl triethylammonium phosphate IP reagent, 25% organic modifier with UV detection at 254 nm was used. Within day and between day variation for the assay were in the range of 1.48-9.46% for iothalamic acid and 1.84-10.36% for para aminohippuric acid for four levels of concentration. Limits of quantitation were 50.0 micrograms ml-1 for iothalamic acid and 75.0 micrograms ml-1 for para aminohippuric acid. Mean recovery was 98.55% for Io and 97.79% for PAH. This isocratic HPLC assay is simple, rapid and relatively inexpensive.

Chromatography, High Pressure Liquid↗
PubMed1994

Safety, activity, and pharmacokinetics of GLQ223 in patients with AIDS and AIDS-related complex.

GLQ223 is a highly purified single-chain ribosome-inactivating protein with selective effects against a variety of cells, including macrophages infected with human immunodeficiency virus. We evaluated the safety, pharmacokinetics, and immunologic effects of multiple doses of GLQ223 in 22 patients with AIDS or AIDS-related complex; CD4+ T-cell counts were between 100 and 350/mm3. GLQ223 was administered intravenously at doses of 8, 16, 24, 36, and 50 micrograms/kg of body weight; the drug was administered by constant infusion over 3 h to achieve a concentration in serum of 50 ng/ml; this concentration is known to be associated with anti-HIV effects in vitro. All patients reported a flu-like syndrome characterized by muscle and joint aches and an increase in creatinine kinase levels; symptoms were controlled easily. For patients who received 36 and 50 micrograms/kg, target concentrations in serum were achieved and an increase in CD4+ and CD8+ T cells was sustained; this sustained increase persisted for at least 28 days after the last infusion. beta 2-Microglobulin levels increased during the infusions and then declined when the infusions ended. Repeat infusions of GLQ223 were safe and relatively well tolerated. The target concentration of GLQ223 in serum was achieved and sustained. Our results suggest that GLQ223 may have activity in treating patients with human immunodeficiency virus infection.

AIDS-Related Complex↗
PubMed1993

Pathophysiology and treatment of clinically resistant cytomegalovirus retinitis.

PURPOSE: To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis. METHODS: Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune deficiency syndrome (AIDS). In 11 of these patients, clinically resistant retinitis developed, defined as new activity or progression, despite at least 8 consecutive weeks of induction doses of either foscarnet or ganciclovir. Fundus photography, pharmacokinetics, CMV cultures and sensitivities, and survival analyses were studied. The therapeutic interventions attempted after clinically resistant retinitis was identified included continuing a high dose (induction level) of the same antiviral drug, changing the antiviral drug, and combining antiviral therapy with foscarnet and ganciclovir. RESULTS: Clinically resistant retinitis occurred in 11 (11%) of 100 patients with CMV retinitis and appeared to be a manifestation of acquired CMV antiviral drug resistance. Drug metabolism and pharmacokinetics in these patients were normal. The use of combination therapy with foscarnet and ganciclovir was effective in halting the progression of retinitis in three (75%) of four patients (6 of 7 eyes able to be evaluated) receiving combination therapy. CONCLUSION: Clinically resistant retinitis is a manifestation of infection by CMV that has acquired drug resistance. In these patients, combination antiviral drug treatment should be considered. It is likely that clinically resistant retinitis will become more frequent as patients with CMV retinitis and AIDS survive longer.

AIDS-Related Opportunistic Infections↗
PubMed1992

Phase I-II trial of foscarnet for prevention of cytomegalovirus infection in autologous and allogeneic marrow transplant recipients.

