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PubMed1994

High dose intravitreal foscarnet in the treatment of cytomegalovirus retinitis in AIDS.

The efficacy and tolerance of high dose intravitreal foscarnet for cytomegalovirus retinitis in patients with AIDS was studied. Foscarnet in a dose of 2400 micrograms was injected directly into the vitreous of 11 patients (15 eyes). Five patients had active retinitis (eight eyes, 53.3%), and received a 3 week induction therapy of six injections as the first step. Six patients had initial inactive retinitis (seven eyes, 46.7%), and received only maintenance therapy which consisted of a weekly injection. The main indications for intravitreal therapy were: myelosuppression, kidney toxicity, catheter related sepsis, or refusal of intravenous therapy. The patients were followed for a mean period of 16 weeks (range 8-28 weeks) and received a total of 304 injections. Vitreous foscarnet levels were measured by high performance liquid chromatography. After a 3 week course of induction therapy, complete resolution of the active retinitis was seen in 62.5% (5/8 cases), while 37.5% (3/8 cases) had partial resolution. No cases failed to respond or progress. The rate of relapse on maintenance therapy was 33% (five of 15 eyes) by 20 weeks, and two of these eyes did not respond to reinduction and progressed in involvement of the macula or optic nerve. Neither important local complications nor intraocular drug toxicity were observed. Vitreous foscarnet levels in two different patients were 896 mumol/l and 74.9 mumol/l at 22 3/4 hours and 42 1/2 hours after the injection. Intravitreal foscarnet appears to be a safe, effective, and useful alternative in patients with intolerance to intravenous and viral therapy.

AIDS-Related Opportunistic Infections↗
PubMed1997

Minimising the dosage-limiting toxicities of foscarnet induction therapy.

This article suggests ways to manage the dose-limiting adverse reactions caused by foscarnet so that this agent may be used with confidence as first-line therapy in patients with cytomegalovirus (CMV) disease. Foscarnet (trisodium phosphonoformate) has been used for the treatment of CMV disease in patients who are infected with HIV. Some physicians who treat patients with CMV infection are reluctant to use foscarnet because of the serious adverse effects that may occur, especially during the induction period. The most frequently reported serious adverse effects are nephrotoxicity, electrolyte disturbances, nausea, penile ulcerations and seizures. The nephrotoxicity associated with foscarnet is attributable to renal tubular damage, and may be minimised by calculating and infusing the appropriate dose after hydrating the patient. Monitoring serum electrolyte levels and replacing electrolytes before symptoms occur may limit the development of dosage-limiting toxicities. Nausea occurring during foscarnet infusions may be ameliorated by using antiemetics and slowing the infusion rate. Seizures associated with the use of this agent are mostly a result of the simultaneous presence of other CNS pathologies. Penile ulcers are best managed by stopping the infusion until the ulcers heal; they may be prevented by paying careful attention to personal hygiene.

Animals↗
PubMed1994

Safety of alternating ganciclovir and foscarnet maintenance therapy in human immunodeficiency virus (HIV)-related cytomegalovirus infections. An open-labeled pilot study.

In the treatment of cytomegalovirus (CMV) disease in patients with AIDS, a life-long suppression therapy following an induction therapy consisting of ganciclovir or foscarnet is essential. Due to drug-related toxicities, anti-CMV therapy frequently has to be discontinued. To determine whether toxicities and side effects may be reduced with an alternating combination therapy consisting of ganciclovir and foscarnet (ganciclovir: 5 mg/kg every other day; foscarnet: 120 mg/kg every other day), 10 AIDS patients with CMV disease received this maintenance therapy for a median time of 18.5 weeks (5-51 weeks). Side effects were reported from 5 patients (nausea 5, malaise/fatigue 2, penile ulcers 1). Hematological or renal toxicities were mild, 1-week discontinuation of therapy due to neutropenia was necessary in 1 patient. Progression of CMV disease was observed in 3 patients at 2, 6, and 30 weeks of maintenance therapy. Median relapse-free interval for all patients was 105 days. We conclude that combination therapy with ganciclovir and foscarnet can be used safely for induction and maintenance therapy. Therefore, this regimen should be assessed in further trials to evaluate safety, efficacy, and the development of resistance in comparison to ganciclovir or foscarnet monotherapy.

