755
Foscarnet and
crystals in glomerular capillary lumens
SIR,-Foscarnet (trisodium phosphonate hexahydrate) is increasingly used for the treatment of cytomegalovirus (CMV) infection in AIDS. Adverse effects include impairment of renal function,l.2 hypo or hypercalcaemia, anaemia, seizures, headache, and vomiting. More recently, genital erosions have been described in patients treated with foscamet.3-6 Nephrotoxicity of foscamet seems to be related to tubulointerstitial lesions.1,2 Among 37 biopsy or necropsy kidney specimens we found, in addition to tubulointerstitial lesions, crystals within glomerular capillary lumens in 5 cases (1 biopsy, 4 necropsy). These patients had been treated with foscamet for CMV retinitis. Foscamet was withdrawn because of renal impairment in 3 cases. 2 other patients died from other AIDS-related conditions with renal dysfunction while being treated with foscamet. 1 of these patients was concomitantly treated with sulfadiazine, which can precipitate within tubules. However, to our knowledge, such crystals have never been described within the glomeruli. Moreover, the crystals seen within the glomeruli had several characteristics (water soluble, alcohol insoluble, and identical appearance by polarisation examination) of foscamet in its crystalline form. Little Conc (nM) Inhibition of ANFdegradation by UK-69 578
(•) and thiorphan
(&Dgr;). Data as percentage of ANFhydrolysing activity in absence of inhibitor and are shown as mean (SE) of three determinations. Sigmoidal inhibition curves for UK-69 578 (-) and thiorphan ( ..) were constructed to derive I Coo values.
is known of the mechanism of foscamet nephrotoxicity. We suggest that crystals within the glomeruli may participate in this mechanism. As in severe oxalosis, crystallised foscamet deposition in arterioles and capillaries could explain some of the drug’s adverse effects, such as genital and oral ulcerations.
(70 pmol/min)
degradation of ANF being measured by reverse-phase highperformance liquid chromatography.4 UK-69 578 and thiorphan were both potent inhibitors of atriopeptidase from rat kidney, independent of which substrate was used. The concentration of inhibitor required to give 50% inhibition of ANF degradation (IC50) was 40 nmol/1 for UK-69 578 and 35 nmol/I for thiorphan (figure). With the synthetic substrate, Kj for UK-69 578 was 32 (SE 3) nmol/1 (n = 6) and the inhibition was competitive. Thiorphan was equipotent in this assay, with a K, of 48 (16) nmol/l (n=4) and its inhibition also appeared competitive. (Inclusion of 01 mmol/1 2-mercaptoethanol in the assay buffers to further prevent oxidation did not alter these results.) Candoxatrilat, the (+ )-enantiomer of UK-69 578, was evaluated by this method and its potency was about twice that of the parent compound, with a K; of 19 (1) nmol/1 (n = 3). This compound, and its indanyl ester pro-drug candoxatril (UK-79 300), are currently undergoing clinical evaluation for the treatment of hypertension and heart failure. Even taking into account resolution of thiorphan, which results in a small (less than 2-fold) increase in enzyme affinity,s these studies do not support the claim of a 20-fold difference in potency between the two compounds. One explanation for the discrepancy between our data and those of Kahn et al could be the substrate; they used methionine-enkephalin or a related analogue,s whilst we believe ANF to be a more relevant substrate for such comparisons.
Pfizer Central Research, Sandwich, Kent CT13 9NJ, UK
P. L. BARCLAY J. C. DANILEWICZ G. M. R. SAMUELS
1. Kahn
JC, Patey M, Dubois-Rande JL, et al. Effect of sinorphan on plasma atrial factor in congestive heart failure. Lancet 1990: 335: 118. 2 Northridge DB, Jardine AG, Alabaster CT, et al. Effects of UK69578: a novel atriopeptidase inhibitor. Lancet 1989; ii: 591-93. 3 Danilewicz JC, Barclay PL, Barnish IT, et al. UK69578, a novel inhibitor of EC3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic. Biochem Biophys Res Commun 1989; 164: 58-65. 4.Matsas R, Fulcher IS, Kenny AJ, Tumer AJ. Substance P and [Leu]enkephalin are hydrolysed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli Proc Natl Acad Sci USA 1983; 80: natriuretic
3111-15. 5 Giros B, Gros C, Schwartz JC, et al. Enantiomers of thiorphan and acetorphan: correlation between enkephalinaseinhibition,protectionofendogenousekephalins and behavioral effects.J Pharm Exp Ther 1987; 243: 666-73.