The safety and efficacy of foscarnet for prevention of cytomegalovirus (CMV) infection was evaluated in 19 CMV-seropositive bone marrow transplant (BMT) recipients. All patients received intermittent intravenous (iv) foscarnet: 40 mg/kg every 8 h from 7 days before to day 30 after BMT, then 60 mg/kg once a day until day 75. The main toxicity was transient renal dysfunction, with a greater than 50 mumol/L increase in serum creatinine above baseline in 5 of the 7 autograft recipients and in 6 of the 12 allograft recipients. Only 4 allograft recipients developed CMV infection during foscarnet prophylaxis, and no patient showed evidence of CMV disease. Because 3 allograft recipients receiving concomitant iv amphotericin B showed rapid impairment of renal function, foscarnet prophylaxis should not be given to allograft recipients requiring amphotericin B; otherwise, foscarnet prophylaxis at this dose appears safe after BMT.

Adolescent↗
PubMed1992

Pharmacokinetics of concomitantly administered foscarnet and zidovudine for treatment of human immunodeficiency virus infection (AIDS Clinical Trials Group protocol 053).

Foscarnet and zidovudine (ZDV) pharmacokinetic parameters were not altered in five patients receiving 14 days of concomitant therapy. Foscarnet clearance in plasma averaged (+/- standard deviation) 0.16 +/- 0.03 and 0.13 +/- 0.05 liter/h/kg of body weight in the absence and presence of ZDV. ZDV parameters were also not significantly altered, with a mean (+/- standard deviation) oral clearance of 2.7 +/- 1.0 and 2.6 +/- 0.8 liter/h/kg for the 2 study days, respectively.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Transfer of autologous haemoglobin from the peritoneal cavity during peritoneal dialysis.

Transfer of autologous haemoglobin from the peritoneal cavity was evaluated retrospectively in 14 patients who received this marker intraperitoneally (group 1) during routine continuous ambulatory peritoneal dialysis (CAPD). Five additional patients were studied during acute peritonitis (group 2). A model for balance of both dialysate volume and amount of haemoglobin is developed to assess movement of the compound into lymph or adjacent tissues. Under the conditions of the study the transfer was slow (8 +/- 10 ml/h) in patients without peritonitis (group 1), and significantly faster (25 +/- 22 ml/h) in those with peritonitis (group 2). These clearance values are the upper limits for lymph flow.

Adult↗
PubMed1992

Ex vivo protein binding of clindamycin in sera with normal and elevated alpha 1-acid glycoprotein concentrations.

Clindamycin is a lincosamide antibiotic that binds primarily to alpha 1-acid glycoprotein (AAG), an acute-phase serum protein. Many studies have shown that AAG concentrations increase in response to stress, including infection, myocardial infarction, and trauma. The objectives of this study were to determine the serum protein binding of various clindamycin concentrations in sera with normal and elevated AAG concentrations. Serum was obtained from 4 healthy volunteers and 12 patients with pathophysiologic conditions known to elevate serum AAG concentrations. Timing for collection was determined from the literature, corresponding with the expected peak concentration for each disease state. Samples were assayed for AAG by radial immunodiffusion and were spiked with clindamycin to achieve total concentrations of 10 micrograms/ml (n = 18), 4 micrograms/ml (n = 10), and 2 micrograms/ml (n = 7). Protein binding was determined by ultrafiltration and subsequent high-performance liquid or gas chromatography. Protein binding was dependent on the serum concentrations of both AAG and clindamycin. When AAG concentrations increased from 101-150 mg/dl to 201 mg/dl or greater, mean protein binding increased from 81.2% to 92.4% (p = 0.1265) and from 61.3% to 88.6% (p less than 0.05) at clindamycin concentrations of 2 and 4 micrograms/ml, respectively. With AAG concentrations between 101 and 150 mg/dl, mean protein binding increased from 62.4% at 10 micrograms/ml to 81.2% at 2 micrograms/ml (p = 0.1514). Since AAG concentrations may increase in certain patients, the concentration of free (pharmacologically active) drug may fall below the minimum inhibitory concentration for several pathogens earlier in a dosing interval.

Chromatography, Gas↗
PubMed1991

Successful foscarnet therapy for cytomegalovirus retinitis in an AIDS patient undergoing hemodialysis: rationale for empiric dosing and plasma level monitoring.

