Comparative Analysis of Iron Homeostasis in Sub-Saharan African Children with Sickle Cell Disease and Their Unaffected Siblings.

Iron is an essential trace element subject to tight regulation to ensure adequate running of biological processes. In sub-Saharan Africa where hemoglobinopathies are common, iron homeostasis is likely to be impaired by these conditions. Here, we assessed and compared key serum proteins associated with iron metabolism between sub-Saharan African children with sickle cell disease (SCD) and their unaffected siblings. Complete blood counts and serum concentrations of four key proteins involved in iron regulation (ferritin, transferrin, sTfR, and hepcidin) were measured for 73 children with SCD and 68 healthy siblings in Benin, West Africa. We found significant differences in concentration of transferrin, sTfR, and ferritin between the two groups. Hepcidin concentrations were found at unusually high concentrations but did not differ among the two groups. We found a significant negative correlation between hepcidin levels and both MCH and MCV in the SCD group and report that sTfR concentrations show a correlation with MCV and MHC in opposite directions in the two groups. These results highlight the unusually high levels of hepcidin in the Beninese population and the patterns of differential iron homeostasis taking place under SCD status. These results lay the foundation for a systematic evaluation of the underlying mechanisms deregulating iron homeostasis in populations with SCD or high prevalence of iron deficiency.

Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV.

BACKGROUND: The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection. AIM: To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773. METHODS: The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg). RESULTS: Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ). CONCLUSION: The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group.

[Problems of rehabilitation in patients with sickle cell disease in Cotonou, Benin]. / Problèmes de rééducation posés par la drépanocytose à Cotonou.

BACKGROUND: Manifestations of sickle cell disease (SCD) are polymorphous from childhood to adulthood. OBJECTIVE: The purpose of this study was to assess outcomes of rehabilitation in the patients with SCD. METHOD: This retrospective analytical descriptive study included 160 SCD patients rehabilitated from 1998 to 2006 at the National University Hospital in Cotonou, Benin. RESULTS: Mean patient was 31 years (range, 3 to 73 years). There was a female predominance (62.5%) with a sex ratio of 0.6. The type of SCD was HbAS in 53.1% of patients, HbSS in 21.3%, HbSC in 16.9%, and HbAC in 8.1%. The main clinical manifestations were classified as ischemic/infectious in 40% of patients, rheumatologic in 40%, and neurologic in 10%. Ischemic manifestations were observed in all patients with HbSS, HbSC, and HbAS while manifestations were preferentially neurological in patients with HbSS (p = 4,43.10(-3)) and rheumatologic in patients with HbAS (p<10(-3)). At the end of rehabilitation, persistent deficiencies, disabilities and limitations involved pain in 43.8% of patients, articular stiffness in 43.8%, muscular weakness in 46.9%, gait anomalies in 33.1%, amyotrophy in 21.2%, shortening of lower extremity in 16.9%, and tilting of the pelvis in 6.3%. CONCLUSION: This study shows that SCD is a highly debilitating disease. Although rheumatologic manifestations are not specific to SCD, the other complications described including femoral head necrosis, osteomyelitis, and stroke have been extensively documented in the literature. If primary prevention is unfeasible, early multidisciplinary management appears to be the most effective approach to reducing SCD-related disability.

Newborn screening for sickle cell disease in the Republic of Benin.

AIMS: To develop a strategy for neonatal screening of sickle cell disease (SCD) and effective enrollment of affected neonates in a comprehensive follow-up programme adapted to the socioeconomic conditions, health structures and cultural background of an African setting. METHODS: The strategy implemented at the two largest maternity services of Cotonou, the economic capital of the Republic of Benin, involves a team of specifically trained midwives, first to identify pregnant women at risk, and second to provide active and repeated information and sensitisation to these women to encourage voluntary demand for newborn screening and enrollment in the follow-up programme. RESULTS: Among the consecutive pregnant women studied (about 3000), 79.5% of the informed women at risk for fetal SCD asked for testing of their offspring, 85.2% of the newborns who tested positive were enrolled in the programme, and more than 80% were still being followed up after 5 years. The under-five mortality rate in this series was 15.5 per 10,000, a figure that is 10 times lower than the general rate recorded in the Republic of Benin. CONCLUSIONS: The results demonstrate that this specifically tailored strategy is relevant to this setting, given the unique conditions of this African country.

Effect of active prenatal management on pregnancy outcome in sickle cell disease in an African setting.