AIDS-Related Opportunistic Infections↗
PubMed1999

Influence of foscarnet on HIV-associated Kaposi's sarcoma derived cell lines.

Recent reports showed a positive therapeutic effect of foscarnet on Kaposi's sarcoma (KS) in HIV-positive patients. We investigated the therapeutic effect of foscarnet on KS-derived cell lines. Three KS spindle cell cultures of HIV-positive patients as well three fibroblast cell cultures of HIV-positive as HIV-negative patients were established. The influence of different foscarnet concentrations (50, 100, 200, 400, 600, 1000 microg/ml) on these cell lines were analysed. There was no significant change in fibroblast cell numbers suggesting that there is neither a proliferative nor an antiproliferative effect of foscarnet on these cell lines. Furthermore, incubation of the three KS-derived cell lines of HIV-positive patients with different foscarnet concentrations did not change KS-cell number significantly.

Antiviral Agents↗
PubMed2001

Intravitreal pharmacokinetics and retinal concentrations of ganciclovir and foscarnet after intravitreal administration in rabbits.

PURPOSE: To perform a detailed pharmacokinetic study and to evaluate the drug levels reached in the retina after the intravitreal administration of ganciclovir and foscarnet to rabbits. METHODS: Retinal and vitreal levels of both drugs were measured by high-performance liquid chromatography at 1, 6, 12, 24, 36, 48, 60, and 72 hours after a single intravitreal injection of 196 microg and 800 microg of ganciclovir and 960 microg of foscarnet to three groups of 24 pigmented rabbits. A noncompartmental pharmacokinetic analysis was used. RESULTS: Both drugs incorporated rapidly into the retina, but no equilibrium was observed between the drug levels in the vitreous humor and retina. Mean ganciclovir levels in vitreous and retina were 179.6 microg/g and 131.3 microg/g (dose of 196 microg), 755.7 microg/g and 381.6 microg/g (dose of 800 microg) at 1 hour after administration, decreasing to 0.1 microg/g, 0.6 microg/g, 0.8 microg/g, and 0.7 microg/g, respectively, by 72 hours. Mean foscarnet levels in vitreous and retina were 944 microg/g and 217.1 microg/g at 1 hour after administration, decreasing to 74 microg/g and 17.1 microg/g, respectively, by 72 hours. Whereas both doses of ganciclovir yielded retinal levels above the mean inhibitory concentration (IC50) of most human cytomegalovirus (CMV) isolates for more than 60 hours, foscarnet retinal levels were lower than the CMV IC50 before 36 hours had elapsed after administration. CONCLUSIONS: The results suggest that the intravitreal administration of ganciclovir has a better pharmacokinetic profile than foscarnet for the treatment of retinitis caused by CMV and other herpes viruses and support the administration of intravitreal ganciclovir twice a week as a treatment for CMV retinitis.

Animals↗
PubMed1996

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.

Adult↗
PubMed1992

Treatment of HIV-related cytomegalovirus disease of the gastrointestinal tract with foscarnet.