INSERM U192. Departments of Nephrology, Tropical and Infectious Medicine, and Neuropathology,
Hôpital Pitié-Salpétrière, 75013 Paris, France
H. BEAUFILS G. DERAY C. KATLAMA E. DOHIN D. HENIN V. SAZDOVITCH
C. JOUANNEAU
1. Deray G, Martinez F, Katlama C, et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol 1989; 9: 316-21. 2. Nyberg G, Blohme I, Persson H, et al. Foscarnet induced tubulo-interstitial nephritis in renal transplant patients. Transplant Proc 1990; 22: 241. 3. Van der Pijl JW, Frissen PH, Reiss R, et al. Foscarnet and penile ulceration. Lancet 1990; 335: 286. 4. Fegueux S, Salmon D, Picard C, et al. Penile ulcerations with foscarnet. Lancet 1990; 335: 547. 5. Moyle G, Nelson M, Barton SE, et al. Penile ulcerations with foscarnet. Lancet 1990; 335: 547. 6. Lemestedt JO, Chanas AC. Penile ulcerations with foscarnet. Lancet 1990; 335: 548.
Treatment of Helicobacter pylori positive duodenal ulcers SIR,—The treatment of duodenal ulcers associated with Helicobacter pylori is difficult because the organism cannot be eradicated by anti-ulcer drugs. However, H pylori can be suppressed for a few months by colloidal bismuth subcitratel in combination with antibiotics, and this approach gives lower peptic ulcer recurrence rates than H2-antagonist or pirenzepine monotherapy.2,3 We report a randomised single-blind study comparing ranitidine plus oxacillin with ranitidine alone in the treatment of duodenal ulcer associated with H pylori. 65 H pylori positive patients (42 men, 23 women), with an endoscopically verified duodenal ulcer 5 mm or more in diameter, were randomly assigned to 4 weeks’ treatment with either ranitidine 300 mg daily plus oxacillin 500 mg four times per day for the first 10 days (32 patients), or ranitidine 300 mg once daily at night (33 patients). Post-treatment endoscopy showed that all patients who received ranitidine plus oxacillin were free from H pylori; all patients receiving ranitidine only were H pylori positive. Ulcers were healed in 32 patients (100%) in the combination group and in 29 patients (88%) in the ranitidine group. The 61 patients with healed ulcers were included in a 12-month follow-up study, with only antacids given as additional therapy. The results of endoscopic and histological assessments are shown in the table. These suggest that suppression of H pylori with ranitidine
756
H PYLORI AND DUODENAL ULCER STATUS DURING FOLLOW-UP
in 13%, all for obstetric
reasons.
By contrast, 12 controls had
symptomatic recurrences within 10 days before or at the time of delivery. 9 of these 12 women had caesarean section because of herpes. 4 women (all controls) excreted virus at the time of delivery,I in the absence of lesions: Outcome
plus oxacillin is associated with a substantial reduction in duodenal ulcer relapse rate. The number of H pylori positive patients slowly increased in the group who received supplementary oxacillin, while all patients in the ranitidine-only group remained H pylori positive, with a significantly higher relapse rate. These fmdings are consistent with the pharmacological properties of ranitidine and oxacillin. Ranitidine alone does not suppress H pylori4or stimulate its recurrence after treatment, and oxacillin is rapidly inactivated at the low stomach pH. However, ranitidine reduces acid secretion and consequently promotes the bactericidal activity of the antibiotic. Thus, there may be some degree of synergism between oxacillin and ranitidine. Our followup study results compare with other investigations of the treatment of H pylori positive duodenal ulcers with combinations of colloidal bismuth subcitrate and antibiotics.2.sFurther controlled trials required to decide which therapy is superior. Department of Gastroenterology, N I Pirogov Moscow Medical Institute, Moscow, USSR
are
V. A. ISAKOV P. YA. GRIGORIEV E. P. YAKOVENKO
1. Goodwin
CS, Armstrong JA. Will antibacterial chemotherapy be efficacious for gastritis and peptic ulcers? J Antimicrob Chemother 1986; 17: 1-4 2. Coghlan JG, Gilligan D, Humphries H, et al. Campylobacter pylori and recurrence of duodenal ulcers: a 12-month follow-up study. Lancet 1987; ii: 1109-11. 3. Domschke S. H2-blocker, pirenzepine, prostaglandin. Therapiewoche 1989; 39: 628-33 4. Bianchi Porro
G, Lazzaroni M. Campylobacter pylon and peptic ulcer therapy. Gastroenterol Clin Biol 1989; 13: 107-11B. 5. Marshall BJ, Goodwin CS, Warren JR, et al Long-term healing of gastritis and low duodenal ulcer relapse after eradication of Campylobacter pyloridis: a prospective double blind study Gastroenterology 1987; 92: 1518 (abstr).