Sickle cell disease (SCD) is associated with an increased risk of medical complications during pregnancy. In sub-Saharan Africa, fetal and maternal mortality rates are particularly high. This study evaluated the effect of an active prenatal management program on pregnancy outcome in patients with SCD in an African setting. Pregnant women with SCD attending the National Teaching Hospital in Cotonou (The Republic of Benin, West Africa) were recruited before the 28th week of gestation. Management was based on providing information and education about SCD and improving nutritional status, malaria prevention, early detection of bacterial infections, and restricted use of blood transfusion. Maternal and fetal mortality rates and SCD-related morbidity were the principal variables assessed. One hundred and eight patients (42 SS and 66 SC) with 111 fetuses were included in the study. Thirteen fetal deaths (from 9 SS and 4 SC mothers) were recorded and 2 deaths of SC mothers. The maternal mortality rate of 1.8% was comparable with the overall maternal mortality rate for this maternity unit (1.2%). Few SCD-related events were recorded. Plasmodium falciparum malaria infection was the major cause of morbidity. Sixty-three patients (19 SS and 44 SC) successfully completed their pregnancy (58.3%) without requiring transfusion. Providing pregnant SCD patients with relevant medical care based on simple cost-effective approaches can have a positive impact on SCD-associated morbidity and mortality in an otherwise difficult setting in Africa. (Blood. 2000;96:1685-1689)

Outpatient management of fever in children with sickle cell disease (SCD) in an African setting.

Because hospitalization and intravenous antibiotics for treatment of a potentially fatal bacterial infection in febrile children with sickle cell disease (SCD) are difficult to apply, outpatient treatment has been considered in developed countries for selected patients. Eligibility criteria and procedures may differ in developing countries because of unique economic and social conditions. After clinical evaluation within 36 hr of the onset of a fever exceeding 38.5 degrees C, children with SCD who are being closely followed as a part of a SCD cohort in Cotonou (West Africa), were treated as outpatients. The antibiotic regimen consisted of intramuscular injection of ceftriaxone 50 mg/kg/day for 2 days followed by amoxicillin 25 mg/kg x 3/day x 4 days and oral hyper-hydration. Patients were observed for 6 hr and thereafter discharged with a medical control at day 2, day 8 + day 15. All 60 children included completed their treatment, and none were lost to follow-up. A definite or a presumed bacterial infection was the cause of the febrile episode in 76.7% of cases. An appreciable decrease in fever was observed from day 2 and only 2 patients were hospitalized at day 3, one for abdominal painful crisis and one other for persistent fever without documented infection. No severe bacterial infections, recurrence of febrile episode, nor death were encountered during the follow-up. The cost of this outpatient approach is US $30 per patient as compared to US $140 per patient if the patient had been hospitalized. Outpatient management of febrile episode in children with SCD is feasible and cost-effective in Sub-Saharan African. It requires, however, improved medical education on SCD and immediate medical attention after the onset of fever.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): assessment of return of ovulation after three monthly injections in surgically sterile women.

The pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) on ovarian function were assessed through changes in serum progesterone concentrations. The data described here were obtained simultaneously with pharmacokinetic data presented in another article in this issue. Sixteen surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Suppression, followed by resumption of ovulation (the dynamic end point), was assessed by serum progesterone levels. Return of ovulation was presumptive based on progesterone concentrations > or = 4.7 ng/mL, as ultrasound was not used to determine the follicular/ovulatory status of these subjects. Luteal-like serum progesterone peaks were observed in all 16 women before drug administration, confirming the presence of ovulatory cycles. After the third monthly injection of MPA/E2C, progesterone concentrations were measured until demonstration of ovulation. Two women discontinued and three were lost to follow-up before this objective was achieved. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks (serum progesterone concentrations did not exceed 1 ng/mL). The first normal ovulatory cycle, based on progesterone concentrations > or = 4.7 ng/mL, was observed in 11 women between days 63 and 112 after the third injection. Select medroxyprogesterone acetate parameters (i.e., area under the curve and minimum concentration) were correlated with return of ovulation. The correlation coefficients (r) were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. In general, the higher the minimum concentration levels, the longer the time to return of ovulation. In conclusion, the return of ovulation, as confirmed by serum progesterone concentrations > or = 4.7 ng/mL, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C, suggesting that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

PIP: This study assessed the pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle monthly contraceptive injection) through changes in serum progesterone concentrations. A total of 16 surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks. The first normal ovulatory cycle, based on progesterone concentrations of 4.7 ng/ml or higher, was noted in 11 women between days 63 and 112 after the third injection. Select MPA parameters were correlated with return of ovulation. The correlation coefficients were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. Generally, the higher the minimum concentration levels, the longer the time to return of ovulation. This study concluded that the return of ovulation, as confirmed by serum progesterone concentrations of 4.7 ng/ml or higher, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C. This indicates that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): effects of body weight and injection sites on pharmacokinetics.

