Hemilaminectomy and vertebral stabilisation for the treatment of thoracolumbar disc protrusion in 28 dogs.

OBJECTIVES: To evaluate the results of hemilaminectomy and vertebral stabilisation (+/- annulectomy) for the treatment of thoracolumbar disc protrusion. METHODS: The medical records of dogs with thoracolumbar annular protrusions treated by hemilaminectomy and vertebral stabilisation were reviewed. Neurological function was assessed 24 hours following surgery. Long-term follow-up was by clinical examination or telephone questionnaire. RESULTS: Twenty-eight dogs fulfilled the criteria. Age ranged from 4 to 12.5 years (median 8 years, mean 7.7 years), bodyweight from 5.1 to 51.5 kg (median 28 kg, mean 27.1 kg), and duration of neurological signs before presentation from 48 hours to 104 weeks (median 5 weeks, mean 9.3 weeks). At presentation 22 dogs were ambulatory and six were non-ambulatory. Myelography and/or magnetic resonance imaging (MRI) identified 31 thoracolumbar protrusions causing spinal cord compression. Unilateral hemilaminectomy was performed in 27 dogs and bilateral hemilaminectomy in one dog. Partial annulectomy was performed in 24 of 31 protrusions. Stabilisation was performed using vertebral body bone plates in 26 dogs and vertebral body screws and bone cement in two dogs. Internal vertebral venous plexus haemorrhage was recorded in nine dogs. A screw was inadvertently placed into an intervertebral disc in two dogs. Neurological examination 24 hours postoperatively revealed deterioration in pelvic limb motor function in 17 dogs. One dog was euthanatised at the owner's request 6 days after surgery. Long-term evaluation of 24 cases was performed 3 to 52 months following surgery (median 21 months, mean 23.9 months). Six dogs had improved from their preoperative status and one had deteriorated as assessed by the authors. Fifteen dogs had improved from their preoperative status and two were unchanged as assessed by owners. CLINICAL SIGNIFICANCE: Hemilaminectomy and vertebral stabilisation are an effective treatment for chronic spinal cord compression due to thoracolumbar annular protrusion in dogs. A temporary deterioration in neurological function is not uncommon following surgery. Internal vertebral plexus haemorrhage and inappropriate vertebral body screw placement are potential complications.

The value of oblique versus ventrodorsal myelographic views for lesion lateralisation in canine thoracolumbar disc disease.

OBJECTIVE: To determine the value of oblique versus ventrodorsal myelographic views for lesion lateralisation in canine thoracolumbar disc disease. METHODS: The ventrodorsal and oblique views from 196 lumbar myelograms of dogs with single thoracolumbar disc extrusions or protrusions were blindly and independently reviewed by two of the authors for evidence of lesion lateralisation. Medical records were reviewed for details regarding hemilaminectomy surgery. The side (left versus right) of the surgery and whether or not the disc material was retrieved were noted. RESULTS: Both reviewers lateralised significantly more disc lesions from the oblique views (93 and 95 per cent) than from the ventrodorsal views (59 and 70 per cent) (P<0.001). Using a combination of oblique and ventrodorsal views, 194 (99 per cent) and 195 (99.5 per cent) lesions were lateralised. Unilateral hemilaminectomy was performed in 193 dogs with myelographic lateralisation and in one dog without myelographic lateralisation. The side of spinal cord decompression corresponded with the myelographic findings in all dogs showing lateralisation on myelography. In the dog without myelographic lateralisation, a left (randomly chosen) hemilaminectomy revealed dorsal protrusion of the annulus fibrosus. CLINICAL SIGNIFICANCE: Myelography, including oblique, ventrodorsal and lateral views, is an accurate method for determining lateralisation of extruded or protruded disc material in the vertebral canal before decompressive surgery. Combined oblique and ventrodorsal views are more useful than either view alone and should be routinely obtained in all lumbar myelographic studies when investigating thoracolumbar disc disease.

Patellar luxation in 70 large breed dogs.

OBJECTIVES: To report the signalment, history, clinical features, and outcome in dogs weighing greater than 15 kg, treated surgically and non-surgically for patellar luxation. Risk factors for the development of patellar luxation, postoperative complications, and outcome were evaluated. METHODS: Details regarding signalment, bodyweight, breed, aetiology, unilateral or bilateral luxation, duration of lameness, grade of luxation, direction of luxation, grade of lameness at presentation, concomitant cranial cruciate ligament rupture, method of treatment, surgical technique, surgeon, and complications were obtained from the medical records. Outcome was graded as excellent, good, fair, or poor, according to the degree of lameness. RESULTS: Seventy dogs (45 males and 25 females) were included. Thirty-five had bilateral luxations (105 limbs). Mean age was two years, and mean weight was 30 kg. The relative risk for Labrador retrievers was 3.3 (P<0.001). All luxations were developmental. Luxations were medial in 102 stifles and lateral in three. Fourteen stifles had concomitant cranial cruciate ligament rupture. As the grade of patellar luxation increased, so did the grade of lameness (P<0.001). Surgery was performed in 70 stifles, and outcome was excellent/good in 94 per cent and fair/poor in 6 per cent of stifles. Complications occurred in 29 per cent of stifles, and increasing bodyweight was found to be a risk factor (P=0.03). Thirty-five stifles were managed non-surgically, and outcome was excellent/good in 86 per cent and fair/poor in 14 per cent of stifles. CLINICAL SIGNIFICANCE: In view of the potential risk of postoperative complications, all surgically treated cases of patellar luxation in large breed dogs should be managed with a femoral trochleoplasty, a tibial tuberosity transposition (stabilised with K-wires and a tension band wire), and soft tissue releasing and tightening procedures.

