Liposomal encapsulation of foscarnet protects against hypocalcemia induced by free foscarnet

Abstract

Hypocalcemia and an increase in creatinine level are the most important serious effects associated with foscarnet (PFA) therapy. In an animal model, we have explored the potential protective role of liposomeencapsulated foscarnet (LE-PFA) on these metabolic abnormalities. PFA administered as one bolus injection (0.5 or 1.0 g/kg) caused significant rapid decreases (ϳ20%) in the levels of calcium and phosphorus in serum within a few minutes and up to 30 min after injection. LE-PFA did not induce any of these changes, while peak levels in serum and the half-life of this formulation were much higher than those of the free drug. PFA administered for 2 weeks (340 or 500 mg/kg/day) resulted in no changes in creatinine or blood urea nitrogen levels in serum at the low-dosage level, but at the higher-dosage level, the creatinine level in serum increased by day 5 posttreatment. Furthermore, there was no increase in the creatinine or blood urea nitrogen level after 2 weeks of treatment with LE-PFA at a dosage of 35 mg/kg/day. When the pharmacokinetics of both free PFA and LE-PFA were compared, the plasma half-life of the encapsulated drug was ϳfour times longer than that of the free drug. In addition, the systemic clearance of LE-PFA was ϳone-fifth of that of the free drug. In conclusion, free PFA causes hypocalcemia and hypophosphatemia and increases the creatinine level in serum, whereas the LE form of this drug seems to protect against the abnormal changes in calcium and phosphorus levels caused by the free drug. By preventing hypocalcemia and increasing its half-life, LE-PFA can be used at lower doses and at longer intervals. Clinical investigations of these formulations may be worthwhile.Foscarnet (PFA) is a pyrophosphate analog which prevents the replication of human herpesviruses, including cytomegalovirus (CMV), by inhibiting viral DNA polymerases (23). PFA also inhibits human immunodeficiency virus reverse transcriptase (13,15,32). Combined with zidovudine (AZT), PFA is synergistic against human immunodeficiency virus (10). This drug has been approved for the treatment of CMV retinitis in patients with AIDS (5, 16). CMV infections are frequent in immunosuppressed patients, notably those with chemotherapy-induced suppression, such as transplant recipients and patients with AIDS. In these patients, CMV infection often becomes a fatal disease, whereas in immunocompetent adults, it is usually of minor importance.Both continuous and intermittent intravenous infusions have been investigated as induction therapy, with the latter approach now preferred. Induction therapy starts with an intravenous bolus injection of PFA (20 or 30 mg/kg), followed by a continuous infusion of 230 mg/kg/day for 2 to 4 weeks. Continuous infusion has largely been superseded by the alternative induction regimen of infusion of PFA at 60 mg/kg every 8 h or 90 to 100 mg/kg every 12 h for 2 to 4 weeks (5). Because relapse occurs in approximately 66% of surviving patients within a month of stopping induction therapy, subsequent maintenance treatment...

[Retracted] Multifunctional Therapeutic Approach of Nanomedicines against Inflammation in Cancer and Aging

“…Highly active antiretroviral therapy (HAART) based on nanotechnology also performed an important role in the treatment of psychosis. Polybutyl cyanoacrylate (PBCA), methyl methacrylate-sulfopropyl methacrylate (MMSPM), polylactide (PLA), and PLGA were nanoformulated with zidovudine, delavirdine, saquinavir, and lamivudine to raise BBP 10-20 times [205,206]. In comparison to typical antiretroviral drug (ARV) medication treatment, liposome-loaded zalcitabine has been found to have enhanced efficacy and a longer half-life [207].…”

Reducing Chorioretinal Viral Counts with Intravitreal Foscarnet Injections in a Rabbit Model of Herpes simplex Virus Type-1 Retinitis

“…The main toxicity associated with foscamet treatment is renal impairment mainly manifested by an increase in serum creatinine (4,11). Other toxicities caused by foscamet include reversible calcium and phosphorus abnormalities (11,(13)(14)(15) and anemia (13,16,17). In many cases, treatments have to be stopped to eliminate those side effects which lead to persistence or recurrence of retinitis.…”

“…This nephrotoxicity is believed to be due to acute tubular necrosis or interstitial tubular nephritis which tends to be reversible on foscamet withdrawal. Reversible calcium and phosphorus abnormalities (both increases and decreases were reported) have been observed in foscamet recipients (11,(13)(14)(15). Therapy with this antiviral is also associated with anemia in 20-50% of AIDS patients (13,16,17).…”

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