A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis.

BACKGROUND: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms. AIM: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis. METHODS: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint. RESULTS: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions. CONCLUSION: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study.

BACKGROUND: PF-04965842 is an oral Janus kinase 1 inhibitor being investigated for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate-to-severe plaque psoriasis. METHODS: Patients in this phase II, placebo-controlled study (NCT02201524) were randomized to receive placebo, 200 mg once daily (OD), 400 mg OD or 200 mg twice daily (TD) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. RESULTS: Fifty-nine patients were randomized and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active -placebo PASI change from baseline) and 90% confidence interval at week 4 was -5·1 (-9·2 to -1·0), -5·6 (-9·6 to -1·6) and -10·0 (-14·2 to -5·8) for the 200 mg OD, 400 mg OD and 200 mg TD groups, respectively. At week 4, the proportion of patients achieving PASI 75 was 17% for the placebo and 200 mg OD groups, 50% for the 400 mg OD group and 60% for the 200 mg TD group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg TD group compared with the OD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. CONCLUSIONS: These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.

Skin cancers in skin types IV-VI: Does the Fitzpatrick scale give a false sense of security?

The Fitzpatrick scale has been in use for skin colour typing according to the tanning potential of skin since its inception in 1975-1976. Thomas Fitzpatrick developed the scale to classify persons with 'white skin' in order to select the correct amount of UVA in Joules/cm2 for PUVA treatment for psoriasis. Since then, it has been widely used in Dermatology to gauge the skin's reaction to UV exposure, tanning potential, assessment of sunburn risk and amount of sun protection required for individual patients. However, the use of this scale has been of limited utility because of different self-perception in different areas of the world, particularly among those with skin of colour. Skin cancer risk is loosely inversely correlated with the initial genetic/inherent amount of melanin (most research has focused on eumelanin) present in the skin, although the pattern of exposure and amount of UV radiation required causing DNA damage varies widely according to different cancers. In this review, we have shown that the Fitzpatrick scale is neither correct nor adequate to reflect sunburn and tanning risk for skin of colour. Therefore, it may give both patients and physicians a false sense of security that there is little risk that people of colour can develop skin cancers. We have reviewed the small but not insignificant risk of skin of colour developing skin cancers and emphasise that there remains much research that needs to be done in this field.

Covid-19 dermatoses: Acral vesicular pattern evolving into bullous pemphigoid.

Bullous pemphigoid (BP) appears to be rising in incidence across the Western World, especially in the elderly. Some of the pathogenetic mechanisms involving antigen mimicry and antibody cross-reactivity have been elucidated for cases associated with neurological disease and certain drugs. There have been reports of cutaneous manifestations of Covid-19 (SARS-Cov2 infection) as the pandemic has raged across the world. We report here a case of prolonged Covid-19, symptomatic with dermatoses only, which was seen to evolve initially from a maculo-papular exanthema with acral vesicular dermatitis, into classical BP disease. This was confirmed histologically by positive skin autoantibody serology, direct IMF on peri-lesional skin and also salt-split IMF. Although possible that the development of BP could be a purely co-incidental finding during Covid-19, we suggest that it is more likely that prolonged SARS-Cov2 infection triggered an autoimmune response to the basement membrane antigens, BP 180 and 230. To our knowledge, this is the first case of BP developing during concurrent Covid-19 disease. It will be necessary to continue dermatological surveillance as the pandemic continues, to collate data on BP incidence and to test these patients for Covid-19 disease. As the pandemic continues, even potential and rare associations such as this will be clarified eventually. What's already known about this topic? Covid-19 disease has been associated with a spectrum of dermatosesCommon presentations in up to 20% of patients include exanthema, pseudo-chilblain like acral lesions 'Covid toes', livedo-/retiform purpuric/necrotic vascular lesions, acute urticarial lesions, and vesicular/varicella-like lesionsA multi-system inflammatory syndrome in children akin to Kawasaki syndrome has been described What does this study add? To our knowledge, this is the first description of classic Bullous Pemphigoid evolving from vesicular lesions caused by prolonged SARS-Cov2 induced skin inflammation.

Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive.

The effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive containing 30 micrograms ethinyl estradiol and 75 micrograms gestodene were assessed in a randomized, double-blind, placebo-controlled parallel-group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg/day felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration-time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during felbamate treatment.

Effects of felbamate on the pharmacokinetics of phenobarbital.

