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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↗
PubMed1989

Comparison of foscarnet and foscarnet esters as anti-influenza virus agents.

Foscarnet is shown to inhibit influenza A virus replication by inhibiting viral RNA synthesis in infected cells. Viral RNA synthesis by isolated nuclei from infected cells was as sensitive to foscarnet as viral RNA synthesis by enzymes from isolated virions or viral cores. It is, therefore, unlikely that the mere association of the polymerase in a replication complex, as in isolated nuclei and infected cells, is the reason for the fact that foscarnet is 10-20 times less active in inhibiting virus replication than cell-free RNA synthesis. We, therefore, tested 44 esters of foscarnet for improved antiviral effect. Of these only a few phenyl esters were more potent than foscarnet itself. These esters did not inhibit the viral RNA polymerase activity and may be hydrolyzed intracellularly to foscarnet. The increased antiviral potency of the phenyl esters was, however, accompanied by increased cellular toxicity, and these compounds, therefore, were less selective antiviral agents than foscarnet. The results suggest that it is not possible to increase the anti-influenza activity of foscarnet by converting it to an ester.

Antiviral Agents↗
PubMed1985

Concentration-dependent effects of foscarnet on the cell cycle.

The mechanism of toxicity of foscarnet was studied by monitoring its effects on the cell cycle of exponentially growing, semisynchronous human embryo cells in culture. The effects of foscarnet on the cell cycle were dependent on the concentration of drug used. At 1 mM, cell division was reduced by 50%, whereas the cell flow was mainly reduced in the G2 phase of the cell cycle, leading to an increase in the proportion of G2+M cells. The minor reduction of thymidine incorporation in S phase cells provided additional evidence that 1 mM foscarnet did not specifically inhibit DNA synthesis. Cell division was greatly reduced at 2.5 mM foscarnet, and the G2 phase was markedly affected, whereas S cell flow was less reduced. S cell flow was 10% per h and thymidine incorporation was 25% that of control cells, while a block in the G2+M phase was evident. On the other hand, at a concentration of 5 mM foscarnet, the cell flow was greatly reduced in the G1 and S phases, with less reduction of G2 cell flow and cells accumulated in the S phase. The effects of foscarnet on the cell cycle were more pronounced with increasing times up to 72 h, which could not be explained by the slow penetration of foscarnet which required only 4 to 8 h to achieve constant levels. At 2.5 and 5 mM foscarnet, there was the additional effect of the cell membranes becoming more leaky as a result of foscarnet toxicity which might contribute to the toxic effects of the drug at high concentrations. When foscarnet was removed from the medium, the effects on the cell cycle were rapidly reversed, in the time needed for foscarnet to diffuse out from the cells, which indicates the reversible nature of the toxic effects of foscarnet.

Antiviral Agents↗
PubMed1989

Foscarnet nephrotoxicity: mechanism, incidence and prevention.

Foscarnet is a pyrophosphate analogue that has been successfully used in severe cytomegalovirus (CMV) infections. Little is known of the incidence and mechanisms of foscarnet-induced nephrotoxicity as most data comes from recipients of renal allografts or from patients with severe underlying disease or with other nephrotoxic drugs. We have retrospectively analyzed the evolution of renal function after 56 courses of foscarnet. In addition, we have prospectively studied the protective effects of hydration on foscarnet nephrotoxicity (2.5 liters of saline/day during the night before the foscarnet therapy and throughout the course of treatment). Foscarnet-induced acute renal failure was defined as a rise in serum creatinine of at least 25% from the basal value. An increase in serum creatinine occurred in 37 cases out of the 56 courses of foscarnet (66%). The mean serum creatinine prior to foscarnet was 80.5 +/- 3.3 mumol/l and the mean increase was 190 +/- 28.3 mumol/l (range 80-1,000). Peak serum creatinine was higher than 200 and 300 mumol/l in 16 and 13 patients, respectively. Kidney obtained at autopsy from a 30-year-old male with AIDS, CMV pneumonitis and acute renal failure secondary to foscarnet administration showed an extensive tubular necrosis. In the group which was prospectively hydrated only 1 patient had an acute renal failure. The mean serum creatinine at the peak (96 +/- 4 mumol/l) and at the end of the treatment (83 +/- 4 mumol/l) was significantly lower (p less than 0.05) than in non hydrated patients. In conclusion, foscarnet is a highly nephrotoxic drug which induces acute tubular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1987

The effect of foscarnet (phosphonoformate) on human immunodeficiency virus isolation, T-cell subsets and lymphocyte function in AIDS patients.