Foscarnet is an investigational antiviral agent that has been used effectively in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. However, it has not been readily available to AIDS patients with renal insufficiency because its major side effect is nephrotoxicity. In this report, the efficacy, safety, and dosing requirements of foscarnet in a hemodialysis-dependent patient with CMV retinitis are presented. Foscarnet was administered for 14 weeks, at an initial dosage of 60 mg/kg after each dialysis session. Plasma concentrations were monitored weekly, and the dosage was adjusted to maintain peak plasma levels in the range of 500-800 microM. Although some laboratory abnormalities occurred (a preexisting anemia continued, serum calcium and phosphorus decreased, and ionized calcium increased), they did not limit therapy. Foscarnet is a potentially useful alternative treatment for CMV retinitis in hemodialysis-dependent AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Pharmacokinetics of GLQ223 in rats, monkeys, and patients with AIDS or AIDS-related complex.

The pharmacokinetics of GLQ223 administered as a single short intravenous infusion to rats, monkeys, and patients with AIDS or AIDS-related complex (ARC) are presented. GLQ223 was given at a dose of 3,500 micrograms/kg of body weight to five Sprague-Dawley rats; a dose of 300 micrograms/kg was given to three cynomolgus monkeys; and doses of 1, 8, 16, 24, and 36 micrograms/kg were given to 10 patients with AIDS and 8 patients with ARC in an escalating dose design. Plasma clearance was 0.85 +/- 0.24 liter/h/kg in rats, 0.16 +/- 0.08 liter/h/kg in monkeys, and 0.13 +/- 0.07 liter/h/kg in patients with AIDS or ARC. The volume of distribution at steady state was 0.42 +/- 0.12, 0.21 +/- 0.20, and 0.18 +/- 0.50 liter/kg in rats, monkeys, and patients, respectively. The elimination half-life was 1.3 +/- 0.4, 3.7 +/- 1.5, and 3.2 +/- 1.0 h in rats, monkeys, and patients, respectively. The disposition of GLQ223 was not dose dependent within the dose range tested in patients with AIDS or ARC. Interspecies pharmacokinetic scaling resulted in a good linear correlation for plasma clearance and the volume of distribution at steady state plotted versus species body weight on a log-log scale, indicating the predictability of elimination and distribution of GLQ223 among species. Allometric equations derived may be useful for the prediction of doses and dosage regimens to be used in animal models.

AIDS-Related Complex↗
PubMed1991

Foscarnet-induced hypocalcemia and effects of foscarnet on calcium metabolism.

Foscarnet (trisodium phosphonoformate), an investigational pyrophosphate analog increasingly used to treat refractory cytomegalovirus retinitis and mucocutaneous herpes simplex virus infections in immunocompromised patients, has been reported to cause abnormalities in serum calcium and phosphate, including cases of fatal hypocalcemia. To further elucidate the magnitude and mechanism of these abnormalities in humans treated with foscarnet for opportunistic herpes virus infections, we analyzed anaerobic serum specimens and 24-h urine samples before and after single and multiple doses of iv foscarnet and performed a series of in vitro experiments with normal human serum and plasma. Plasma ionized calcium concentrations acutely decreased by a mean 0.17 mmol/L in the 6 individuals who received a 90 mg/kg dose of foscarnet and by a mean 0.28 mmol/L in the 11 individuals who received a 120 mg/kg dose (P = 0.016, 90 vs. 120 mg/kg dose). Results of in vitro experiments showed a highly significant inverse linear relationship between foscarnet and ionized calcium concentrations, but no correlation between foscarnet and total calcium or phosphate concentration. Dialysis experiments suggested that the complexing of foscarnet with ionized calcium could be a cause of this ionized hypocalcemia. Physicians must be aware of this phenomenon and should measure serum ionized calcium during foscarnet therapy (preferably at the end of a foscarnet infusion) whenever neurological or cardiological abnormalities occur.

Antiviral Agents↗