The effects of felbamate on the pharmacokinetics of phenobarbital and one of its main metabolites, parahydroxyphenobarbital, were assessed in a parallel-group, placebo-controlled, double-blind study, in 24 healthy volunteers. Pharmacokinetic parameters of phenobarbital and parahydroxyphenobarbital were determined from plasma and urine samples obtained after 28 days of daily administration of 100 mg phenobarbital and after a further 9 days of phenobarbital plus 2400 mg/day felbamate or placebo. Felbamate increased phenobarbital values for area under the plasma concentration-time curve from 0 to 24 hours and maximum concentration by 22% and 24%, respectively, whereas placebo had no effect. This increase was caused by a reduction in parahydroxylation of phenobarbital and possibly through effects on other metabolic pathways. Because felbamate inhibits the S-mephenytoin hydroxylase (CYP2C19) isozyme in vitro, it appears that phenobarbital hydroxylation is mediated in part by this isozyme.

Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine.

The effects of felbamate on the multiple dose pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine were assessed in a placebo-controlled, randomized, double-blind crossover study in 18 healthy male volunteers. Oxcarbazepine, 1200 mg/day, was administered on an open basis in combination with double-blind placebo or 2400 mg/day felbamate for two 10-day treatment periods separated by a 14-day washout period. Pharmacokinetic parameters of monohydroxyoxcarbazepine and dihydroxyoxcarbazepine were determined from plasma and urine samples obtained on the tenth day of each treatment period. Felbamate had no effect on monohydroxyoxcarbazepine plasma or urine pharmacokinetics compared with placebo, but it significantly increased values for dihydroxyoxcarbazepine maximum concentration and area under the curve from 0 to 12 hours, as well as urinary excretion of free and total dihydroxyoxcarbazepine. The mechanism that may account for the observations is the induction of oxidative metabolism of monohydroxyoxcarbazepine. Despite these changes, the relative amount of dihydroxyoxcarbazepine is small in comparison to monohydroxyoxcarbazepine, and antiepileptic activity is associated with monohydroxyoxcarbazepine rather than dihydroxyoxcarbazepine. Therefore we conclude that felbamate has no clinically relevant effects on the pharmacokinetics of oxcarbazepine in humans.

Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation.

This article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with epilepsy and healthy individuals, and in vitro studies which identified the cytochromes P450 (CYP) inhibited by felbamate and those involved in its metabolism. In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions. Felbamate has been shown in vitro to inhibit CYP2C19, which would account for its effect on phenytoin clearance, and it had been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by felbamate. Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. Interactions involving felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in valproic acid (valproate sodium) clearance by felbamate is through the inhibition of beta-oxidation. No clinically relevant pharmacokinetic interactions were noted between felbamate and lamotrigine, clonazepam, vigabatrin, nor the active monohydroxy metabolite of oxcarbazepine. Information on the mechanisms underlying felbamate's drug:drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.

Effect of felbamate on the pharmacokinetics of lamotrigine.

To assess the possible interaction between lamotrigine and felbamate, a double-blind, randomized, placebo-controlled, two-way crossover study was conducted in 21 healthy male volunteers. Volunteers were given lamotrigine (100 mg every 12 hours) and felbamate (1,200 mg every 12 hours) or matching placebo for 10 days during each period of the crossover. After morning administration on day 10, blood samples were obtained over 12 hours for measurement of lamotrigine. Felbamate increased the maximum concentration (Cmax) and and area under the concentration-time curve from time 0 to 12 hours (AUC0-12) of lamotrigine by 13% and 14%, respectively, compared with placebo. The 90% confidence intervals of the log-transformed pharmacokinetic parameters were within the 80-125% bioequivalance limits, however. Felbamate had no significant effect on the urinary excretion of lamotrigine (total), unconjugated lamotrigine, or the N-glucuronide. One volunteer discontinued the study after developing a rash while taking lamotrigine and placebo. All other adverse events were primarily related to the central nervous system and gastrointestinal tract, with a higher incidence reported during coadministration of lamotrigine and felbamate than with placebo. Overall, felbamate appears to have no clinically relevant effects on the pharmacokinetics of lamotrigine.

The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children aged 2 to 5 years.

