Uterine artery blood flow remains unchanged in pregnant mares in response to short-term administration of pentoxifylline.

The objective of this study was to use Doppler ultrasound technology to determine whether pentoxifylline administration increased uterine blood flow in normal pregnant pony mares. Thirteen pregnant pony mares between 18 and 190 d of gestation (mean ± SEM, 101 ± 55) were utilized for the study during two trial periods. In each trial, pentoxifylline (17 mg/kg by mouth every 12h, diluted in syrup) was administered to half of the mares for 3 d, while the other mares were treated with syrup only. Doppler measurements were obtained from the right and left uterine arteries from each mare for 2 d prior to treatment and throughout the treatment period. The mean Resistivity Index (RI), Pulsatility Index (PI), Uterine Artery Diameter (D), and Total Arterial Blood Flow (TABF) from each day were compared over time and between groups. Administration of pentoxifylline did not alter uterine blood flow parameters compared with controls (values for all treatment days combined were RI: 0.517 ± 0.014 vs 0.543 ± 0.016; PI: 0.876 ± 0.048 vs 0.927 ± 0.057; D: 0.388 ± 0.018 vs 0.379 ± 0.023 cm; and TABF: 35.26 ± 7.38 vs 30.73 ± 5.29 mL/min). Uterine blood flow increased over the course of the 5 d study, irrespective of treatment, and was higher in mares of greater gestational age than in early gestational mares (RI: r(2) = 0.35; PI: r(2) = 0.37; D: r(2) = 0.66; and TABF: r(2) = 0.67 - P < 0.00001). We concluded that any immediate benefits of pentoxifylline administration in the pregnant mare were not mediated through enhanced uterine artery blood flow.

B-mode and Doppler ultrasonography in pony mares with experimentally induced ascending placentitis.

REASONS FOR PERFORMING STUDY: Early, accurate diagnosis of ascending placentitis in mares remains a key challenge for successful treatment of the disease. Doppler ultrasonography has shown promise as a tool to diagnose pregnancy abnormalities and is becoming more available to equine clinicians. However, to date, no studies have prospectively compared this technique to standard B-mode measurement of the combined thickness of the uterus and placenta (CTUP). OBJECTIVES: The objective of the current study was to compare Doppler and B-mode ultrasonography for the detection of experimentally-induced ascending placentitis in mares. METHODS: Eleven healthy pony mares in late gestation were used in this study. Placentitis was induced in 6 mares between Days 280 and 295, while 5 mares served as negative controls. All mares were intensively monitored until delivery. Fetal heart rate, CTUP, uterine artery blood flow (resistance index, pulsatility index, arterial diameter and total arterial blood flow) and physical examination findings were recorded at each examination. Mares with an increased CTUP above published values were treated in accordance with published recommendations. Foals and fetal membranes were examined at birth. Ultrasonographic parameters were compared between groups using ANOVA. Foal viability and histological presence of placentitis were compared using a Fisher's exact test. RESULTS: The CTUP was increased above normal in 5 of 6 inoculated mares within 3 days after inoculation (P = 0.05). The sixth inoculated mare was excluded from subsequent data analysis. Uterine artery blood flow, physical examination findings and fetal heart rate were not different between groups. Gradual increases in CTUP, arterial diameter and total arterial blood flow were detected with increasing gestational age in the control mares (P = 0.02, P = 0.00001 and P = 0.00001, respectively). CONCLUSION: The CTUP, but not uterine blood flow, was different between groups (P = 0.00001). Recorded CTUP values for control pony mares were similar to previously published values for light breed horses.

Pharmacokinetics of carbetocin, a long-acting oxytocin analogue, following intravenous administration in horses.

REASON FOR PERFORMING STUDY: Current therapy protocols to treat persistent post mating endometritis and retained fetal membranes in mares typically include the administration of ecbolic drugs. Evaluation of the pharmacokinetics and tolerability of carbetocin, a long-acting oxytocin analogue, after i.v. administration is required. OBJECTIVES: To determine the pharmacokinetic parameters (principally half-life) of carbetocin in horses. METHODS: Five mature mares and one gelding received 0.175 mg carbetocin i.v. All animals were monitored periodically throughout the study for elevation in rectal temperature, heart rate, respiratory rate and signs of pain or discomfort. Plasma samples were collected for determination of carbetocin concentrations by radioimmunoassay. RESULTS: Administration of carbetocin was well tolerated by all horses and its half-life was 17.2 min. CONCLUSIONS: The half-life of carbetocin is greater than that previously reported for oxytocin (6.8 min). POTENTIAL RELEVANCE: Carbetocin is an attractive alternative to oxytocin therapy in broodmare management.

