A double-blind placebo-controlled crossover trial of intravenous magnesium sulfate for foscarnet-induced ionized hypocalcemia and hypomagnesemia in patients with AIDS and cytomegalovirus infection.

Foscarnet (trisodium phosphonoformate hexahydrate) is an antiviral agent used to treat cytomegalovirus disease in immunocompromised patients. One common side effect is acute ionized hypocalcemia and hypomagnesemia following intravenous administration. Foscarnet-induced ionized hypomagnesemia might contribute to ionized hypocalcemia by impairing excretion of preformed parathyroid hormone (PTH) or by producing target organ resistance. Prevention of ionized hypomagnesemia following foscarnet administration could blunt the development of ionized hypocalcemia. To determine whether intravenous magnesium ameliorates the decline in ionized calcium and/or magnesium following foscarnet infusions, MgSO(4) at doses of 1, 2, and 3 g was administered in a double-blind, placebo-controlled, randomized, crossover trial to 12 patients with AIDS and cytomegalovirus disease. Overall, increasing doses of MgSO(4) reduced or eliminated foscarnet-induced acute ionized hypomagnesemia. Supplementation, however, had no discernible effect on foscarnet-induced ionized hypocalcemia despite significant increases in serum PTH levels. No dose-related, clinically significant adverse events were found, suggesting that intravenous supplementation with up to 3 g of MgSO(4) was safe in this chronically ill population. Since parenteral MgSO(4) did not alter foscarnet-induced ionized hypocalcemia or symptoms associated with foscarnet, routine intravenous supplementation for patients with normal serum magnesium levels is not recommended during treatment with foscarnet.

Treatment of mucocutaneous herpes simplex virus infections unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study.

The efficacy and toxicity of foscarnet cream for the treatment of mucocutaneous herpes simplex virus lesions or lesions that were clinically unresponsive to systemic acyclovir treatment (median, 30.5 days) in AIDS patients were studied in a phase I/II, open-label, nonrandomized multicenter trial. In the study, 20 patients with advanced stages of AIDS were treated with foscarnet 1% cream five times a day for a mean duration of 34.5 days. Response of index lesions (n = 20) was judged to be completely healed (8 lesions), excellent (4 lesions), or good (1 lesion) in 65% of lesions. The median time to first negative herpes simplex virus culture of index lesion was 8 days. Among 15 patients with pain at baseline, 11 had complete resolution of pain and 2 had at least a 50% reduction. Clinical adverse events included skin ulceration (4 patients), application site reactions (3 patients), fever (3 patients), and headache (3 patients). Five (25%) patients developed new lesions due to herpes simplex virus at sites other than those being treated topically while enrolled in the study. Topical foscarnet 1% cream appears to be a safe and effective treatment for acyclovir-unresponsive mucocutaneous herpes simplex virus infection in AIDS patients.

Effect of renal disease and hemodialysis on foscarnet pharmacokinetics and dosing recommendations.

BACKGROUND: Foscarnet is an antiviral agent commonly used for managing patients with cytomegalovirus infection. Despite its clinical usefulness, foscarnet is associated with substantial adverse effects including nephrotoxicity. Moreover, foscarnet is primarily eliminated unchanged through the kidneys, thus requiring aggressive dose adjustment during kidney failure. To develop specific dosage guidelines, information on the disposition of this compound in patients with varying degrees of renal function and those requiring dialysis is essential. DESIGN: Twenty-six subjects were enrolled in this study and divided into five groups depending on their degree of renal dysfunction. Group 1 included subjects with normal renal function; group 5 included subjects requiring maintenance hemodialysis. Nondialysis study subjects received a single 60-mg/kg intravenous dose of foscarnet whereas hemodialysis subjects received two intravenous doses, separated by 1 week, to compare the effects of conventional and high-flux dialysis methods. RESULTS: Mean plasma clearance in control subjects averaged 2.1+/-0.7 ml/minute/kg and declined proportionally with changing renal function as indicated by the regression equation: Clp (ml/minute/kg) = 1.48 [CrCl (ml/minute/kg)]-0.08 (r2 = 0.82). Mean half-life averaged 1.9+/-0.1 hours in normal subjects and increased to a mean of 25+/-19 hours in study subjects with severe impairment not on dialysis. Foscarnet dialysis clearance (based on dialysate recovery) averaged 183 ml/minute with conventional dialysis methods and 253 ml/minute during high-flux procedures, which resulted in removal of 37% and 38% of a dose for the two methods, respectively. CONCLUSIONS: These data indicate that substantial dosage adjustments must be made in renal failure patients. Therefore, a patient-specific dosage nomogram has been developed.