OBJECTIVE: We assessed the pharmacokinetics and tolerability of 5 mg loratadine syrup (1 mg/mL) in children aged 2 to 5 years. METHODS: Two studies were undertaken. A single-dose, open-label bioavailability study was performed to characterize the pharmacokinetic profiles of loratadine and its metabolite desloratadine. Plasma concentrations of loratadine and desloratadine were determined at 0, 1, 2, 4, 8, 12, 24, 48, and 72 hours after a single administration of 5 mg loratadine syrup to 18 healthy children (11 male, 7 female; 12 black, 5 white, 1 other; mean age +/- SD, 3.8 +/- 1.1 years; mean weight +/- SD, 17.4 +/- 4.4 kg). In addition, a randomized, double-blind, placebo-controlled, parallel-group study was performed to assess the tolerability of 5 mg loratadine syrup after multiple doses. Loratadine (n = 60) or placebo (n = 61) was given once daily for 15 days to children with a history of allergic rhinitis or chronic idiopathic urticaria. In the loratadine group, 27 boys and 33 girls (52 white, 8 black) were enrolled, with a mean age +/- SD of 3.67 +/- 1.13 years and a mean weight +/- SD of 17.2 +/- 3.8 kg. In the placebo group, 27 boys and 34 girls (53 white, 7 black, 1 Asian) were enrolled, with a mean age +/- SD of 3.52 +/- 1.12 years and a mean weight +/- SD of 17.3 +/- 2.9 kg. Tolerability was assessed based on electrocardiographic results, occurrence of adverse events, changes in vital signs, and results of laboratory tests and physical examinations. RESULTS: The peak plasma concentrations of loratadine and desloratadine were 7.78 and 5.09 ng/mL, respectively, observed 1.17 and 2.33 hours after administration of loratadine; the areas under the plasma concentration-time curve to the last quantifiable time point for loratadine and desloratadine were 16.7 and 87.2 ng x h/mL, respectively. Single and multiple doses were well tolerated, with no adverse events occurring with greater frequency after multiple doses of loratadine than after placebo. Electrocardiographic parameters were not altered by loratadine compared with placebo. There were no clinically meaningful changes in other tolerability assessments. CONCLUSION: Loratadine was well tolerated in this small, selected group of children aged 2 to 5 years at a dose providing exposure similar to that with the adult dose (ie, 10 mg once daily).

Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study.

BACKGROUND: Significant cardiac toxicity has been associated with some older antihistamines (eg, terfenadine and astemizole) when their plasma concentrations are increased. There is thus a need for a thorough assessment of the cardiac safety of newer antihistamine compounds. OBJECTIVE: This study was undertaken to assess the effects of coadministration of desloratadine or fexofenadine with azithromycin on pharmacokinetic parameters, tolerability, and electrocardiographic (ECG) findings. METHODS: Healthy volunteers aged 19 to 46 years participated in this randomized, placebo-controlled, parallel-group, third-party-blind, multiple-dose study. Subjects received desloratadine 5 mg once daily, fexofenadine 60 mg twice daily, or placebo for 7 days. An azithromycin loading dose (500 mg) followed by azithromycin 250 mg once daily for 4 days was administered concomitantly starting on day 3. Group 1 received desloratadine and azithromycin, group 2 received desloratadine and placebo, group 3 received placebo and azithromycin, group 4 received fexofenadine and azithromycin, and group 5 received fexofenadine and placebo. RESULTS: The results of the pharmacokinetic analysis revealed little change in mean maximum concentration (Cmax) and area under the concentration-time curve (AUC) values for desloratadine with concomitant administration of azithromycin: Cmax ratio, 115% (90% CI, 92-144); AUC, ratio 105% (90% CI, 82-134). The corresponding ratios for 3-hydroxydesloratadine were 115% (90% CI, 98-136) and 104% (90% CI, 88-122), respectively. A substantial increase was observed in mean Cmax and AUC values for fexofenadine when administered with azithromycin: Cmax, ratio, 169% (90% CI, 120-237); AUC ratio, 167% (90% CI, 122-229). Compared with the group receiving desloratadine and azithromycin, subjects receiving fexofenadine and azithromycin also displayed greater variability in pharmacokinetic parameters for the antihistamine. Mean Cmax and AUC values of azithromycin were slightly higher when administered with desloratadine (Cmax ratio, 131% [90% CI, 92-187]; AUC ratio, 112% [90% CI, 83-153]) but were lower when given in combination with fexofenadine (Cmax ratio, 87% [90% CI, 61-124]; AUC ratio, 88% [90% CI, 65-1201). The most common adverse event for all regimens was headache, reported in 20 (22%) subjects. All combinations of desloratadine or fexofenadine with and without azithromycin were well tolerated, and no statistically significant changes in PR, QT, or QT, interval, QRS complex, or ventricular rate were observed. CONCLUSIONS: Small increases (<15%) in mean pharmacokinetics of desloratadine were observed with coadministration of azithromycin. By contrast, peak fexofenadine concentrations were increased by 69% and the AUC was increased by 67% in the presence of the azalide antibiotic. Based on the reported adverse-events profile and the absence of changes in ECG parameters, the combination of desloratadine and azithromycin was well tolerated. This study suggests that desloratadine has a more favorable drug-interaction potential than does fexofenadine.