Foscarnet was administered by continuous intravenous infusion in 15 patients with the acquired immunodeficiency syndrome (AIDS) in an open, uncontrolled study. Mean steady state serum concentrations of foscarnet was 261 mumol/l. Treatment was given for 6-21 days, median 14 days, being interrupted prematurely due to renal function impairment in seven patients, and due to other reasons in three patients. Foscarnet therapy was accompanied by improvement of some, probably cytomegalovirus (CMV) related, symptoms but did not otherwise affect the clinical condition of the patients. The occurrence of positive CMV cultures decreased significantly during therapy. Human immunodeficiency virus (HIV) detection by culture was positive in 70-80% of cultures and was unaffected by foscarnet treatment. Eight patients had detectable, free HIV antigen in serum before therapy, and in five of these HIV antigen disappeared during therapy, but reappeared 4-23 weeks after therapy. No patient lost HIV antigen, except during foscarnet therapy. No patient became HIV antigen positive during foscarnet therapy. Immunological parameters did not change during or after foscarnet therapy. Renal function impairment was seen in 9 patients (95% confidence limits, 32-84%), apparently due to reversible tubular damage. At follow-up, serum creatine was normal in all surviving patients. Concomitant medication may have contributed to the renal side-effects. Severe renal function impairment, i.e. serum creatinine above 0.25 mumol/l, was only seen in patients who at the start of foscarnet therapy were chronically affected by their disease. Thus, foscarnet reduces HIV antigen production in AIDS patients. Renal function impairment limits foscarnet use in AIDS patients, but in individuals with less severe manifestations of HIV infection, this side effect may be less frequent.

Acquired Immunodeficiency Syndrome↗
PubMed1991

A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group.

BACKGROUND AND METHODS: Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both foscarnet and vidarabine. We conducted a randomized trial to compare foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to foscarnet and vidarabine. RESULTS: The lesions in all eight patients assigned to foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after foscarnet was discontinued. CONCLUSIONS: For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis.

BACKGROUND AND METHODS: We performed a multicenter, randomized, unblinded clinical trial (the Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial) designed to compare ganciclovir with foscarnet in the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Of 234 patients, 127 were randomly assigned to ganciclovir and 107 to foscarnet; the study drugs were administered according to a common protocol at the 11 participating clinical centers. Antiretroviral therapy (with zidovudine, didanosine, or dideoxycytidine) was given as dictated by best medical judgment. The patients were followed for the progression of retinitis, visual loss, and death. RESULTS: Excess mortality in the ganciclovir group (as compared with the foscarnet group) led the Policy and Data Monitoring Board to recommend suspension of the treatment protocol 19 months after the trial started. As of that time, 65 of the patients assigned to ganciclovir had died, as compared with 36 of those assigned to foscarnet (51 percent vs. 34 percent, P = 0.007; relative risk, 1.79; 95 percent confidence interval, 1.17 to 2.73). The median survival was 8.5 months in the ganciclovir group and 12.6 months in the foscarnet group. Although the patients assigned to ganciclovir received less antiretroviral therapy on average than those assigned to foscarnet, the excess mortality could not be explained entirely by differences in exposure to antiretroviral drugs. In the forscarnet group, the only subgroup of patients identified as having excess mortality were those whose renal function was compromised at entry. There was no difference between the two treatment groups in the rate of progression of retinitis (relative risk, 0.95; P = 0.751). CONCLUSIONS: These results suggest that for patients with AIDS, and cytomegalovirus retinitis, treatment with foscarnet offers a survival advantage over treatment with ganciclovir, although the patients may not tolerate foscarnet as well as ganciclovir.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis.

The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Foscarnet in the treatment of cytomegalovirus infection of the esophagus and colon in patients with the acquired immune deficiency syndrome.

