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PubMed2000

Sodium lauryl sulfate increases the efficacy of a topical formulation of foscarnet against herpes simplex virus type 1 cutaneous lesions in mice.

The influence of sodium lauryl sulfate (SLS) on the efficacies of topical gel formulations of foscarnet against herpes simplex virus type 1 (HSV-1) cutaneous infection has been evaluated in mice. A single application of the gel formulation containing 3% foscarnet given 24 h postinfection exerted only a modest effect on the development of herpetic skin lesions. Of prime interest, the addition of 5% SLS to this gel formulation markedly reduced the mean lesion score. The improved efficacy of the foscarnet formulation containing SLS could be attributed to an increased penetration of the antiviral agent into the epidermis. In vitro, SLS decreased in a concentration-dependent manner the infectivities of herpesviruses for Vero cells. SLS also inhibited the HSV-1 strain F-induced cytopathic effect. Combinations of foscarnet and SLS resulted in subsynergistic to subantagonistic effects, depending on the concentration used. Foscarnet in phosphate-buffered saline decreased in a dose-dependent manner the viability of cultured human skin fibroblasts. This toxic effect was markedly decreased when foscarnet was incorporated into the polymer matrix. The presence of SLS in the gel formulations did not alter the viabilities of these cells. The use of gel formulations containing foscarnet and SLS could represent an attractive approach to the treatment of herpetic mucocutaneous lesions, especially those caused by acyclovir-resistant strains.

Administration, Topical↗
PubMed1986

Topical treatment of recurrent genital herpes simplex virus infections with trisodium phosphonoformate (foscarnet): double blind, placebo controlled, multicentre study.

A double blind, placebo controlled trial was performed in nine sexually transmitted diseases (STD) clinics in the United Kingdom and the Netherlands to investigate the efficacy of trisodium phosphonoformate (foscarnet) cream in treating recurrent genital herpes simplex virus (HSV) infection. The study group comprised 145 male and 85 female patients. Men received 0.3% foscarnet cream and women 1% foscarnet cream for five days. The difference in time to healing between patients receiving foscarnet or placebo was not significant. Fewer patients treated with foscarnet had positive viral cultures after treatment, but the difference was not significant. The development of new lesions, however, was significantly less common in patients given foscarnet. Though topical foscarnet is a safe drug, no appreciable efficacy in treating recurrent genital HSV infection could be shown.

Administration, Topical↗
PubMed1998

Treatment of acyclovir-resistant herpetic ulceration with topical foscarnet and antiviral sensitivity analysis.

BACKGROUND: Herpes simplex virus (HSV) can produce persistent mucocutaneous disease in patients with the acquired immunodeficiency syndrome (AIDS). In this case report, we evaluate the efficacy, safety and viral resistance after topical foscarnet in severe genital ulceration due to acyclovir-resistant HSV-2. CASE REPORT: A 45-year-old African woman was known for an HIV infection with severe immunosuppression (CD4 <100/mm3). She had received a long-term prophylaxis with acyclovir (400 mg b.i.d.) for a recurrent genital herpes. Few weeks after stopping this prophylaxis, she developed large genital ulcerations progressing despite valacyclovir treatment (1,000 mg t.i.d.). Cultures were positive for HSV-2, resistance to acyclovir was shown by the plaque reduction assay and topical foscarnet was tried. Treatment consisted of a 20-min application of topical foscarnet 2.4% twice a day. Dramatic improvement was observed with rapid antalgia, and cicatrization of the genital ulcerations was observed after 50 days. HSV could not be detected on the mucosal surface. Initially, HSV-2 was resistant to acyclovir but sensitive to foscarnet. After 1 month of topical treatment, HSV-2 became sensitive to acyclovir and was still sensitive to foscarnet. Finally, after 6 weeks of treatment, no virus could be detected by culture. CONCLUSION: Topical foscarnet (2.4%) is a convenient treatment for chronic genital herpes. Resistance to acyclovir disappears few weeks after stopping this drug and sensitivity to foscarnet persists during the 50 days of treatment.