Effect of Felbamate on The Pharmacokinetics of Clonazepam.

To assess the possible interaction between clonazepam and felbamate, a double-blind, randomized, placebo-controlled, two-way crossover study was conducted in 18 healthy male volunteers. Volunteers were administered clonazepam (1 mg q12h) and felbamate (1200 mg q12h) or matching placebo for 10 days during each period of the crossover. Following morning dosing on day 10, blood samples were obtained over 12 h for the determination of clonazepam and the metabolites 7-amino-clonazepam and 7-acetamido-clonazepam. Felbamate increased clonazepam's C(max) and AUC(0--12 h) by 17% and 14%, respectively (p < 0.01). The 90% confidence intervals following log-transformation for each of these pharmacokinetic parameters were within the generally accepted interval (80--125%) for bioequivalence. Felbamate had no significant effect on the pharmacokinetics of 7-amino-clonazepam, whereas 7-acetamido-clonazepam concentrations were below the limit of quantification in all but one subject. Adverse events were mainly central nervous system in nature, with a greater incidence reported during coadministration with felbamate compared with placebo. Overall, felbamate appears to have no clinically relevant effects on the pharmacokinetics of clonazepam.

Stereospecific high-performance liquid chromatographic analysis of warfarin in plasma.

A stereospecific high-performance liquid chromatographic assay has been developed to determine R(+)- and S(-)-warfarin simultaneously in plasma. The method involved the formation of diastereoisomeric esters, using carbobenzyloxy-L-proline, with subsequent separation using silica as the stationary phase. The method permits characterization of the pharmacokinetics of warfarin enantiomers following administration of racemic drug.

Stereospecific fluorescence high-performance liquid chromatographic analysis of warfarin and its metabolites in plasma and urine.

A stereospecific assay for the simultaneous determination of the enantiomers of warfarin and its major metabolites, 6- and 7-hydroxywarfarin and warfarin alcohols, in plasma and urine was developed. Involved in this determination was the formation of diastereoisomeric esters with carbobenzyloxy-L-proline, separation by normal-phase high-performance liquid chromatography, and detection by fluorescence after postcolumn aminolysis with n-butylamine. The determination limit for any enantiomer is in the order of 50-100 ng. The method was applied to the analysis of the enantiomers of warfarin and metabolites in plasma and urine of human subjects receiving racemic drug. The results for warfarin enantiomers are comparable with those obtained by an MS method, involving administration of a synthetic pseudoracemate [12C(R), 13C(S)]warfarin. In addition to all known metabolites, the detection of 7-R-hydroxywarfarin indicates that 7-hydroxylation is stereoselective rather than stereospecific.

Application of a variance-stabilizing transformation approach to linear regression of calibration lines.

A variance-stabilizing transformation (VST) was applied to the linear regression of calibration standards of different drugs in plasma. This transformation involved the normalization of the dependent variable peak height or peak area ratio (Y), and the independent variable, plasma drug concentration (C). This transformation led to a constant variance in the regression error term across the measured concentration range and allowed the evaluation of the unbiased slope and y intercept with minimum variance. The utility of the VST procedure in comparison with the ordinary least squares (OLS) approach, routinely used in pharmaceutical studies for constructing calibration lines, is described. The principal advantage of the VST approach is allowing a lower minimum level of drug quantification while using a single calibration line over a wide range of drug concentrations. The VST method is especially useful to quantify drug plasma levels in pharmacokinetic evaluation of sustained-release dosage forms, where the precise quantification of low levels of drug is critical. The application of the VST method was explored and evaluated in comparison with the OLS method for pharmacokinetic assays of diltiazem, gallopamil, nitroglycerin, and nicotine.

Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study.