Is there a pharmacokinetic interaction between foscarnet and zalcitabine during concomitant administration?

Foscarnet, an antiviral agent used in the treatment of cytomegalovirus infection, and zalcitabine, an antiretroviral nucleoside analogue used in the treatment of human immunodeficiency virus infection, are commonly used concomitantly. Foscarnet and zalcitabine may interact pharmacokinetically, as both compounds are partially eliminated by renal tubular secretion. Owing to dose-related toxicities associated with these two drugs, it is essential that we have data regarding their pharmacokinetic disposition during concomitant therapy. Twelve patients randomly received either foscarnet (four doses) or zalcitabine (five doses) (Phase 1), followed by concomitant foscarnet (four doses) and zalcitabine (six doses) (Phase 2), followed by dosing with the drug not received in Phase 1 (Phase 3). Following the last dose in each phase of the study, serial plasma samples were collected over 8 hours for zalcitabine and over 12 hours for foscarnet to determine the pharmacokinetics of each drug using noncompartmental analysis. Foscarnet plasma and urine levels were determined using high-performance liquid chromatography, and zalcitabine levels were determined using radioimmunoassay. No clinically significant alterations in the pharmacokinetics of foscarnet or zalcitabine occurred in this study. Thus despite the potential for foscarnet and zalcitabine to compete for renal tubular secretion, no apparent pharmacokinetic interaction exists between these two drugs at the clinically relevant doses studied.

Pharmacokinetics and absolute bioavailability of oral foscarnet in human immunodeficiency virus-seropositive patients.

The pharmacokinetics, absolute bioavailability, accumulation, and tolerability over 8 days of an oral formulation of foscarnet (90 mg/kg of body weight once daily [QD] [n = 6], 90 mg/kg twice daily [BID] [n = 6], and 180 mg/kg QD [n = 31) were investigated in 15 asymptomatic, human immunodeficiency virus-seropositive male patients free of active cytomegalovirus infection and with normal upper gastrointestinal function. Peak plasma drug concentrations were (mean +/- standard deviation) 46.4 +/- 10.8 microM (90 mg/kg QD), 45.7 +/- 6.9 microM (90 mg/ kg BID), and 64.9 +/- 31.7 microM (180 mg/kg QD) on day 1 and rose to 86.2 +/- 35.8, 78.7 +/- 35.2, and 86.4 +/- 25.0 microM, respectively, on day 8. The mean peak concentration in plasma following the intravenous administration of foscarnet (90 mg/kg) was 887.3 +/- 102.7 microM (n = 13). The terminal half-life in plasma remained unchanged, averaging 5.5 +/- 2.2 h on day 1 (n = 15) and 6.6 +/- 1.9 h on day 8 (n = 13), whereas it was 5.7 +/- 0.7 h following intravenous dosing. Oral bioavailabilities were 9.1% +/- 2.2% (90 mg/kg QD), 9.5% +/- 1.7% (90 mg/kg BID), and 7.6% +/- 3.7% (180 mg/kg QD); the accumulation ratios on the 8th day of dosing were 2.1 +/- 1.1, 1.8 +/- 0.4, and 1.7 +/- 0.7, respectively. The overall 24-h urinary excretion of oral foscarnet averaged 7.8% +/- 2.6% (day 1) and 13.4% +/- 6.0% (day 8), whereas it was 95.0% +/- 4.9% after intravenous dosing. The glomerular filtration rate and creatinine clearance remained constant, and the mean 24-h renal clearances of foscarnet for the entire study group were 96 +/- 18 ml/min (day 1), 88 +/- 13 ml/min (day 8), and 103 +/- 16 ml/min after intravenous dosing. Adverse effects were largely confined to gastrointestinal disturbances, with all subjects experiencing diarrhea that was dose dependent in its severity. The results suggest that the formulation studied would require significant improvement with respect to tolerability and bioavailability to gain clinical acceptance.