Acyclovir↗
PubMed1993

Foscarnet-induced severe hypomagnesemia and other electrolyte disorders.

OBJECTIVE: To report a case of possible foscarnet-induced severe hypomagnesemia and other electrolyte disorders. CASE SUMMARY: An AIDS patient experienced an exacerbation of cytomegalovirus retinitis and was treated with foscarnet. The patient experienced muscle twitches, tremulousness, and anxiety on day 17 of foscarnet therapy. Laboratory results indicated hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia. After electrolyte supplementation and discontinuation of foscarnet, the symptoms resolved and laboratory indices returned to normal. DISCUSSION: Electrolyte disorders associated with foscarnet are reviewed. Severe hypomagnesemia occurred in this patient and published literature is highlighted. In addition, known and/or possible mechanisms of the disorders are discussed. CONCLUSIONS: It is probable that foscarnet contributed to the electrolyte disorders and symptomatology in this patient. Electrolytes must be monitored frequently during foscarnet therapy. Also, concomitant therapy with antianxiety medications that may mask the symptoms of electrolyte disorders should be undertaken with caution.

Adult↗
PubMed1994

Neurologic sequelae associated with foscarnet therapy.

OBJECTIVE: To report three cases of possible foscarnet-induced neurologic sequelae. CASE SUMMARY: We report two cases of seizures and one case of hand cramping and finger paresthesia after starting foscarnet therapy with no evidence of predisposing risk factors, such as serum laboratory abnormalities, renal dysfunction, or known central nervous system (CNS) involvement. All three patients had stable laboratory values during therapy and when the neurologic adverse effects occurred. All patients were receiving appropriate dosages of foscarnet. DISCUSSION: The incidence of seizures in AIDS patients was reviewed. A history of CNS lesions, infections, and/or AIDS per se may increase the risk of a neurologic adverse effect while receiving foscarnet therapy. Acute ionized hypocalcemia may cause these neurologic adverse effects. Ionized hypocalcemia is transitory, is related to the rate of foscarnet infusion, and may not be reflected as a change in total serum calcium concentration. CONCLUSIONS: Foscarnet probably contributed to the neurologic adverse effects reported here. Foscarnet may need to be administered at a slower rate than is recommended by the manufacturer. Electrolytes must be monitored closely; however, a neurologic adverse effect may not be foreseen.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection.

OBJECTIVE: To determine whether foscarnet has potential efficacy in the treatment of acyclovir-resistant mucocutaneous varicella-zoster infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Open-label study. SETTING: Three university medical centers. PATIENTS: Five patients with AIDS who were infected with thymidine-kinase-deficient or -altered strains of varicella-zoster virus. INTERVENTION: Foscarnet, 40 mg/kg body weight every 8 hours in 1-hour infusions for 10 or more days. MAIN RESULTS: Four patients had healing in response to foscarnet therapy, and each of four tested patients became culture negative for virus during foscarnet therapy. Results of fluorescent antigen testing remained positive during therapy in two patients; one of these patients had concomitant clinical failure but the other patient healed fully. One patient had complete healing despite the emergence of resistance to foscarnet in serial specimens obtained during foscarnet therapy. CONCLUSION: Foscarnet is a potentially effective and tolerable antiviral agent for patients with acyclovir-resistant, varicella-zoster virus infection; however, the optimal dosage and duration of therapy require further study, as does the relation between clinical findings and in-vitro susceptibility results.

Acquired Immunodeficiency Syndrome↗
PubMed2001

[In vitro susceptibility to ganciclovir and foscarnet of cytomegaloviruses].