Gastrointestinal cytomegalovirus (CMV) disease occurs in a significant proportion of patients with AIDS. A series of 66 AIDS patients with first-episode gastrointestinal CMV disease diagnosed on the basis of clinical and histopathologic findings were treated with foscarnet as first-line therapy at our institution between January 1987 and January 1991. Primary sites of infection were the colon (28 patients) and the esophagus (22 patients). Foscarnet was administered as a continuous infusion of 200 mg/kg (prior to 1988) or as an intermittent infusion of 60 mg/kg t.i.d. or 90 mg/kg b.i.d., with saline hyperhydration accompanying each infusion. Patients were treated initially for 2 weeks, with an additional 1-2 weeks of treatment being given in those not having a complete response during initial treatment; maintenance therapy was given only in cases of concurrent CMV retinitis. Complete response to foscarnet therapy (resolution of symptoms and endoscopic findings) was observed in 17 esophagitis patients (77%) within 3 weeks, with only 4 patients relapsing (at 1-7 months) and none developing colitis or retinitis. Complete response was observed in 16 colitis patients (57%) within 3 weeks, with relapse occurring in 5. Asymptomatic hypocalcemia occurred in 19.7% of patients and penile ulceration occurred in 6.1%; increases in serum creatinine were observed in five patients (7.6%), but did not require discontinuation of treatment. These findings indicate that foscarnet is an effective first-line treatment for gastrointestinal CMV infection. They also suggest that maintenance therapy with foscarnet may not be required in all patients.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Foscarnet salvage therapy for patients with late-stage HIV disease and multiple drug resistance.

OBJECTIVE: To evaluate the efficacy of foscarnet on HIV infection in patients with late-stage HIV disease and multiple drug resistance. METHODS: Three drugs experienced patients with plasma viral load (pVL) > 50,000 copies/ml and CD4+ T-cell counts < 100/mm3 were eligible for this open-label, single-arm, add-on pilot study. Foscarnet induction therapy consisted of 5 g intravenously twice daily for 6 weeks, in addition to a stable antiretroviral regimen. Patients with at least 1 log10 decrease in pVL at week 6 (W6), were given foscarnet 5 g intravenously twice daily on two consecutive days each week. Primary endpoint was the virological response rate at W6. RESULTS: Eleven patients were enrolled with a median baseline pVL at 5.16 log10 copies/ml, median CD4+ T-cell count at 10/mm3 and median number of mutations of 9, 2 and 12 associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs and protease inhibitors, respectively. One patient discontinued foscarnet at W2 because of renal toxicity. In an intent-to-treat analysis, the median change in pVL from baseline was -1.99 log10 copies/ml at W2 and -1.79 log10 copies/ml at W6. Eight out of eleven patients had a fall in pVL of at least 1 log10 at W6, and six started maintenance therapy. The median fall in pVL after 12 weeks of maintenance therapy was -0.85 log10 copies/ml in the four patients who reached W12, and the median increase of CD4+ T-cell count was 60/mm3. CONCLUSION: In patients with HIV mutations conferring resistance to all antiretroviral drug classes, foscarnet markedly reduced plasma HIV load and improved immunological status.

Adult↗
PubMed1988

Efficacy and safety of foscarnet for recurrent orolabial herpes: a multicentre randomized double-blind study.

Foscarnet sodium (trisodium phosphonoformate hexahydrate) has been shown to inhibit herpes simplex virus (HSV) in vitro and to be efficacious for topical treatment of experimental HSV infection in animals. To assess its clinical efficacy in the treatment of recurrent orolabial herpes a multicentre collaborative, double-blind, placebo-controlled trial was conducted. The study patients were randomly assigned to receive either 3% foscarnet cream (78 patients) or placebo (cream vehicle) (75 patients) and were asked to start treatment at the earliest indication of a recurrence. Efficacy was evaluated in 143 patients (74 in the foscarnet group and 69 in the placebo group). There was no significant difference in time to healing or duration of virus shedding between the two groups. However, in the subgroup of patients who started treatment before vesicles appeared, the duration of virus shedding was shorter in the foscarnet group than in the placebo group (p = 0.04), and the proportion of lesions that evolved to the vesicular stage was smaller (p = 0.03). No significant difference in the incidence of local or systemic adverse effects was noted between the two groups. We conclude that the beneficial effect of foscarnet was limited to a subgroup of patients who started treatment in the prevesicular stage.

Administration, Topical↗
PubMed1994

CMV prophylaxis with foscarnet in allogeneic bone marrow transplant recipients at high risk of developing CMV infections.