Foscarnet, administered via a central line, was used for the treatment of 18 episodes of cytomegalovirus (CMV) esophageal ulceration in 15 patients, and in the treatment of 27 episodes of CMV colitis in 22 patients. In 15 of the 18 episodes of the esophageal disease, there was complete loss of symptoms within 2 wk. Only three of the 15 patients responding to foscarnet therapy had a relapse of their esophageal disease. Two of these patients were successfully retreated with foscarnet. Of the 22 patients receiving foscarnet for CMV colitis, four died during foscarnet therapy. Of the 18 patients completing the course of treatment with foscarnet for first-episode CMV colitis, 11 remitted completely and six had a partial remission. All patients with partial remission had a second pathogen responsible for the continuation of their diarrhea. Only one patient completing a course of foscarnet failed to respond microscopically to treatment. Three patients experienced relapse of their CMV colitis, two of whom responded to further courses of foscarnet. Foscarnet is an effective therapy for CMV disease of the gastrointestinal tract, with rapid resolution of clinical symptoms, long-term remission of esophageal disease, and shorter disease-free periods for CMV colitis.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Review of the toxicities of foscarnet.

The primary dose-limiting adverse effects associated with foscarnet treatment of cytomegalovirus retinitis in patients with AIDS are renal impairment and ionized hypocalcemia. Dose-limiting renal impairment, consisting of significant alterations in serum creatinine levels or creatinine clearance or acute renal failure, has been observed in 10-20% of AIDS patients receiving foscarnet via intermittent i.v. infusion. Nephrotoxicity can be minimized by adjusting dosage according to creatinine clearance and by ensuring that adequate hydration is provided throughout foscarnet therapy. Transient decreases in serum or plasma ionized calcium levels appear to occur in all patients during foscarnet infusion, with these decreases being observed in the absence of changes in total calcium levels. Hypocalcemia produces mild symptoms in some patients and may play a role in unexplained cases of arrhythmia or seizure. Careful attention should be given to levels of total calcium and other minerals during foscarnet treatment, and the occurrence of symptomatic hypocalcemia should prompt evaluation of ionized calcium concentrations and foscarnet dose reduction. Another potentially treatment-limiting effect attributed to foscarnet is penile ulceration, which appears to result from exposure of the glans penis to unchanged foscarnet in the urine.

Antiviral Agents↗
PubMed1986

Sensitivity of cytomegalovirus to intravenous foscarnet treatment.

Intravenous foscarnet was given on an emergency basis to 30 immunosuppressed patients with cytomegalovirus (CMV) disease, of whom 28 were organ transplant recipients. Thirteen patients responded to foscarnet by cessation of CMV secretion. The in vitro sensitivity to foscarnet of the CMV isolates from non-responders before, during and after foscarnet treatment was similar to that of viral isolates from responders before or during foscarnet treatment and also to CMV isolates from non-treated patients, with mean in vitro IC50 values of 239-294 microM of foscarnet. Thus, there was no evidence of increased resistance of the CMV isolates obtained after foscarnet treatment. A higher total foscarnet dose appeared to favor response.

Antiviral Agents↗
PubMed1992

Design of a randomized controlled trial of foscarnet in patients with cytomegalovirus retinitis associated with acquired immunodeficiency syndrome.

In a controlled trial of foscarnet in the treatment of cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS), patients with non-immediately sight-threatening lesions were randomized to receive immediate treatment with foscarnet or foscarnet treatment delayed until the first signs of retinitis progression. Foscarnet induction therapy was administered at a dosage of 60 mg/kg 3 times/day via 1-hour intravenous infusion for 21 days. Foscarnet maintenance therapy was administered at a dosage of 90 mg/kg/day via 2-hour infusion. Foscarnet was well tolerated and effective in delaying progression of CMV retinitis in these patients. Final analysis of data from this study and data from other studies will help to determine what role foscarnet will have in the treatment of CMV retinitis in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Effect of foscarnet therapy on human immunodeficiency virus p24 antigen levels in AIDS patients with cytomegalovirus retinitis.

Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured in 22 AIDS patients who had detectable serum antigen at baseline after induction and maintenance therapy of foscarnet for cytomegalovirus retinitis in phase I/II multicenter trials. The HIV p24 antigen levels decreased from a baseline value of 199 +/- 236 (mean +/- SD) and 140 pg/mL (median) to 106 +/- 218 and 28 pg/mL after 14 days of foscarnet induction therapy (60 mg/kg every 8 h). During chronic foscarnet maintenance, there was a sustained decrease in mean HIV p24 antigen levels below pre-foscarnet therapy baseline concentrations for a median of 16 weeks after foscarnet induction. These results provide evidence for a sustained clinical antiretroviral effect of chronic foscarnet maintenance therapy, consistent with a recent report that foscarnet-treated AIDS patients live longer than ganciclovir-treated patients.

Acquired Immunodeficiency Syndrome↗
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↗
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↗
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↗
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↗