Acyclovir in late pregnancy to prevent neonatal herpes simplex SiR,—Up to 8% of women with a history of recurrent genital herpes simplex virus (HSV) infection who are actively infected at the time of delivery may transmit infection to their newborn babies.1-3 For those with symptomatic lesions close to or at the onset of labour caesarean section is recommended.’ For those with viral shedding but
no
symptoms the obstetrician is faced with
a
dilemma since
screening by ante-partum culture is of no value in predicting HSV excretion at delivery.’ Acyclovir suppresses recurrent genital herpes.6 In the newborn, including premature babies, this antiviral agent is safe even in high doses.’ Suppressive treatment in late pregnancy has been proposed.3,5.7-9Ipresent here a controlled study of acyclovir in the ante-partum period, the objective being to see if acyclovir administered preterm to women with frequently recurring genital herpes would prevent recurrences and/or HSV shedding at delivery. 92 women with recurrent genital herpes were allocated to receive acyclovir 200 mg four times daily, starting preferably 1 week before expected term: 46 women were not treated. Both groups were informed about our routine policy-namely caesarean section in patients with genital lesions or prodromes at the time of labour. Material for viral culture was collected from cervix and vulva at the start of treatment, at parturition, and from suspected lesions. During the last 6 months of pregnancy both groups had had an average of 3 symptomatic recurrences. 21 treated women (46%) and 18 controls (39%) displayed lesions 10-30 days before delivery. Acyclovir was given for an average of 10 days (range 3-27 days). Treatment was well tolerated without side-effects. No treated woman had a symptomatic recurrence during the treatment period or excreted virus at the start of labour. Caesarean section was done
No treatment
Acyclovir (n=46)
HSV recurrences/positive cultures < 10 days before delivery 0 0 During delivery Total 0 Caesarean section for 0 Herpes Obstetnc reasons 6 (13%) Total 6 (13%)
(n = 46) 8 4 12
(17%) (p < 0’001) ( 9%J (269%) (p < 0 001 )
9 (20%) 6 (13%) 15 (33%)
(p< 0-001) (p
Foscarnet and
crystals in glomerular capillary lumens
SIR,-Foscarnet (trisodium phosphonate hexahydrate) is increasingly used for the treatment of cytomegalovirus (CMV) infection in AIDS. Adverse effects include impairment of renal function,l.2 hypo or hypercalcaemia, anaemia, seizures, headache, and vomiting. More recently, genital erosions have been described in patients treated with foscamet.3-6 Nephrotoxicity of foscamet seems to be related to tubulointerstitial lesions.1,2 Among 37 biopsy or necropsy kidney specimens we found, in addition to tubulointerstitial lesions, crystals within glomerular capillary lumens in 5 cases (1 biopsy, 4 necropsy). These patients had been treated with foscamet for CMV retinitis. Foscamet was withdrawn because of renal impairment in 3 cases. 2 other patients died from other AIDS-related conditions with renal dysfunction while being treated with foscamet. 1 of these patients was concomitantly treated with sulfadiazine, which can precipitate within tubules. However, to our knowledge, such crystals have never been described within the glomeruli. Moreover, the crystals seen within the glomeruli had several characteristics (water soluble, alcohol insoluble, and identical appearance by polarisation examination) of foscamet in its crystalline form. Little Conc (nM) Inhibition of ANFdegradation by UK-69 578
(•) and thiorphan
(&Dgr;). Data as percentage of ANFhydrolysing activity in absence of inhibitor and are shown as mean (SE) of three determinations. Sigmoidal inhibition curves for UK-69 578 (-) and thiorphan ( ..) were constructed to derive I Coo values.
is known of the mechanism of foscamet nephrotoxicity. We suggest that crystals within the glomeruli may participate in this mechanism. As in severe oxalosis, crystallised foscamet deposition in arterioles and capillaries could explain some of the drug’s adverse effects, such as genital and oral ulcerations.