Eleven patients underwent bone marrow transplant (BMT) from an HLA-identical sibling following single dose total body irradiation (TBI), with in vivo and ex vivo T cell depletion (TCD). In spite of CMV prophylaxis with acyclovir and high-dose i.v. Ig, 10 of 11 patients developed CMV antigenemia, at a median interval from BMT of 34 days (range 16-72 days) and five died with CMV disease. Foscarnet was then given prophylactically in 11 additional TCD patients to test whether we could (1) prevent CMV reactivation, and (2) reduce transplant-related mortality. Foscarnet was given daily from days +10 to +15 (180 mg/kg/day), then thrice weekly (90 mg/kg/day) until day +100. Five patients developed CMV antigenemia at a median interval from BMT of 42 days (range 16-65 days); one progressed to CMV pneumonitis and died. The risk of developing CMV antigenemia within day 100 is currently 91% for the historical control group and 45% for the foscarnet group (p = 0.005). At diagnosis of CMV, the median number of CMV antigen-positive cells was 6.5 (range 1-13) vs 1 (range 1-5) in acyclovir vs foscarnet patients (p = 0.02) and the median highest number of CMV antigen-positive cells was 7 (range 3-110) vs 1 (range 1-12), respectively, (p = 0.03). The actuarial 1 year transplant-related mortality (TRM) is 49% and 13% in the two groups (p = 0.08). This study suggests that foscarnet prophylaxis starting on day +10 post-BMT may be helpful in reducing the risk of CMV disease and early mortality following TCD BMT.

Acyclovir↗
PubMed1994

In vitro anti-human cytomegalovirus activity of liposome-encapsulated foscarnet.

Foscarnet is a pyrophosphate analogue that possesses substantial activity against human cytomegalovirus (HCMV) in patients with CMV retinitis. In this in vitro study we tested whether liposome encapsulation of foscarnet would provide the drug with anti-HCMV activity comparable with that of nonencapsulated foscarnet. The drug was entrapped in large unilamellar vesicles of homogeneous size at a concentration of 10 mg/ml. The vesicles were prepared by the method of fast and controlled dialysis of mixed detergent-lipid micelles using N-Octyl--D-glucopyranoside as the detergent. The activity of drugs against two laboratory HCMV strains (AD169 and Towne) was tested in a plaque-reduction assay using monolayers of human foreskin fibroblasts. The dose of encapsulated or nonencapsulated foscarnet required for a 50% reduction in the number of plaques (IC50) for the AD169 strain was 106 and 113 mumol/l, respectively. For the HCMV Towne strain the dose was 112 and 109 mumol/l, respectively. Treatment with concentrations of up to 400 mumol/l (maximal concentration tested) demonstrated that foscarnet is released at efficient doses from liposomes and that it is not toxic in the range of concentrations tested.

Cells, Cultured↗
PubMed1993

Foscarnet treatment of cytomegalovirus gastrointestinal infections in acquired immunodeficiency syndrome patients who have failed ganciclovir induction.

This compassionate-use study examined the efficacy of foscarnet in patients with AIDS and cytomegalovirus (CMV) gastrointestinal disease who had failed ganciclovir induction. Nineteen male homosexuals with AIDS and biopsy-proven CMV gastrointestinal disease who had twice failed standard ganciclovir induction (defined as progression of clinical CMV disease) were studied. Foscarnet 60 mg/kg every 8 h was administered intravenously for 14 days, then maintenance was utilized at 90 or 120 mg/kg every day with 1 L normal saline daily. Endpoints included endoscopic appearance, blinded histopathologic analysis of biopsies for CMV inclusions, and changes in symptoms by 50% from baseline. Patients were evaluated before and 2-3 wk after foscarnet. Histopathologic improvement was seen in 67%, whereas 74% improved clinically after a median duration of 7.5 days (1-12). Among the nine with esophageal disease, six patients (68%) had a clinical response and six of eight (75%) had a pathologic response. Among the 10 with colonic disease, eight patients (80%) had a clinical response and six (60%) had a pathologic response. Reversible elevations in creatinine were seen in two of 17 (12%). Three patients with esophageal disease developed strictures late in therapy requiring dilation. Median survival after foscarnet induction was 5.0 months. Foscarnet appears to induce remission of CMV gastrointestinal disease in 67% of patients when ganciclovir induction has failed. Reversible nephrotoxicity occurred in 12%. Strictures may be a late complication of CMV esophagitis.