Ganciclovir is the drug of choice for the treatment of acute cytomegalovirus infections. This antiviral agent is a nucleoside analog of guanine whose activity is dependent upon its intracellular phosphorylation to the triphosphate derivative. Foscarnet is used to treat immunosuppressed patients such as organ transplant recipients and AIDS patients with cytomegalovirus who do not tolerate or develop resistance to ganciclovir. Foscarnet is a pyrophosphate analog that directly inhibits viral DNA polymerase. Resistant isolates have been recovered from immunocompromised patients treated with both anticytomegalovirus compounds. The aims of this study were to prepare a plaque reduction assay to study the in vitro susceptibility of cytomegalovirus to ganciclovir and foscarnet, and to apply it to the knowledge of in vitro susceptibility values of cytomegalovirus isolated from clinical samples. Eighty isolates from patients who had never been treated with ganciclovir or foscarnet were tested for antiviral susceptibility. The plaque reduction assay took 6-8 weeks. The results are expressed as ID(50) (inhibitory dose 50), and the ID(50) values of ganciclovir were between 2.14 and 13.49 microM. The ID(50) for ganciclovir was higher that 12 microM in only two cases (2%). The molecular study of the DNA of these did not show any mutation in the UL97 gene. The ID(50) values of foscarnet were between 46.65 and 460.22 microM. In 78 cases (98%) foscarnet ID(50) was lower than 400 microM. These results were comparable with those obtained by other authors. To summarize, the frequency of cytomegalovirus strains resistant in vitro to ganciclovir and foscarnet in previously untreated patients was low and when it was present it did not involve therapeutic failure since the patients progressed favorably.

Antiviral Agents↗
PubMed1986

Foscarnet (phosphonoformate sodium) in the treatment of recurrent male genital herpes.

Foscarnet 0.3% cream was compared with placebo in a randomised double-blind study. The objective was to investigate the therapeutic efficacy and safety in men with recurrent genital herpes simplex virus (HSV) infections. A total of 51 patients were selected, of which 49 (25 treated with foscarnet) were valid for efficacy analysis. Different variables were analysed including the time to healing, alleviation of symptoms, side effects and the results of viral cultures. The median time to healing was 4 days in foscarnet treated patients compared to 5 days in placebo controls. The difference was not statistically significant (p = 0.22). However, foscarnet alleviated the severity of pain and also significantly reduced the median time to abolition pain to 3 days from 6.6 days in placebo treated patients (p = 0.0028). An antiviral effect of foscarnet was evident. The percentage of positive viral cultures found after starting treatment was 15% in the foscarnet-treated group compared to 44% in the placebo-treated group (p = 0.01). Treatment with foscarnet cream was not associated with any significant side effects.

Administration, Topical↗
PubMed1994

Stability of foscarnet sodium in 0.9% sodium chloride injection.

The stability of foscarnet sodium in 0.9% sodium chloride injection was studied. Foscarnet sodium 24 mg/mL was added to polyvinyl chloride i.v. bags containing 0.9% sodium chloride injection to give a theoretical foscarnet sodium concentration of 12 mg/mL. Ten bags of solution were stored at 25 degrees C in normal laboratory light, 10 bags were stored at 25 degrees C in the dark, and 10 bags were stored at 5 degrees C in the dark. Samples were analyzed for foscarnet concentration by high-performance liquid chromatography on days 0, 3, 8, 10, 15, and 30. The solutions were visually inspected for particulates, and pH was measured. Foscarnet sodium was stable in all the solutions for up to 30 days under all the storage conditions; mean foscarnet concentrations did not decline below 99% of initial values. No particulates appeared, and there were no important changes in pH. Foscarnet sodium 12 mg/mL in 0.9% sodium chloride injection was stable for up to 30 days when stored at 25 degrees C and exposed to light, 25 degrees C and protected from light, or 5 degrees C and protected from light.

Chromatography, High Pressure Liquid↗
PubMed1992

Clinical pharmacology: foscarnet.