Posaconazole is an antifungal with a wide-spectrum of activity against common and emerging fungal pathogens. In this randomised, open-label, two-way crossover study, the potential for drug interactions with posaconazole via the cytochrome P450 (CYP450) enzyme pathway was evaluated. Thirteen subjects received posaconazole tablets (2 x 100 mg) once daily for 10 days or no treatment; following a 14-day washout period, subjects were crossed over to the alternate treatment. The inhibition spectra of posaconazole were examined using a cocktail of the following probe substrates: caffeine (CYP1A2), tolbutamide (CYP2C8/9), dextromethorphan (CYP2D6 and total CYP3A4), chlorzoxazone (CYP2E1), and midazolam (hepatic CYP3A4). Except for midazolam, which was intravenously infused on Day 10, the cocktail probes were administered simultaneously on Day 9 during both treatment periods. Blood and urine samples were collected at specified times to quantitate probe substrates and/or metabolites. Based on insignificant differences in mean probe ratios, posaconazole did not inhibit CYP1A2, 2C8/9, 2D6, or 2E1. However, the midazolam AUC((tf)) was higher in the posaconazole than no-treatment group (93.4 n gh/ml versus 51.4 ng h/ml, P<0.01), indicating inhibition of hepatic CYP3A4. Drug interactions mediated by various CYP450 are common with the currently available triazole antifungals, however these results suggest that posaconazole may have an improved and more narrow drug interaction profile (CYP3A4 only) compared with other triazoles.

Association between postoperative outcome and results of magnetic resonance imaging and computed tomography in working dogs with degenerative lumbosacral stenosis.

OBJECTIVE: To determine whether results of magnetic resonance imaging (MRI) and computed tomography (CT) are associated with postoperative outcome in working dogs with degenerative lumbosacral stenosis. DESIGN: Prospective cohort study. ANIMALS: 12 dogs treated surgically for degenerative lumbosacral stenosis. PROCEDURE: The lumbosacral vertebral column was examined before surgery by use of MRI and CT and after surgery by use of CT. Outcome, based on performance in standardized training exercises, was assessed 6 months after decompressive surgery. Associations between imaging results and postoperative outcome were determined by use of a Fisher exact test and logistic regression. RESULTS: None of the dogs were able to perform their duties before surgery. By 6 months after surgery, 8 of 12 dogs had been returned to full active duty. Nerve tissue compression was effectively localized by use of CT and MRI. Significant associations between results of imaging studies and postoperative outcome were not identified. CONCLUSIONS AND CLINICAL RELEVANCE: Surgical intervention is justified in high-performance working dogs with degenerative lumbosacral stenosis. However, results of imaging studies may be less important than clinical or surgical factors for predicting outcome in affected dogs.

Hepatozoonosis in dogs: 22 cases (1989-1994).

OBJECTIVE: To document hepatozoonosis in dogs from Alabama and Georgia and to report associated clinical signs, method of diagnosis, response to treatment, and course of disease. DESIGN: Retrospective case series. ANIMALS: 22 dogs in which Hepatozoon canis was identified by microscopic examination of skeletal muscle. PROCEDURE: We reviewed medical records of all dogs with a definitive diagnosis of hepatozoonosis that were referred to the Auburn University Small Animal Clinic between 1989 and 1994. RESULTS: Diagnoses were confirmed by microscopic identification of H canis schizont or merozoite stages in skeletal muscle. The gametocyte stage was not detected in smears of blood obtained from a peripheral vein, buffy-coat smears, or bone marrow evaluation. Common clinical signs included fever, cachexia, ocular discharge, pain, stiffness, and paresis. Laboratory abnormalities included marked leukocytosis, hypoglycemia, hypoalbuminemia, mild anemia, hyperphosphatemia, and high alkaline phosphatase activity. Periosteal bone proliferation was evident radiographically in 18 of 22 dogs. Renal lesions included amyloidosis (1 dog), interstitial nephritis (3), and mesangioproliferative glomerulonephritis (4). Treatment with the anticoccidial drug toltrazuril, despite an initial favorable response, failed to prevent relapse in all but 3 of 21 treated dogs. Mean survival time was 12.6 +/- 2.2 months, with a mean time of remission before recurrence of clinical signs of 6 months. CLINICAL IMPLICATIONS: H canis infection in dogs can be associated with a distinct clinical syndrome that involves chronic myositis, debilitation, and death. The dogs of this report represent the first substantial number of domestic dogs naturally infected with H canis in the United States outside of the Texas Gulf Coast. Hepatozoon canis appears to be a serious pathogen in the United States that is becoming more widespread geographically.