Pharmacokinetics and endometrial tissue concentrations of enrofloxacin and the metabolite ciprofloxacin after i.v. administration of enrofloxacin to mares.

Enrofloxacin was administered i.v. to five adult mares at a dose of 5 mg/kg. After administration, blood and endometrial biopsy samples were collected at regular intervals for 24 h. The plasma and tissue samples were analyzed for enrofloxacin and the metabolite ciprofloxacin by high-pressure liquid chromatography. In plasma, enrofloxacin had a terminal half-life (t(1/2)), volume of distribution (area method), and systemic clearance of 6.7 +/- 2.9 h, 1.9 +/- 0.4 L/kg, and 3.7 +/- 1.4 mL/kg/min, respectively. Ciprofloxacin had a maximum plasma concentration (Cmax) of 0.28 +/- 0.09 microg/mL. In endometrial tissue, the enrofloxacin Cmax was 1.7 +/- 0.5 microg/g, and the t(1/2) was 7.8 +/- 3.7 h. Ciprofloxacin Cmax in tissues was 0.15 +/- 0.04 microg/g and the t(1/2) was 5.2 +/- 2.0 h. The tissue:plasma enrofloxacin concentration ratios (w/w:w/v) were 0.175 +/- 0.08 and 0.47 +/- 0.06 for Cmax and AUC, respectively. For ciprofloxacin, these values were 0.55 +/- 0.13 and 0.58 +/- 0.31, respectively. We concluded that plasma concentrations achieved after 5 mg/kg i.v. are high enough to meet surrogate markers for antibacterial activity (Cmax:MIC ratio, and AUC:MIC ratio) considered effective for most susceptible gram-negative bacteria. Endometrial tissue concentrations taken from the mares after dosing showed that enrofloxacin and ciprofloxacin both penetrate this tissue adequately after systemic administration and would attain concentrations high enough in the tissue fluids to treat infections of the endometrium caused by susceptible bacteria.

Ovarian follicular development following administration of progesterone or aspiration of ovarian follicles in Holstein cows.

The objective of this study was to compare the effects of administration of a single injection of progesterone (P4) and follicle aspiration on Day 7 of the estrous cycle on the timing and synchrony of follicular wave emergence, time of ovulation, and concentrations of P4, estradiol and FSH in Holstein cows. Twenty cows were assigned to 4 groups (n=5 cows per group) in a 2 by 2 factorial arrangement. Cows were treated on Day 7 (Day 0 = estrus) of the estrous cycle with either sham follicular aspiration and an oil vehicle administered intramuscularly (control), aspiration of ovarian follicles (aspiration), 200 mg of P4 im, or aspiration and 200 mg of P4 im (aspiration + P4). On Day 11, PGF(2alpha)(25mg) was administered to all groups. Synchrony of ovulation was less variable in each of the treatment groups compared with the control group (P<0.05), whereas ovulation was delayed in cows in the P4 group (P<0.05). Day of follicular wave emergence was delayed in the cows of the P4 group compared with cows in the aspiration and aspiration + P4 groups (P<0.01), whereas variability in wave emergence was less among both groups of aspirated cows compared with the cows in the control group (P<0.01). More follicles 4 to 7 mm in diameter were detected in the 2 aspiration groups compared with the cows in the control and P4 group (P<0.05). No difference was detected among groups in the maximum concentration of FSH associated with follicular wave emergence. We conclude that both the administration of P4 and the aspiration of follicles on Day 7 of the estrous cycle improves the synchrony of ovulation when luteolysis is induced on Day 11 and results in similar concentrations of FSH at the time of follicular wave emergence, but the timing of wave emergence and the number of follicles post-emergence differ.

Effects of anti-inflammatory drugs following cataract extraction.