Foscarnet exerts its antiviral effects via reversible inhibition of viral polymerases. Pharmacodynamic data indicate that herpesvirus and human immunodeficiency virus replication is inhibited by therapeutically achievable concentrations of foscarnet; however, the concentrations of foscarnet required for such inhibition have been found to vary widely. Pharmacokinetic data indicate that foscarnet is eliminated via the renal route, undergoes negligible metabolism, and appears to be distributed widely from the circulation. However, the available data indicate that the pharmacokinetics of the drug varies among patients and within the individual patient, particularly with regard to plasma drug levels; furthermore, such factors as the intracellular kinetics of the drug have yet to be well characterized. It is thus difficult to formulate optimal dosing regimens on the basis of what is known of foscarnet pharmacodynamics and pharmacokinetics. Nevertheless, dosages that produce clear-cut therapeutic benefits without unacceptable toxicity have been identified in clinical trials of foscarnet in acquired immunodeficiency syndrome (AIDS) patients with cytomegalovirus (CMV) retinitis.

Antiviral Agents↗
PubMed1992

Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: preliminary results of a controlled, randomized, regimen-comparative trial.

Herpes simplex virus (HSV) resistant to acyclovir can produce persistent mucocutaneous ulcerative disease in patients with the acquired immunodeficiency syndrome (AIDS). The incidence of clinically significant acyclovir-resistant HSV disease has dramatically increased since the advent of the AIDS epidemic. The primary mechanism of acyclovir resistance is induction of viral mutants defective or deficient in thymidine kinase, the viral-encoded enzyme, which catalyzes the rate-limiting step in the triphosphorylation of acyclovir to its active form (acyclovir triphosphate). Foscarnet, a potent inhibitor of HSV DNA polymerase, does not require phosphorylation for its antiviral activity. This compound has been found to be effective in the treatment of acyclovir-resistant HSV infection by several investigators. A recently completed dose-comparative trial of foscarnet in AIDS patients with acyclovir-resistant HSV has confirmed the safety and efficacy of two doses of foscarnet (40 mg/kg every 8 or 12 hours) in the treatment of this disease, as well as providing preliminary evidence supporting the utility of foscarnet maintenance therapy in delaying recurrence of HSV lesions. Analysis of data from this trial has been complicated by the tremendous variability in lesion size at initiation of therapy, making any statistically valid comparison of treatment regimens almost impossible. A further trial in AIDS patients with acyclovir-resistant HSV infection has been designed to define better the role of foscarnet maintenance and, in light of evidence that a significant proportion of initial recurrences are due to acyclovir-sensitive HSV, to examine the potential utility of acyclovir maintenance following foscarnet induction therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1983

Effects of foscarnet on the cell kinetics of Madin-Darby canine kidney cells.

The antiherpes compound, foscarnet (trisodium phosphonoformate), showed concentration-dependent effects on the cell kinetics of Madin-Darby canine kidney cells. At 1 mM, only minor effects could be seen on cell proliferation and cell cycle distribution, as measured by flow cytometry DNA analysis. Treatment with 5 mM foscarnet resulted in an accumulation of cells in the S-phase although no complete cell cycle block was evident. At 10 mM foscarnet, cells accumulated earlier in the S phase, probably at the G1/S border. However, at both 5 and 10 mM foscarnet the block was not established until after 15 h incubation. Upon removing 10 mM foscarnet after 24 h incubation, G1 cells rapidly entered the S phase, whereas the progression through S and G2 + M was delayed considerably. The DNA synthesizing S phase seems, therefore, to be the main cell cycle phase affected by foscarnet.

Animals↗
PubMed2007

Development and validation of a non-radioactive DNA polymerase assay for studying cytomegalovirus resistance to foscarnet.