(70 pmol/min)
degradation of ANF being measured by reverse-phase highperformance liquid chromatography.4 UK-69 578 and thiorphan were both potent inhibitors of atriopeptidase from rat kidney, independent of which substrate was used. The concentration of inhibitor required to give 50% inhibition of ANF degradation (IC50) was 40 nmol/1 for UK-69 578 and 35 nmol/I for thiorphan (figure). With the synthetic substrate, Kj for UK-69 578 was 32 (SE 3) nmol/1 (n = 6) and the inhibition was competitive. Thiorphan was equipotent in this assay, with a K, of 48 (16) nmol/l (n=4) and its inhibition also appeared competitive. (Inclusion of 01 mmol/1 2-mercaptoethanol in the assay buffers to further prevent oxidation did not alter these results.) Candoxatrilat, the (+ )-enantiomer of UK-69 578, was evaluated by this method and its potency was about twice that of the parent compound, with a K; of 19 (1) nmol/1 (n = 3). This compound, and its indanyl ester pro-drug candoxatril (UK-79 300), are currently undergoing clinical evaluation for the treatment of hypertension and heart failure. Even taking into account resolution of thiorphan, which results in a small (less than 2-fold) increase in enzyme affinity,s these studies do not support the claim of a 20-fold difference in potency between the two compounds. One explanation for the discrepancy between our data and those of Kahn et al could be the substrate; they used methionine-enkephalin or a related analogue,s whilst we believe ANF to be a more relevant substrate for such comparisons.
Pfizer Central Research, Sandwich, Kent CT13 9NJ, UK
P. L. BARCLAY J. C. DANILEWICZ G. M. R. SAMUELS
1. Kahn
JC, Patey M, Dubois-Rande JL, et al. Effect of sinorphan on plasma atrial factor in congestive heart failure. Lancet 1990: 335: 118. 2 Northridge DB, Jardine AG, Alabaster CT, et al. Effects of UK69578: a novel atriopeptidase inhibitor. Lancet 1989; ii: 591-93. 3 Danilewicz JC, Barclay PL, Barnish IT, et al. UK69578, a novel inhibitor of EC3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic. Biochem Biophys Res Commun 1989; 164: 58-65. 4.Matsas R, Fulcher IS, Kenny AJ, Tumer AJ. Substance P and [Leu]enkephalin are hydrolysed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli Proc Natl Acad Sci USA 1983; 80: natriuretic
3111-15. 5 Giros B, Gros C, Schwartz JC, et al. Enantiomers of thiorphan and acetorphan: correlation between enkephalinaseinhibition,protectionofendogenousekephalins and behavioral effects.J Pharm Exp Ther 1987; 243: 666-73.
INSERM U192. Departments of Nephrology, Tropical and Infectious Medicine, and Neuropathology,
Hôpital Pitié-Salpétrière, 75013 Paris, France
H. BEAUFILS G. DERAY C. KATLAMA E. DOHIN D. HENIN V. SAZDOVITCH
C. JOUANNEAU
1. Deray G, Martinez F, Katlama C, et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol 1989; 9: 316-21. 2. Nyberg G, Blohme I, Persson H, et al. Foscarnet induced tubulo-interstitial nephritis in renal transplant patients. Transplant Proc 1990; 22: 241. 3. Van der Pijl JW, Frissen PH, Reiss R, et al. Foscarnet and penile ulceration. Lancet 1990; 335: 286. 4. Fegueux S, Salmon D, Picard C, et al. Penile ulcerations with foscarnet. Lancet 1990; 335: 547. 5. Moyle G, Nelson M, Barton SE, et al. Penile ulcerations with foscarnet. Lancet 1990; 335: 547. 6. Lemestedt JO, Chanas AC. Penile ulcerations with foscarnet. Lancet 1990; 335: 548.
Treatment of Helicobacter pylori positive duodenal ulcers SIR,—The treatment of duodenal ulcers associated with Helicobacter pylori is difficult because the organism cannot be eradicated by anti-ulcer drugs. However, H pylori can be suppressed for a few months by colloidal bismuth subcitratel in combination with antibiotics, and this approach gives lower peptic ulcer recurrence rates than H2-antagonist or pirenzepine monotherapy.2,3 We report a randomised single-blind study comparing ranitidine plus oxacillin with ranitidine alone in the treatment of duodenal ulcer associated with H pylori. 65 H pylori positive patients (42 men, 23 women), with an endoscopically verified duodenal ulcer 5 mm or more in diameter, were randomly assigned to 4 weeks’ treatment with either ranitidine 300 mg daily plus oxacillin 500 mg four times per day for the first 10 days (32 patients), or ranitidine 300 mg once daily at night (33 patients). Post-treatment endoscopy showed that all patients who received ranitidine plus oxacillin were free from H pylori; all patients receiving ranitidine only were H pylori positive. Ulcers were healed in 32 patients (100%) in the combination group and in 29 patients (88%) in the ranitidine group. The 61 patients with healed ulcers were included in a 12-month follow-up study, with only antacids given as additional therapy. The results of endoscopic and histological assessments are shown in the table. These suggest that suppression of H pylori with ranitidine
756
H PYLORI AND DUODENAL ULCER STATUS DURING FOLLOW-UP
in 13%, all for obstetric
reasons.