A new contraceptive option, medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C, Lunelle Monthly Contraceptive Injection), will soon be available for women in the US. This article reports the results of a US trial that assessed the effects of body weight and injection site on the pharmacokinetics of MPA, the progestin mediating contraceptive efficacy. This assessment was part of a nonrandomized, open-label, multicenter US study in healthy women receiving a monthly injection of MPA/E2C for 60 weeks. A total of 77 women (aged 18-47 years) at four centers participated in the pharmacokinetics assessment during the sixth or the seventh injection. For determination of serum MPA concentration-time profiles, blood samples were collected before the sixth and seventh injections (day 0) and on days 3, 7, 14, 21, and 28 after the sixth and seventh monthly administrations. For effects of injection site, MPA pharmacokinetics were compared at injection sites of the arm, hip, and leg. The pharmacokinetics of MPA, determined at the sixth and seventh injection, were not significantly affected by injection sites. The mean area under the curve (AUC0-28), however, was different between the arm and the leg injection sites; the difference was < 20%. More important, the average MPA trough concentrations (Cmin) at the fifth and sixth monthly injections were similar (range 0.42-0.51 ng/mL) for the three injection sites and well above the threshold levels of 0.10-0.20 ng/mL required to suppress ovulation. For effects of body mass index (BMI) on pharmacokinetics, women were stratified into three groups: thin/normal (BMI 18-28, n = 48), obese (BMI 29-38, n = 23), and highly obese (BMI > 38, n = 6). There were no significant differences in the pharmacokinetics of MPA among the three BMI categories. The only significant difference (p = 0.0387) was the AUC0-28 between BMI 18-28 and BMI 29-38. Because of the small sample size in the highly obese group, a reanalysis was performed by pooling subjects of the obese and highly obese groups. Results of the pooled statistical analysis remained the same. In summary, these results suggest that minor differences observed in the MPA pharmacokinetics--whether due to injection site or body weight or both--have no impact on the contraceptive efficacy of MPA/E2C, as trough concentrations (Cmin) are well above the threshold levels required to suppress ovulation. No dose adjustment is necessary based on body weight or injection site.

PIP: A nonrandomized, open-label, multicenter study assessed the effects of body weight and injection site on the pharmacokinetics of medroxyprogesterone acetate (MPA) and its progestin medicating contraceptive efficacy among 77 healthy, fertile women aged 18-47 years. For determination of serum MPA concentration-time profiles, blood samples were collected before the 6th and 7th injections (day 0) and on days 3, 7, 14, 21, and 28 after the 6th and 7th monthly administrations. For injection site effects, MPA pharmacokinetics were compared at the injection sites of the arm, hip, and leg; there was no significant finding. For effects of body mass, no significant differences were noticed in the pharmacokinetics of MPA among the 3 body mass indices (thin/normal, obese, highly obese). However, a difference (p = 0.0387) was found between normal and obese women (20%). The findings suggest that minor differences observed in MPA pharmacokinetics have no impact on the contraceptive efficacy of MPA/E2C, may it be due to injection sites or body weight, since trough concentrations are well above the threshold levels required to suppress ovulation.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women.