Cycloplegics, corticosteroids, and nonsteroidal anti-inflammatory drugs have been applied in the treatment of postoperative inflammation following cataract extraction. Of these, topical preparations of nonsteroidal anti-inflammatory drugs, such as ketorolac tromethamine 0.5% and diclofenac sodium 0.1%, offer comparable efficacy to corticosteroids in the reduction of postoperative inflammation, and offer lower risks of adverse events in most patients. Comparative studies of these drugs from the past 5 years are highlighted.

Administration of ticarcillin in combination with clavulanic acid intravenously and intrauterinely to clinically normal oestrous mares.

Ticarcillin and clavulanic acid (potassium clavulanate) were administered to normal oestrous mares intravenously (i.v.) at a dose of 50 and 1.67 mg/kg for ticarcillin and clavulanate, respectively. In a crossover design, the same drugs were administered intrauterine (i.u.) at a dose of 12.4 and 0.4 mg/kg for ticarcillin and clavulanate, respectively. The i.u. dose was administered in 100 mL of saline solution. Endometrial tissue biopsies and plasma samples were collected after drug administration for the determination of ticarcillin and clavulanate concentrations by high-pressure liquid chromatography and pharmacokinetic calculations. After i.u. administration both drugs were poorly absorbed into the plasma. The ticarcillin half-life from tissue and plasma was short after i.v. administration. Although concentrations in tissue were higher after i.u. administration than i.v., concentrations of ticarcillin declined rapidly, which would necessitate frequent treatment in order to maintain drug concentrations above the minimum inhibitory concentrations (MIC) throughout the treatment period. Clavulanate concentrations in tissue were either low or persisted for only a short time after administration via either route. It appears that addition of clavulanate to the formulation for treatment of i.u. infections in mares is of questionable value based on these concentrations.

The effect of excimer laser photorefractive keratectomy on intraocular pressure measurements using the Goldmann applanation tonometer.

PURPOSE: The authors determined whether photorefractive keratectomy (PRK) affects Goldmann applanation readings in human eyes. METHODS: The intraocular pressure (IOP) of 111 patients was measured using Goldmann applanation tonometry at baseline and 12 months after PRK. Ultrasonic corneal thickness measurements and keratometry were also obtained. Contralateral eyes were used as controls. RESULTS: There was a statistically significant decrease in mean tonometer readings in the treated eyes when compared with the control eyes (0.5 +/- 2.1 mmHg, P = 0.01) accompanied by a significant reduction in mean central pachymetry in the treated eyes (23 +/- 23 microns, P < 0.001). In the treated eyes, the mean spherical equivalent and mean central keratometry readings were significantly reduced by 3.3 +/- 1.5 and 2.2 +/- 1.2 diopters, respectively (P < 0.001). CONCLUSION: Photorefractive keratectomy causes a mild lowering of the Goldmann tonometer readings. The reduction in IOP measurement is probably not enough to alter a therapeutic decision in an individual patient known to have glaucoma, but it may delay recognition and treatment of glaucoma.

Immunization against growth hormone releasing factor or chronic feed restriction initiated at 3.5 months of age reduces ovarian response to pulsatile administration of gonadotropin-releasing hormone at 6 months of age and delays onset of puberty in heifers.

A severe or moderate suppression of serum insulin-like growth factor I (IGF-I) was induced in heifers, beginning at 104 days of age, by active immunization against growth hormone-releasing factor (GRFi) or by chronic feed restriction (RES), respectively. We hypothesized that reduced serum IGF-I results in decreased serum estradiol-17 beta (E2), which in turn delays onset of puberty. The objectives of this experiment were to determine 1) whether GRFi and RES would alter follicular development and delay onset of puberty through similar mechanisms, and 2) whether GnRH would enhance follicular growth in control, GRFi, and RES heifers at 6 mo of age. Changes in IGF-I, somatotropin, LH, FSH, and E2 were evaluated. Serum IGF-I was greater in control than in RES heifers, and was greater in both these groups than in GRFi heifers by 169 days of age. Basal LH decreased in control and RES but not in GRFi heifers from 136 to 157 days of age. During the same period, a decrease in mean FSH was detected in control but not in GRFi and RES heifers. RES decreased mean serum E2 from 148 to 183 days of age. At 6 mo of age, pulsatile administration of GnRH (5 micrograms every 2 h for 42-46 h) increased serum LH and FSH similarly across treatments but had no effect on the number of follicles > or = 8 mm in GRFi and RES heifers relative to saline treatment. Serum E2 and IGF-I in follicular fluid from follicles > or = 8 mm were increased in all GnRH-treated heifers; however, concentrations of both hormones were lower in GRFi than in control or RES heifers. The main effect of treatments on serum IGF-I was reflected in follicles < or = 7 mm; follicular fluid IGF-I was greater in control than in RES heifers and was greater in both these groups than in GRFi heifers. Serum E2 was lower in RES than in control and GRFi heifers from 253 to 281 days of age. Because of an interaction, E2 was lower in GRFi-GnRH than in control-GnRH heifers but similar in GRFi-saline and control-saline heifers. By 393 days of age, 0% of RES and 32% of GRFi heifers had reached puberty compared to 71% of control heifers. These data support our hypothesis that decreased serum IGF-I results in decreased serum E2. GRFi appears to delay puberty in heifers because decreased serum IGF-I impairs the ovary's ability to synthesize preovulatory concentrations of E2, thereby delaying stimulation of an LH surge. In contrast, RES may delay puberty by delaying follicular development at two stages: a) decreased IGF-I in follicles < or = 7 mm may delay predominant follicular growth, and b) decreased LH may delay maturation of the preovulatory follicle.