By contrast, 12 controls had
symptomatic recurrences within 10 days before or at the time of delivery. 9 of these 12 women had caesarean section because of herpes. 4 women (all controls) excreted virus at the time of delivery,I in the absence of lesions: Outcome
plus oxacillin is associated with a substantial reduction in duodenal ulcer relapse rate. The number of H pylori positive patients slowly increased in the group who received supplementary oxacillin, while all patients in the ranitidine-only group remained H pylori positive, with a significantly higher relapse rate. These fmdings are consistent with the pharmacological properties of ranitidine and oxacillin. Ranitidine alone does not suppress H pylori4or stimulate its recurrence after treatment, and oxacillin is rapidly inactivated at the low stomach pH. However, ranitidine reduces acid secretion and consequently promotes the bactericidal activity of the antibiotic. Thus, there may be some degree of synergism between oxacillin and ranitidine. Our followup study results compare with other investigations of the treatment of H pylori positive duodenal ulcers with combinations of colloidal bismuth subcitrate and antibiotics.2.sFurther controlled trials required to decide which therapy is superior. Department of Gastroenterology, N I Pirogov Moscow Medical Institute, Moscow, USSR
are
V. A. ISAKOV P. YA. GRIGORIEV E. P. YAKOVENKO
1. Goodwin
CS, Armstrong JA. Will antibacterial chemotherapy be efficacious for gastritis and peptic ulcers? J Antimicrob Chemother 1986; 17: 1-4 2. Coghlan JG, Gilligan D, Humphries H, et al. Campylobacter pylori and recurrence of duodenal ulcers: a 12-month follow-up study. Lancet 1987; ii: 1109-11. 3. Domschke S. H2-blocker, pirenzepine, prostaglandin. Therapiewoche 1989; 39: 628-33 4. Bianchi Porro
G, Lazzaroni M. Campylobacter pylon and peptic ulcer therapy. Gastroenterol Clin Biol 1989; 13: 107-11B. 5. Marshall BJ, Goodwin CS, Warren JR, et al Long-term healing of gastritis and low duodenal ulcer relapse after eradication of Campylobacter pyloridis: a prospective double blind study Gastroenterology 1987; 92: 1518 (abstr).
Acyclovir in late pregnancy to prevent neonatal herpes simplex SiR,—Up to 8% of women with a history of recurrent genital herpes simplex virus (HSV) infection who are actively infected at the time of delivery may transmit infection to their newborn babies.1-3 For those with symptomatic lesions close to or at the onset of labour caesarean section is recommended.’ For those with viral shedding but
no
symptoms the obstetrician is faced with
a
dilemma since
screening by ante-partum culture is of no value in predicting HSV excretion at delivery.’ Acyclovir suppresses recurrent genital herpes.6 In the newborn, including premature babies, this antiviral agent is safe even in high doses.’ Suppressive treatment in late pregnancy has been proposed.3,5.7-9Ipresent here a controlled study of acyclovir in the ante-partum period, the objective being to see if acyclovir administered preterm to women with frequently recurring genital herpes would prevent recurrences and/or HSV shedding at delivery. 92 women with recurrent genital herpes were allocated to receive acyclovir 200 mg four times daily, starting preferably 1 week before expected term: 46 women were not treated. Both groups were informed about our routine policy-namely caesarean section in patients with genital lesions or prodromes at the time of labour. Material for viral culture was collected from cervix and vulva at the start of treatment, at parturition, and from suspected lesions. During the last 6 months of pregnancy both groups had had an average of 3 symptomatic recurrences. 21 treated women (46%) and 18 controls (39%) displayed lesions 10-30 days before delivery. Acyclovir was given for an average of 10 days (range 3-27 days). Treatment was well tolerated without side-effects. No treated woman had a symptomatic recurrence during the treatment period or excreted virus at the start of labour. Caesarean section was done
No treatment
Acyclovir (n=46)
HSV recurrences/positive cultures < 10 days before delivery 0 0 During delivery Total 0 Caesarean section for 0 Herpes Obstetnc reasons 6 (13%) Total 6 (13%)
(n = 46) 8 4 12
(17%) (p < 0’001) ( 9%J (269%) (p < 0 001 )
9 (20%) 6 (13%) 15 (33%)
(p< 0-001) (p