The steady-state pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol (E2, released from E2C by esterase enzymes) were characterized after administration to surgically sterile women. This report describes the pharmacokinetics of this multiple-dose and open-labeled study (pharmacodynamics are reported in a subsequent article in this issue). Women with regular menstrual cycles were studied for one control cycle, 3 consecutive treatment months, and 3-5 months of follow-up. Blood samples were drawn before each monthly dose and at specified time points after the third monthly injection. A total of 16 women were enrolled, 14 of whom completed the study. These 14 women (13 white, one black) ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. Mean serum MPA concentrations peaked in the first week after administration of MPA/E2C (Lunelle Monthly Contraceptive Injection). The mean MPA Cmax and AUC0-t(last) were 1.25 ng/mL and 32.13 ng.day/mL, respectively. Serum MPA concentrations declined with a mean terminal half-life of 14.7 days, indicating that absorption from the injection site is prolonged after administration of MPA/E2C. The time for MPA concentrations to fall below the lower limit of quantitation (i.e., < 10 pg/mL) after the third injection ranged from 63 to 84 days. The average MPA trough (Cmin' day 28) concentrations for the three consecutive monthly injections ranged from 0.44 to 0.47 pg/mL, indicating that steady-state conditions were achieved after the first injection. The MPA Cmin values were well above threshold levels required to suppress ovulation throughout the injection interval. Absorption of E2 from the injection site was also prolonged after injection of MPA/E2C. Mean concentrations of E2 peaked at approximately 2 days after the third injection, and the average Cmax was 247 pg/mL. Serum E2 levels declined with a terminal half-life of approximately 8 days; E2 levels returned to baseline (typically, approximately 100 pg/mL) by 14 days after each injection. The average trough (Cmin' day 28) levels for E2 ranged from 40 to 55 pg/mL. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E2C; no further MPA or E2 accumulation occurs beyond the first injection. Furthermore, the E2 peak observed after injection of MPA/E2C is similar to the nontreated preovulatory E2 range and returns to baseline levels by approximately 14 days after injection.

PIP: This paper characterized the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) in 14 healthy, surgically sterile women. These women ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E2C; no further MPA or E2C accumulation occurs beyond the first injection. Moreover, the E2 peak observed after injection of MPA/E2C is similar to the nontreated preovulatory E2 range and returns to baseline levels by approximately 14 days after insertion.

In vitro evaluation of polymeric matrix and porous biodegradable reservoir devices for slow-release drug delivery.

BACKGROUND AND OBJECTIVE: Biodegradable polymeric devices were evaluated in vitro for intravitreal drug delivery. MATERIALS AND METHODS: The matrix (short-term drug delivery) and the porous (longer-term drug delivery) reservoir devices were made from polycaprolactone of two molecular weights (30,000 and 56,000). Matrix devices were loaded with 5-fluorouracil or ganciclovir. Porous reservoirs were loaded with 5-fluorouracil, ganciclovir, 5-carboxyfluorescein, or foscarnet. The release was monitored in phosphate-buffered solution using ultraviolet spectrophotometry. RESULTS: Release from the matrix devices was characterized by an initial burst, followed by a nonlinear release. The porous reservoirs demonstrated zero order linear release of drugs, sustained up to 250 days in this experiment. CONCLUSIONS: The matrix device is capable of sustained release over several months; the porous reservoir can deliver drugs for over 1 year. Further studies are needed to evaluate in vivo biodegradation behavior and toxicity of drugs used for sustained release.

[From the murine model to human cerebral malaria]. / Du modèle murin au neuropaludisme humain.

The pathophysiology of cerebral malaria remains incompletely understood. Several mechanisms have been proposed to explain the aetiology of the neurological signs including reduction of cerebral blood flow, parasite toxin, hyperproduction of nitric oxide, immune response. Different models of murine and primate have been developed to investigate the different hypothesis. The role of nitric oxide was analysed in the murine and human malaria. Cerebral blood flow reduction is not compatible with the absence of sequelae observed in the majority of recovering cerebral malaria patients. Experimental data from primates and mice show that cerebral sequestration picture of circulating cells did not implicate the development of neurological signs. Brain haemodynamic data from human also argue for a "luxury perfusion" rather than a diminution of blood flow during cerebral malaria. The role of coinfection in the occurrence of cerebral malaria is discussed.

Suppression of experimental proliferative vitreoretinopathy by sustained intraocular delivery of 5-FU.

Treatment of proliferative vitreoretinopathy (PVR) requires a multidimensional approach. Recent studies have focused on pharmacologic techniques to inhibit intraocular cell proliferation by applying antimetabolite drugs. Side effects associated with these drugs and difficulties in achieving effective concentration inside the eye make drug delivery an important and difficult part of this approach. We have developed a sustained-release bioerodible device with modifiable release properties for intraocular drug delivery. In this study, we evaluated the efficacy of the device with two different concentrations of 5-fluorouracil (5-FU) in an experimental model of PVR in rabbit eyes. Both devices showed significant (P < 0.05) efficacy in prevention of PVR. Devices containing 20% 5-FU (total of 1 mg) were 100% effective in prevention of tractional retinal detachment. No significant complications, other than mild vitreous hemorrhage in a few cases, were associated with this method. Because pharmacologic therapy is used as an augmenting method to surgical therapy, these devices can be easily implanted inside the eye through a sclerotomy at the completion of surgery without any discomfort to patients. Slow release of drug by this method reduces the incidence of toxicity and increases the efficacy by providing a constant concentration of drug during the active period of the disease.