Phenotypic characterisation of the human cytomegalovirus (HCMV) pUL54 DNA polymerase is a useful tool for testing for mutations in the UL54 gene thought to render HCMV resistant to foscarnet. In this study, an in-house non-isotopic method for assessing polymerase enzymatic activity in the presence and absence of foscarnet was developed and its utility for HCMV polymerase phenotyping evaluated. Polymerase activity was assessed by monitoring the incorporation of digoxigenin-labelled nucleotides into the growing DNA chain and foscarnet concentrations inhibiting enzymatic activity by 50% were determined. HCMV DNA polymerases were synthesised in vitro by expression of UL54 under the control of the T7 promoter. Mutations of interest were introduced into the wild-type UL54 gene by site-directed mutagenesis. Mutated polymerases and polymerases from HCMV reference strains were studied. The activity of polymerases containing mutations known to confer resistance to foscarnet (V715M, T700A and N495K) was inhibited by concentrations of foscarnet eight to 14 times higher than those required to inhibit wild-type polymerases. Our in-house non-radioactive phenotypic assay was sensitive and reproducible. It is also easy to perform and could provide a convenient method for characterising mutations conferring resistance to foscarnet in HCMV.

Antiviral Agents↗
PubMed2005

[A novel colorimetric test to study the susceptibility of human cytomegalovirus DNA polymerase to foscarnet].

We described a colorimetric method to determine the biochemical phenotype of wild-type and mutated cytomegalovirus (HCMV) DNA polymerases by measuring the incorporation of digoxigenin-labelled nucleotides into the growing DNA chain. Mutations V715M and E756K, which are known to confer foscarnet-resistance, were used as controls. Mutation N495K and a combination of changes K415R and S291P, both observed in foscarnet-resistant isolates, were studied. The mutations were introduced by site-directed mutagenesis into wild-type gene UL54 cloned in an expression vector and then polymerases were synthesised by using a commercially available coupled transcription-translation system. The polymerase activity was measured with and without foscarnet. The activity of polymerases containing the V715M or E756K mutations was inhibited by foscarnet at concentrations 70- and 30-fold higher than that of wild-type polymerase, respectively. Change N495K and combination of K415R and S291P, induced a five- and ten-fold decrease in susceptibility to foscarnet, respectively. The results of this non-radioactive assay were consistent with those obtained with the conventional radioactive assay. Therefore, this novel phenotypic method could be useful for the characterisation of mutations that confer HCMV resistance to foscarnet.

Antiviral Agents↗
PubMed1995

Combined intravenous ganciclovir and foscarnet for children with recurrent cytomegalovirus retinitis.

PURPOSE: Children with the acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis may not complain of symptoms despite the presence of advanced sight-threatening disease. Although little data exist regarding CMV retinitis in this population, the treatment of this disease may be difficult because of frequent, extensive recurrences after reduction of drug dose from induction to maintenance levels. The authors reported the results of the use of combined ganciclovir and foscarnet for treatment of recurrent CMV retinitis in three children with AIDS. METHODS: Three children with recurrent CMV retinitis were treated with combined ganciclovir and foscarnet administered intravenously. All patients initially received induction dosages of ganciclovir followed by maintenance therapy, at which time they experienced reactivation of their disease. The dosing regimen for induction with the combined therapy was foscarnet (60 mg/kg every 8 hours) and ganciclovir (5 mg/kg daily for 3 weeks). Maintenance with combined therapy consisted of foscarnet (90 mg/ kg daily) and ganciclovir (5 mg/kg daily). RESULTS: All patients showed complete healing of the retinitis during the first 3 weeks of combined therapy. Median survival after initiation of combined therapy was 15 weeks (range, 12-33 weeks). None of the children experienced reactivation of CMV retinitis during combined therapy with ganciclovir and foscarnet. Combined therapy was well tolerated in all patients without major side effects. No patient required discontinuation or interruption of either drug during combined therapy. CONCLUSION: Children with recurrent CMV retinitis may not report visual symptoms, which can delay therapeutic intervention. Therefore, recurrent disease in children should be treated aggressively to avoid potentially devastating visual loss. A combination of ganciclovir and foscarnet appears to be a safe and effective therapeutic option for treatment of recurrent CMV retinitis in children with AIDS. This approach causes no additional toxic reactions and may provide improved long-term control of recurrent CMV retinitis in children.