AIDS-Related Opportunistic Infections↗
PubMed1995

Double resistance to ganciclovir and foscarnet of four human cytomegalovirus strains recovered from AIDS patients.

Four human cytomegalovirus (HCMV) isolates from four different AIDS patients treated with both ganciclovir and foscarnet and not responding clinically to antiviral treatment, were studied in order to verify the occurrence of double resistance to both drugs, and to define whether single or multiple HCMV strains could be responsible for the double resistance. Peripheral blood leukocytes (PBL), the relevant conventional viral isolates, and plaque-purified strains from all four patients were examined by antiviral drug susceptibility testing by an immediate-early antigen plaque reduction assay and by restriction fragment length polymorphism (RFLP) analysis using polymerase chain reaction (PCR)-amplified multiple genome regions and endonucleases. All four HCMV strains had a high level of resistance to both ganciclovir and foscarnet. A single HCMV strain was shown to be responsible for the dual resistance in each patient. HCMV strain identity and uniqueness were shown for each of the four patients in blood samples, viral isolates, and plaque-purified strains. In addition, in two patients the same single HCMV strain shifted progressively from drug sensitivity to ganciclovir and then to ganciclovir-foscarnet resistance. These findings document that resistance to both ganciclovir and foscarnet of HCMV strains recovered from blood of AIDS patients represents an emerging problem. Although it is known that multiple HCMV strains may cocirculate in the blood of AIDS patients, single strains appear to be responsible for the dual resistance. Molecular mechanisms responsible for the double resistance of the four reported strains are under study.

AIDS-Related Opportunistic Infections↗
PubMed2002

Herpes simplex virus isolates with reduced adefovir susceptibility selected in vivo by foscarnet therapy.

Sequential herpes simplex virus (HSV) isolates from AIDS patients receiving foscarnet therapy were evaluated for susceptibility to adefovir. Foscarnet-resistant isolates with DNA polymerase mutations in regions II, VI, and between I and VII were also associated with an important decrease in susceptibility to adefovir (mean IC50 increase: 4.6-fold compared to pre-foscarnet or wild-type isolates) suggesting that adefovir-resistant HSV could be selected in vivo by foscarnet therapy.

AIDS-Related Opportunistic Infections↗
PubMed2007

A pilot phase II study of alternate day ganciclovir and foscarnet in preventing cytomegalovirus (CMV) infections in at-risk pediatric and adolescent allogeneic stem cell transplant recipients.

BACKGROUND: Prophylaxis with ganciclovir or foscarnet post allogeneic stem cell transplant (AlloSCT) reduces cytomegalovirus (CMV) disease. Combination ganciclovir/foscarnet is more effective than monotherapy in HIV patients with CMV retinitis. We hypothesized that alternate day ganciclovir and foscarnet for the prevention of CMV during the first 100 days after AlloSCT would be safe and effective. PROCEDURE: Fifty-three pediatric and adolescent AlloSCT recipients receiving 57 AlloSCTs where donors and/or recipients were CMV seropositive received ganciclovir (5 mg/kg/48 hr) alternating with foscarnet (90 mg/kg/48 hr) from myeloid recovery (>or=ANC 750/mm3) until Day +100. RESULTS: Patients were: M:F 31:22; age 6 years (0.8-18 years); donor sources: 25 related peripheral blood/bone marrow, 3 unrelated adult peripheral blood, 26 unrelated cord blood, and 3 related cord blood. GVHD prophylaxis included tacrolimus/mycophenolate mofetil (MMF). Median-nucleated and CD34 cell counts were 7.3x10(8)/kg and 5.07x10(6)/kg, respectively, for BM/PBSC; 4.07x10(7)/kg and 1.69x10(5)/kg, respectively, for CB. Despite a 36.5% probability of Grades II-IV acute GVHD, no patient developed systemic CMV disease. Five percent had Grade IV hematological toxicity that required discontinuation of ganciclovir. Twenty-five percent required discontinuation of foscarnet secondary to electrolyte abnormalities and/or renal dysfunction that were presumed to be multifactorial in origin. Probability of 1-year overall survival was 58.8%. CONCLUSIONS: Alternate day ganciclovir/foscarnet in AlloSCT recipients where recipient and/or donor is seropositive appears to be tolerable and 100% effective in preventing CMV systemic disease. A randomized study will be required to determine if this approach is superior to other CMV prophylactic designs.