Ovarian expression of insulin-like growth factor-I (IGF-I), IGF binding proteins, and growth hormone (GH) receptor in heifers actively immunized against GH-releasing factors.

Active immunization against GRF at 6 months of age delays puberty in beef heifers. The objectives of the present study were to determine whether active immunization against GRF at an earlier age would affect normal onset of puberty and follicular growth and to determine whether these changes were related to alterations in ovarian insulin-like growth factor I (IGF-I) or IGF binding protein (IG-FBP) messenger RNA (mRNA) levels. Heifers were immunized against human serum albumin (HSAi; n = 15) or against GRF conjugated to HSA (GRFi; n = 18) at 3 months of age. A third group of heifers was not immunized (CON; n = 16). Immunization against GRF delayed puberty beyond 13 months of age in 75% of treated heifers. Unilateral ovariectomy at 191 days of age revealed that the delay in puberty was associated with a reduction in the number of large ( > or = 7 mm in diameter) follicles. Large follicles were present in only 22% of GRFi heifers compared to 77% of HSAi heifers. The number of small ( < or = 3 mm in diameter) and medium (4 to 6 mm in diameter) follicles was not affected by GRFi. The percentage of 1- to 3-mm follicles that were atretic was not different between HSAi (65%) and GRFi (62%) heifers. Unilateral ovariectomy had no effect on age at puberty. Immunization against GRF decreased (P < 0.01) concentrations of IGF-I in serum (23 +/- 2 ng/ml) compared to HSAi heifers (109 +/- 11 ng/ml). IGF-I levels in follicular fluid (FFL) of medium and small follicles were also decreased by GRFi from 82 +/- 3 ng/ml in HSAi heifers to 48 +/- 6 ng/ml (P < 0.01). Levels of IGFBP-3 (determined by ligand blot analysis) in serum and FFL of small follicles were decreased by GRFi (P < 0.01). In contrast, IGFBP-2 serum levels were increased from 422 +/- 32 ng/ml in HSAi heifers to 657 +/- 6 ng/ml in GRFi heifers (P < 0.05). Likewise, IGFBP-2 levels in FFL from small and medium follicles were increased from 785 +/- 44 ng/ml to 926 +/- 44 ng/ml (P < 0.05). Ligand blot analysis indicated that IGFBP levels were lower in FFL from large vs. small follicles. The band intensities of IGFBP-4 and -5 were drastically reduced ( > 80%) while the decreases in IGFBP-2 and -3 were less marked ( < 50%). The decreased levels of IGFBP-5 in FFL from large follicles was not associated with an increase in proteolytic fragments detectable by immunoblot analysis. While mRNA transcripts for IGF-I, GH receptor, and IGFBP-2, -3, -4, and -5 were readily detectable in ovarian tissue, GRFi had no effect on ovarian levels of mRNA for each of these proteins. This suggests that the decrease in follicular development associated with GRFi may be related to changes in circulating IGF-I and/or IGFBPs.

Rapidly progressive outer retinal necrosis caused by varicella zoster virus in a patient infected with human immunodeficiency virus.