AIDS-Related Opportunistic Infections↗
PubMed2001

Generation of hydroxyl radicals by the antiviral compound phosphonoformic acid (foscarnet).

Phosphonoformic acid (foscarnet) is an antiviral agent that is used to treat severe cytomegalovirus infections in AIDS patients. We demonstrate by using the ferrous iron indicator Ferrozine and ascorbic acid (vitamin C) that foscarnet can chelate ferric iron and form a redox-active iron complex. By using the hydroxyl radical indicator coumarin-3-carboxylic acid we found that the foscarnet-Fe3 complex formed can readily catalyze hydroxyl radical (.OH) generation by the Fenton reaction: (Fe2+ + H2O2-4Fe3+ + .OH + -OH) if hydrogen peroxide and ascorbic acid are present. Hydroxylation of coumarin-3-carboxylic acid could be blocked by addition of known hydroxyl radical scavengers such as mannitol, sucrose, glucose and dimethyl sulfoxide. Moreover, by using a DNA nicking assay, we found that foscarnet catalyzed hydroxyl radicals can induce single strand brakes in DNA. The potency of the hydroxyl radicals formed to induce damage could also be demonstrated in a phosphate-free buffer where the hydroxyl radicals formed attacked and liberated phosphate from the foscarnet molecule. Our results indicate that foscarnet catalyzed hydroxyl radical formation might take place during conditions where a peroxide generating system(s), vitamin C and transitions metals are present.

Antiviral Agents↗
PubMed1999

Irreversible glomerular lesions induced by crystal precipitation in a renal transplant after foscarnet therapy for cytomegalovirus infection.

AIMS: Foscarnet is an antiviral agent used to treat cytomegalovirus infection in AIDS patients and in transplant recipients. In most cases, foscarnet induces reversible tubulo-interstitial lesions which can be avoided by correct hydration. We report the first case of crystal foscarnet precipitation within glomerular capillaries in a renal transplant. METHODS AND RESULTS: The recipient, a 49-year-old man, developed a nephrotic syndrome with haematuria and an acute renal failure after foscarnet therapy for cytomegalovirus (CMV) infection. The polarization examination of the first graft biopsy revealed the presence of birefringent crystals within glomeruli and tubules. Infrared analysis attested to the presence of trisodium foscarnet salts and mixed sodium calcium salts coloured by Von Kossa's reaction. A second biopsy showed glomerular sclerosis, interstitial fibrosis, tubular atrophy and crystal vanishing. Polymerase chain reaction (PCR) in situ applied to this biopsy confirmed the diagnosis of cytomegalovirus infection. CONCLUSIONS: These adverse effects might be the result of a toxic synergy between foscarnet and other drugs. In cases with crystalline precipitation, graft biopsy remains the best mean of diagnosis and follow-up of glomerular damage.

Biopsy↗
PubMed1999

Foscarnet-induced crystalline glomerulonephritis with nephrotic syndrome and acute renal failure after kidney transplantation.

Foscarnet nephrotoxicity has been reported to be associated with acute tubulointerstitial nephritis. Crystals in glomerular capillary lumens have also been observed in patients with acquired immunodeficiency syndrome who were treated with foscarnet for cytomegalovirus disease. We describe a kidney transplant recipient who developed a nephrotic syndrome with microscopic hematuria and nonoliguric acute renal failure within 15 days after starting foscarnet therapy for cytomegalovirus infection. A kidney biopsy specimen showed the presence of crystals in all glomeruli and in proximal tubules. Fourier transform infrared microscopy analysis demonstrated that crystals were made from several forms of foscarnet salts: mixed calcium and sodium salts, and unchanged trisodium foscarnet salts. Renal function and proteinuria spontaneously improved, and a second transplant biopsy performed 8 months after the first one revealed fibrotic organization of half of the glomeruli and of interstitial tissue, and crystal vanishing. We were thus able to provide proof of the possible precipitation of foscarnet in a transplanted kidney.

AIDS-Associated Nephropathy↗