The clomethiazole acute stroke study in ischemic, hemorrhagic, and t-PA treated stroke: Design of a phase III trial in the united states and canada.

Clomethiazole is a drug with sedative properties effective in laboratory studies of brain ischemia. A large European multicenter trial of clomethiazole in acute stroke patients showed no benefit overall, but subgroup analysis indicated that patients with large infarctions may have benefited from treatment. To confirm this preliminary finding, we have designed CLASS-IHT, the Clomethiazole for Acute Stroke Study in Ischemic, Hemorrhagic and TPA Treated Patients, to be conducted in North America. Patients who suffer large cerebral infarctions and present within 12 hours of symptom onset are eligible. Patients will be randomized to receive clomethiazole 68 mg/kg over 24 hours or vehicle, using a dosing scheme based on the pharmacokinetics measured in the first trial. Outcome assessments include stroke scales, the Barthel Index, and lesion volume. An additional study of health economic outcomes is planned. The primary endpoint for CLASS-I will be the Barthel Index 90 days after stroke. A total of 1,200 patients will be randomized to CLASS-I, and in safety-only trials, 200 patients with cerebral hemorrhage will be randomized into CLASS-H and another 100 to 200 patients will be randomized into CLASS-T. The details of the protocols for all three studies are presented.

Effect of foscarnet cream on experimental UV radiation-induced herpes labialis.

A topical 3% foscarnet cream formulation was evaluated for its ability to treat experimental UV radiation (UVR)-induced herpes labialis in a double-blind study. Healthy adult volunteers with a history of sunlight-induced herpes labialis were randomly assigned at four centers to receive either foscarnet cream (n = 152) or a vehicle control (n = 150). Following measurement of the minimal erythematous dose (MED), the subjects' lips were exposed to 4 MEDs of UV light. Subjects applied the cream on the UVR-exposed area approximately eight times daily beginning immediately after UVR exposure and continuing for 7 days, or until all lesions had a minimum of 4 days of treatment. There were no significant differences between groups in the percentages of subjects that developed any lesion, aborted lesions (did not progress beyond a papule), immediate lesions (developed within 48 h of UVR), or delayed classic lesions (developed 48 h to 7 days after UVR). Treatment with foscarnet significantly reduced the mean lesion area (49 versus 81 mm2; P = 0.01), the maximum lesion area (80 versus 141 mm2; P = 0.01), and the time to healing (P = 0.03) of the delayed classic lesions (n = 78). There was also a trend for a decrease in the mean duration of these lesions (156 versus 191 h; P = 0.08) and the duration of pain (3.9 versus 4.3 days; P = 0.06) in foscarnet-treated subjects. There were no clinically significant adverse reactions. These data suggest that topical foscarnet can be efficacious and deserves further evaluation for the treatment of herpes labialis.

Treatment of gastrointestinal cytomegalovirus infection with twice-daily foscarnet: a pilot study of safety, efficacy, and pharmacokinetics in patients with AIDS.

Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 microM following the first dose and 687 microM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose 1 and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose 1 and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients.

Effect of foscarnet on quantities of cytomegalovirus and human immunodeficiency virus in blood of persons with AIDS.

Four intravenous dosages of foscarnet given for 10 days were compared with no therapy in persons with AIDS who had asymptomatic cytomegalovirus (CMV) viremia. CMV viremia was quantitated by endpoint cell dilution microcultures, pp65 antigenemia assay, and measurement of CMV DNA in peripheral blood leukocytes by a quantitative-competitive PCR. Human immunodeficiency virus type 1 (HIV-1) viremia was quantitated by endpoint cell dilution microculture, serum p24 antigen assay, and PCR for HIV-1 RNA in plasma. Twenty-seven subjects who had received a median of 22 months of nucleoside antiretroviral therapy were enrolled. Twenty-two subjects received foscarnet, which was well tolerated and decreased the CMV burden, as reflected by all three indicator assays. During the 10 days of dosing, the level of CMV viremia, as measured by 50 percent tissue culture infective doses, decreased from 117.5 to 12.7 (P = 0.001), the amount of CMV DNA decreased from 20,328 copies to 622 copies per 150,000 leukocytes (P = 0.02), and the level of CMV pp65 antigenemia decreased from 14.9 to 1.6 positive peripheral blood mononuclear cells per 50,000 leukocytes (P = 0.008). A significant pharmacodynamic relationship was found between the peak foscarnet concentration and a decrease in the level of CMV antigenemia (P < 0.05). Foscarnet had no effect on quantitative HIV-1 microcultures during the 10 days of treatment, but the HIV-1 p24 antigen level in serum decreased significantly, from 454 to 305 pg/ml (P = 0.01). Also, a significant pharmacodynamic relationship was seen between plasma HIV-1 RNA concentrations and both peak foscarnet concentration (P < 0.01) and the area under the foscarnet time-concentration curve (P < 0.05). Reductions in the levels of CMV and HIV-1 viremia correlated quantitatively with systemic exposure to foscarnet, whereas control subjects actually experienced an increase in CMV and HIV-1 burdens. The dual antiviral activity of foscarnet shown in this trial encourages investigation of its use in combination with other antiretroviral therapies for persons with AIDS.