We describe a 21-year-old immunocompromised patient with a unique type of necrotizing herpetic retinitis. The retinitis progressed with loss of vision when acyclovir or ganciclovir alone was used for treatment. Examination of a chorioretinal biopsy specimen revealed that varicella zoster virus was the causative agent. Foscarnet monotherapy also failed to prevent progression of the retinal infection. Combination antiviral therapy with ganciclovir and foscarnet appeared to delay progression of disease and helped maintain a visual acuity of 20/200 for at least 6 months after the onset of infection.

Does decompression diminish the discomfort of severe dysthyroid orbitopathy?

We assessed whether patients perceived that surgical decompression had reduced the discomfort of dysthyroid orbitopathy. Standard pain instruments were administered to 13 consecutive patients of a university-based oculoplastic practice who had undergone two-wall orbital decompression for dysthyroid optic neuropathy. We used visual analog scale (VAS) ratings of pre- and postoperative orbital discomfort. On a 0 to 10 scale, relief of discomfort after decompression was rated as moderate or better (VAS > 9.0) in 13 of 13 patients (mean VAS = 9.22, SD = 0.91) and complete (VAS = 10.0) in 8 of 13. Patients perceived that surgical decompression was associated with a clinically and statistically significant (p < 0.001) reduction of discomfort.

Effect of somatotropin and/or equine chorionic gonadotropin on serum and follicular insulin-like growth factor I and insulin-like growth factor binding proteins in cattle.

We investigated the effect of administration of somatotropin (ST) and/or eCG on insulin-like growth factor I (IGF-I) and IGF-binding proteins (IGFBP) in serum and follicular fluid (FFL) of cattle actively immunized against growth hormone-releasing factor (GRF). Cyclic beef cattle, previously immunized against GRF-(1-29)-Gly-Gly-Cys-NH2 conjugated to human serum albumin (synthesized and provided by Hoffmann-LaRoche, Inc., Nutley, NJ; GRFi, n = 31) or to human serum albumin alone (HSAi, n = 26), received (i.m.): 1) 25 mg recombinantly derived methionyl somatotropin (rbST, n = 14; sometribove provided by Monsanto Co., St. Louis, MO); 2) 1100 IU eCG (n = 10); 3) rbST and eCG (rbST-eCG, n = 15); or 4) vehicle (VEH, n = 17) at 0 and 24 h after receiving prostaglandin F2 alpha (PGF2 alpha). Serum samples were collected at 0 and 40 h after PGF2 alpha, and the ovary bearing the largest follicle (DOM) was removed 44.0 +/- 0.5 h after PGF2 alpha; FFL was harvested from DOM and the subordinate follicle (SUB). Before treatment (0 h), GRFi cows had lower serum ST (0.6 +/- 0.2 vs. 2.2 +/- 0.2 ng/ml; p < 0.01) and IGF-I (26 +/- 4 vs. 72 +/- 4 ng/ml; p < 0.01), but greater IGFBP-2 (594 +/- 48 vs. 384 +/- 52 ng/ml; p < 0.01) than HSAi cows. Serum and FFL concentrations of IGF-I or IGFBP-2 were not different between rbST- and rbST-eCG-treated cows or between VEH- and eCG-treated cows at Hour 40 after the initial treatment injection; therefore, data were combined and designated as rbST and VEH, respectively. Serum IGF-I was increased to a greater extent (percentage increase above 0 h) by rbST treatment in GRFi (362 +/- 24) than in HSAi (176 +/- 16) cows (immunization by treatment, p < 0.01). Across GRFi and HSAi, rbST lowered serum IGFBP-2 (342 +/- 31 vs. 541 +/- 27 ng/ml, rbST vs. VEH; p < 0.01). Diameters of DOM or SUB were not affected by immunization or treatment. Concentrations of IGF-I and IGFBP-3 (determined by ligand blot analysis) in FFL from both DOM and SUB were lower (p < 0.05) in GRFi than in HSAi cows. In contrast, IGFBP-2 in FFL was elevated in SUB, but not DOM, in GRFi compared to HSAi cows.(ABSTRACT TRUNCATED AT 400 WORDS)

Light distribution of ocular endophotocoagulator probes and its surgical implications.