Noninvasive monitoring of intraocular pharmacokinetics of daunorubicin using fluorophotometry.

PURPOSE: Daunorubicin is a cytotoxic drug, which, in nontoxic doses, is effective in preventing cellular proliferation in experimental vitreoretinopathy. We studied dose and clearance of daunorubicin in various ocular tissues using fluorophotometry techniques. METHODS: In vitro tests: The emission of fluorescence from the daunorubicin solution having a concentration range of 0.1 to 10 micrograms/mL in phosphate buffer was measured using an excitation wavelength range of 489 +/- 10 nm. The emission of fluorescence was measured at 514 nm; the linearity of the response was determined using linear regression analysis. There is a fluorescence peak of daunorubicin at 485 nm. The validity and reproducibility of the method were examined. In vivo tests: The rabbits were randomized into three groups and daunorubicin concentrations of 4, 6, or 8 micrograms/mL were injected into the vitreous. Fluorophotometry scanning from the retina to the anterior chamber was performed with a commercially available fluorophotometer at various times up to 48 hours after injection to quantify fluorescence emission of daunorubicin. RESULTS: The standard curve of fluorescence versus concentration of daunorubicin was linear in the range of 0.1 to 8 micrograms/mL. It was sensitive up to 0.1 microgram. The daunorubicin time concentration profile showed a dose response relationship over the 48-hour period studied. The half-life of daunorubicin in the vitreous was about 5 hours. CONCLUSION: We performed fluorophotometry using a fluorophotometer whose exciter emits light at 489 nm, which is very close to an absorption peak of daunorubicin. These two values are close enough to obviate the need for modifying the commercial fluorophotometer. Therefore the concentration of daunorubicin in the vitreous cavity can be measured noninvasively.

Treatment of cytomegalovirus retinitis with intravitreal injection of liposome encapsulated ganciclovir in a patient with AIDS.

To study its safety and efficacy in treating cytomegalovirus (CMV) retinitis, an AIDS patient received an intravitreal injection of liposome encapsulated ganciclovir in the right eye. The left eye served as a control, receiving intravitreal free ganciclovir. The right eye showed no retinal haemorrhages or detachment; however, vision declined initially, stabilising later. Weekly examination showed neither progression of the CMV retinitis nor new lesions in the right eye. The left eye showed reactivation of old CMV retinitis. Liposome encapsulated ganciclovir reduced the number of intravitreal injections, stabilising CMV retinitis, and warrants further study.

Retinal toxicity of intravitreally injected faeriefungin.

Faeriefungin is a new antibacterial and antifungal agent derived from a strain of Streptomyces griseus var. autotrophicus. Under anesthesia, 12 albino rabbits underwent injection in their right eyes with 400, 200, 100, 40, 20, and 10 micrograms of faeriefungin. Retinal toxicity was assessed by electroretinography and light and transmission electron microscopy. Injection of 400 micrograms resulted in severe retinal toxicity, although indirect ophthalmoscopy was unremarkable. At 200 micrograms, there was moderate toxicity. Intravitreal injection of concentrations of 100 micrograms or less produced no neuroretinal toxicity. These data suggest that faeriefungin is a potentially useful drug in the treatment of fungal or bacterial endophthalmitis.

Vitreoretinal toxicity of acetazolamide following intravitreal administration in the rabbit eye.

Acetazolamide, a carbonic anhydrase inhibitor, has been shown effective in the treatment of cystoid macular edema; however, chronic use of the drug is limited by its serious systemic side effects. Intraocular administration can eliminate these systemic complications. We evaluated vitreoretinal toxicity after intravitreal injection of acetazolamide in the rabbit eye. The right eye of each rabbit received a single acetzolamide injection; the left eye received balanced salt solution and served as a control. The effect of the drug was evaluated by clinical observation, electroretinography, and histopathologic study. Intravitreal injection of up to 0.5 mg acetazolamide did not cause vitreoretinal toxicity. Injection of 1 mg or higher doses depressed the b-wave amplitude of electroretinograms and damaged the outer segments of the photoreceptors, as determined by light and electron microscopy.