Relationship between foscarnet exposure, baseline cytomegalovirus (CMV) blood culture and the time to progression of CMV retinitis in HIV-positive patients.

OBJECTIVE: To determine some of the factors influencing the time to progression of cytomegalovirus (CMV) retinitis among HIV-infected patients being treated with foscarnet. DESIGN: A retrospective analysis of two open-label Phase I/II studies in multiple university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of the patients in the databases examined, 31 had adequate pharmacokinetic information and 29 had information on outcome and the other patient covariates. INTERVENTION: After induction therapy with foscarnet at a dose of 60 mg/kg three times daily was completed, patients had maintenance therapy with 60-120 mg/kg foscarnet once daily. Doses were subsequently adjusted for changed estimated creatinine clearance. MEASUREMENTS: The measured endpoint was time to progression of CMV retinitis. The independent variables examined to determine influence on time to progression included mean peak foscarnet concentration, mean area under the concentration-time curve (AUC) for foscarnet, the positive or negative outcome of a baseline blood culture for CMV, the initial CD4 cell count for a patient and the peak CD4 cell count observed during maintenance therapy. RESULTS: A wide range (-10-fold) of foscarnet AUC was observed, even though only a fourfold dose range was employed, and doses were altered for changing estimated creatinine clearance. In a multivariate Cox model, only AUC and the status of the baseline CMV blood culture significantly affected the time to progression of the retinitis. CONCLUSION: The AUC produced by a dose of foscarnet has a wide interindividual range. The AUC of foscarnet significantly altered time to progression of the retinitis. However, patients with positive baseline CMV blood cultures had a significantly more shallow dose-response curve. This indicates that the added risk of nephrotoxicity which is present with aggressive foscarnet dosing might be best borne by the subgroup of patients with a positive CMV blood culture at baseline.

Foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium in HIV-positive patients.

The time course and magnitude of foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium were investigated in 13 male HIV-positive patients who had no active cytomegalovirus-associated disease. The patients had a mean age of 36 years (range 25-49 years) and a mean CD4 cell count of 550 cells/mm3 (range 130-1280 cells/mm3). Peak (mean +/- SD) plasma concentrations of foscarnet (0.89+/-0.10 mmol/l) were seen at the end of the period of drug infusion (90 mg/kg of foscarnet was infused over 2 hours) and declined with a terminal half-life of 5.7+/-0.7 hours. Plasma concentrations of total calcium declined over an 8-hour period, with the lowest concentration occurring after 4 hours (baseline: 2.29+/-0.09 mmol/l; lowest: 2.18+/-0.07 mmol/l; P < 0.001). By contrast, the lowest plasma concentration of ionized calcium occurred after 2 hours (baseline: 1.25+/-0.04 mmol/l; lowest: 0.99+/-0.05 mmol/l; P < 0.001), before gradually recovering to baseline levels over the next 10 hours. The mean maximal decrease in total calcium was 0.11+/-0.06 mmol/l, compared with 0.26+/-0.04 mmol/l for ionized calcium (P < 0.001). Plasma concentrations of total magnesium declined from 0.79+/-0.06 mmol/l (baseline) to 0.74+/-0.04 mmol/l (P < 0.05) after 4 hours and remained at this level after 8 hours. However, plasma concentrations of ionized magnesium fell steeply from 0.56+/-0.03 mmol/l to 0.39+/-0.03 mmol/l at 2 hours (P < 0.001), followed by a gradual recovery over the next 10 hours. The mean maximal decrease in total magnesium was 0.05+/-0.08 mmol/l, compared with 0.18+/-0.03 mmol/l (P < 0.001) for ionized magnesium. In summary, we found that foscarnet-induced changes in the plasma concentrations of total calcium and magnesium were dissociated from the corresponding changes in ionized calcium and magnesium. The maximal decreases in the plasma concentrations of total calcium and magnesium were smaller in magnitude and occurred much later than did the changes in ionized calcium and magnesium. The relative changes in the plasma concentration of ionized magnesium were greater than those of ionized calcium, indicating that foscarnet binds preferentially to the magnesium ion.