Adolescent↗
PubMed1992

Mechanism of action of foscarnet against viral polymerases.

Foscarnet is a pyrophosphate analogue with activity against herpesviruses, human immunodeficiency virus (HIV), and other RNA and DNA viruses. Foscarnet and its analogues achieve their antiviral effects via inhibition of viral polymerases, with such inhibition not being dependent on activation or phosphorylation of the compounds by viral or cellular proteins. Current evidence indicates that foscarnet interferes with exchange of pyrophosphate from deoxynucleoside triphosphate during viral replication by binding to a site on the herpesvirus DNA polymerase or HIV reverse transcriptase. Reviewed herein are basic findings regarding the mechanism of action and antiviral activity of foscarnet and the related compound phosphonoacetic acid (PAA), as well as findings regarding potential mechanisms of viral resistance and interactions with other antiviral agents.

Antiviral Agents↗
PubMed1993

Foscarnet inhibits vascular smooth muscle contraction.

Foscarnet inhibited noradrenaline and calcium-mediated contractions of the isolated perfused tail artery of the rat. When the noradrenaline contractile response was split into two components, where the first was due to the release of calcium from intracellular stores and the second to the influx of calcium from the extracellular fluid, foscarnet (30 microM) inhibited only the first component of the response. Foscarnet did not inhibit the calcium influx component of the noradrenaline contraction, nor did it affect the inhibition of this component by the L-type calcium channel antagonists verapamil and nicardipine. These results indicate that foscarnet inhibits vascular smooth muscle contraction by inhibiting calcium release from intracellular stores.

Animals↗
PubMed2004

Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with phosphates, carbamoyl phosphate, and the phosphonate antiviral drug foscarnet.

A detailed inhibition study of five carbonic anhydrase (CA, EC 4.2.1.1) isozymes with inorganic phosphates, carbamoyl phosphate, the antiviral phosphonate foscarnet as well as formate is reported. The cytosolic isozyme hCA I was weakly inhibited by neutral phosphate, strongly inhibited by carbamoyl phosphate (K(I) of 9.4 microM), and activated by hydrogen- and dihydrogenphosphate, foscarnet and formate (best activator foscarnet, K(A)=12 microM). The cytosolic isozyme hCA II was weakly inhibited by all the investigated anions, with carbamoyl phosphate showing a K(I) of 0.31 mM. The membrane-associated isozyme hCA IV was the most sensitive to inhibition by phosphates/phosphonates, showing a K(I) of 84 nM for PO(4)(3-), of 9.8 microM for HPO(4)(2-), and of 9.9 microM for carbamoyl phosphate. Foscarnet was the best inhibitor of this isozyme (K(I) of 0.82 mM) highly abundant in the kidneys, which may explain some of the renal side effects of the drug. The mitochondrial isozyme hCA V was weakly inhibited by all phosphates/phosphonates, except carbamoyl phosphate, which showed a K(I) of 8.5 microM. Thus, CA V cannot be the isozyme involved in the carbamoyl phosphate synthetase I biosynthetic reaction, as hypothesized earlier. Furthermore, the relative resistance of CA V to inhibition by inorganic phosphates suggests an evolutionary adaptation of this mitochondrial isozyme to the presence of high concentrations of such anions in these energy-converting organelles, where high amounts of ATP are produced by ATP synthetase, from ADP and inorganic phosphates. The transmembrane, tumor-associated isozyme hCA IX was on the other hand slightly inhibited by all these anions.

Antiviral Agents↗