Ophthalmic endophotocoagulator probe cone angle affects the spot size, working distance, laser output power requirement, tissue exposure time, and uniformity of tissue irradiance, which all affect ease and safety of clinical use. The cone angle and irradiance distribution of several ophthalmic endophotocoagulator delivery systems were studied by directing the laser energy emitted by them on a CCD video sensor at several angles of incidence. The irradiances followed a Gaussian distribution. The measured irradiances were compared to a mathematical model of tissue irradiance that adjusted for the cone angle, probe-tissue distance, and angle of incidence. Using this model, laser irradiances produced by endophotocoagulator probes can be estimated under a wide variety of conditions. At highly oblique angles of incidence, wide-angle probes produce unexpectedly higher and uneven tissue irradiance. When numerous characteristics are considered, probes with a cone angle in the range of 10 degrees have many advantages over narrower or wider angle probes.

Sources of error with use of Goldmann-type tonometers.

There are many sources of error in the use of Goldmann-type applanation tonometers. In clinically normal corneas hypofluorescence of the precorneal tear film, accommodation, the Valsalva maneuver and vertical gaze are preventable causes of large tonometric errors. Repeated tonometry may induce a decline in the intraocular pressure (IOP). Variations in the corneal resistance to indentation between eyes cause significant errors. The most significant cause of error in clinically abnormal eyes is corneal epithelial edema, which causes a marked underestimation of IOP. Measurements obtained with Goldmann-type tonometers can be used with confidence to monitor changes in the IOP of an individual, but should not be relied on to determine the absolute manometric pressure within an eye or to compare the IOPs in eyes of different individuals.

The effect of corneal thickness on applanation tonometry.

Simultaneous manometry and Perkins tonometry were performed at 10.0, 20.0, and 30.0 mm Hg on 15 eyes on which intraocular procedures were performed. There was a statistically significant relationship between corneal thickness and the error of Perkins tonometry. Thin corneas produced underestimations of the intraocular pressure by as much as 4.9 mm Hg, whereas thick corneas produced overestimations by as much as 6.8 mm Hg. Measuring the corneal thickness is necessary to interpret properly the results of Goldmann applanation tonometry, particularly in eyes with thin corneas.

Phase I and pharmacokinetic trial of liposome-encapsulated doxorubicin.

A total of 21 patients with advanced cancer were entered into a phase I study to determine the maximum tolerable dose (MTD) of liposome-encapsulated doxorubicin (LED) given weekly for 3 consecutive weeks at doses of 20, 30, or 37.5 mg/m2 per week. For a comparison of the pharmacokinetic behavior of LED with that of standard-formulation doxorubicin, 13 patients received a dose of standard-formulation doxorubicin 2 weeks prior to the first dose of LED. All doses were given by 1-h infusion through a central vein. Toxicity was evaluated in 22 courses delivered to 17 patients. The MTD with this schedule was 30 mg/m2 per week x 3. The single patient treated at 37.5 mg/m2 weekly could not complete the entire course due to myelosuppression. At the dose of 30 mg/m2 per week, three of eight patients had grade > or = 3 leukopenia. Other toxicities included mild to moderate thrombocytopenia, nausea, vomiting, fever, alopecia, diarrhea, fatigue, stomatitis, and infection. At the dose of 30 mg/m2 per week, the total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 8.75 +/- 8.80 microM h (mean +/- SD) and 3.07 +/- 1.45 microM, respectively, after LED administration. The total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 3.92 +/- 2.47 microM h and 2.75 +/- 2.70 microM, respectively, after the infusion of standard-formulation doxorubicin. The total body clearance of doxorubicin was 18.42 +/- 11.23 l/h after the infusion of LED and 31.21 +/- 15.48 l/h after the infusion of standard-formulation doxorubicin. The mean elimination half-lives of doxorubicin were similar: 8.65 +/- 5.16 h for LED and 7.46 +/- 5.16 h for standard-formulation doxorubicin. Interpatient variability in pharmacokinetic parameters as demonstrated by the percentage of coefficients of variation was 33%-105%. There was no relationship between the percentage of WBC decrease or the duration of WBC suppression and the total doxorubicin or doxorubicinol AUC. There was no correlation between the duration of leukopenia and drug exposure as reflected by the AUC of liposome-associated doxorubicin. LED can be given in doses similar to those of standard-formulation doxorubicin and produces acute toxicities similar to those caused by standard doxorubicin.