Familial lipoprotein disorders in patients with premature coronary artery disease.

BACKGROUND: Genetic lipoprotein disorders have been associated with premature coronary artery disease (CAD). METHODS AND RESULTS: The prevalence of such disorders was determined in 102 kindreds (n = 603 subjects) in whom the proband had significant CAD documented by angiography before the age of 60 years. Fasting plasma cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) B, and lipoprotein (a) [Lp(a)] values above the 90th percentile and high density lipoprotein (HDL) cholesterol and apo A-I below the 10th percentile of age- and sex-specific norms were defined as abnormal. An abnormality was noted in 73.5% of probands compared with 38.2% in age-matched controls (p less than 0.001), with a low HDL cholesterol level (hypoalphalipoproteinemia) being the most common abnormality (39.2% of cases). In these kindreds, 54% had a defined phenotypic familial lipoprotein or apolipoprotein disorder. The following frequencies were observed: Lp(a) excess, 18.6% (includes 12.7% with no other dyslipidemias); hypertriglyceridemia with hypoalphalipoproteinemia, 14.7%; combined hyperlipidemia, 13.7% (11.7% with and 2.0% without hypoalphalipoproteinemia); hyperapobetalipoproteinemia (elevated apo B only), 5%; hypoalphalipoproteinemia, 4%; hypercholesterolemia (elevated LDL only), 3%; hypertriglyceridemia, 1%; decreased apo A-I only, 1%. Overall, 54% of the probands had a familial dyslipidemia; unclassifiable lipid disorders (spouse also affected) were found in 3%. No identifiable familial dyslipidemia was noted in 43% of kindreds of those; nearly half (45%) had a sporadic lipid disorder. Parent-offspring and proband-spouse correlations for these biochemical variables revealed that lipoprotein and apolipoprotein levels are in part genetically determined, with Lp(a) showing the highest degree of parent-offspring correlation. CONCLUSIONS: Our data indicate that more than half of patients with premature CAD have a familial lipoprotein disorder, with Lp(a) excess, hypertriglyceridemia with hypoalphalipoproteinemia, and combined hyperlipidemia with hypoalphalipoproteinemia being the most common abnormalities.

Comparison of techniques for estimating nutrient intake: the Framingham Study.

We compared estimates of nutrient intake by three diet assessment methods (24-hour recall, 3-day food record, food frequency questionnaire) in a random sample of 73 females and 77 males from the Framingham Offspring/Spouse Study. The results differed according to analytic method. Estimates of group mean intake from the 24-hour recall and 3-day records were similar in both women and men, with differences of less than 10% for most nutrients. The estimates of mean intake calculated from the food frequency questionnaire generally differed from those obtained by the other methods, with higher estimated intakes in women and generally lower estimated intakes in men. Spearman rank correlations between the individuals' nutrient intakes estimated by the three diet assessment methods were modest (r = 0.08-0.68, most below 0.50) and comparable in the comparisons of the 24-hour recall or food frequency questionnaire with the 3-day records. Our data suggest the interchangeability of the recall and record methods and their preference over the food frequency questionnaire for mean estimates of group nutrient intake. The food frequency questionnaire appears to be of some utility in ranking individuals according to the usual intake, although these data are not informative in comparing this method with multiple days of recall or records beyond 3 days. This research underscores the need to develop and evaluate short methods of diet assessment in specific populations of interest.