Y-T humeral fractures with supracondylar comminution in five cats.

Five cats with Y-T fractures of the humeral condyle were reviewed. Breeds presented included domestic shorthair (four cats) and Maine Coon (one cat). Age ranged from two to 16 years. All the cats were neutered males. A road traffic accident was suspected in all cases. Four of the fractures were severely comminuted and one fracture had four fragments. The fractures were repaired via combined medial and lateral approaches. Fixation of the epicondylar ridges was performed using buttress plates in four cases and neutralisation plates in one case. The intracondylar fracture was stabilised using a 2.7 mm lag screw in four cases and a 3.5 mm lag screw in the other. A corticocancellous bone graft was applied in two cases. The intracondylar fracture was accurately reduced in all cases. Complete radiographic healing was documented in two cases 6 and 11 weeks following surgery. Failure of the fixation occurred in the most severely comminuted fracture five days postoperatively. Surgical revision was not performed, and the limb was amputated. Three cats were free of lameness and had resumed outdoor activities at follow-up (five to eight months after surgery). Marked lameness due to loss of elbow movement was observed in the other case.

The use of therapeutic drug monitoring in the management of protease inhibitor-related toxicity.

The aim of this project was to determine whether therapeutic drug monitoring (TDM) and subsequent dose modification is effective in the management of protease inhibitor (PI)-associated toxicity. A retrospective case-notes review of patients who had had TDM for suspected antiretroviral drug toxicity from November 2000 to March 2002 was carried out. This identified six symptomatic patients in whom high plasma drug levels of a PI had been found and subsequent dose modification was associated with improvement/resolution of symptoms. In 5/6 patients viral loads were below the level of detection prior to TDM and remained so after dose reduction of PI. TDM-directed dose modification of PI enables patients to continue effective regimens of highly active antiretroviral therapy, thus avoiding the need to switch the regimen.

Spontaneous healing of a trophic ulcer of the metatarsal pad in a dog.

A two-year-old whippet cross presented with a large ulcer of the right metatarsal pad. Laceration of the plantar aspect of the metatarsal region involving the flexor tendons had occurred 10 days prior to ulcer formation. Pain sensation was absent distal to the wound, indicating tibial nerve damage. A presumptive diagnosis of trophic ulceration of the metatarsal pad secondary to tibial nerve injury was made. Sensory nerve function returned within 14 weeks and the trophic ulcer subsequently healed. Spontaneous resolution of trophic ulceration has been reported in humans but, to the authors' knowledge, not in dogs.

Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users.

Administration of nevirapine to HIV-infected injection drug users who also receive methadone results in a significant reduction in methadone exposure after 7-10 days of therapy. Many patients require an increase in methadone dose to counteract this effect.

Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir.

Variable drug penetration of antiretroviral drugs into the genital tract may contribute to the differential evolution of HIV and the emergence of drug resistance. This, in turn, may have an impact on the sexual transmission of resistant HIV in patients treated with antiretroviral drugs. We have measured concentrations of the HIV-1 protease inhibitors indinavir, ritonavir and saquinavir in the blood plasma (BP) and seminal plasma (SP) of 23 HIV-1-positive men. Forty-five time-matched blood and semen samples were obtained. SP concentrations of indinavir exceeded the EC95 of indinavir, corrected for protein binding, of 42 ng/mL at all time intervals. In contrast, the median ritonavir and saquinavir SP concentrations were below the relevant EC95 at all times post drug ingestion. The median SP:BP concentration ratios for indinavir were 0.6, 0.8 and 1.4, respectively, at 0-2, 2-6 and 6-8 h post-drug ingestion. In contrast, the median SP:BP concentration ratios at 0-3, 3-9 and 9-12 h post-drug ingestion were <0.02, <0.04 and <0.04, respectively, for both ritonavir and saquinavir. These differences justify further study of HIV-1 evolution and development of resistance in the genital tract of men taking these anti-HIV drugs.

The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz.

AIMS: Methadone is predominantly metabolized by cytochrome P450 3A4 and the non nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is a recognized inducer of this enzyme. We evaluated the pharmacokinetics of methadone in the presence and absence of efavirenz when administered to HIV infected patients with a history of injection drug use (IDU). METHODS: Eleven patients on stable methadone maintenance therapy, due to commence antiretroviral therapy (ART), participated in this study. Steady state methadone kinetic profiles were obtained on two occasions 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h post dosing. Following centrifugation, separated plasma was heated at 58 degrees C for 30 min to inactivate HIV and stored at -80 degrees C until methadone analysis by high performance liquid chromatography. RESULTS: When combined with efavirenz there was a marked decrease in the maximum plasma concentration (Cmax) of methadone from 689 (range 212-1568) to 358 (range 205-706) ng ml(-1), P = 0.007 : 95% confidence interval (CI) 112-549. The mean area under the methadone concentration curve 0-24 h (AUC(0,24 h)) was also significantly reduced from 12341 (range 3682-34147) to 5309 (range 2430-10349) ng ml(-1) h in the presence of efavirenz, P = 0.012 : 95% CI 1921-12143. Nine patients described symptoms of methadone withdrawal and received a dose increase. Although methadone AUC(0,24 h) was reduced by over 50% following efavirenz the mean increase in methadone dose required was 22% (range 15-30 mg). CONCLUSION: The inclusion of the NNRTI efavirenz in once daily ART for HIV patients with a history of IDU receiving methadone maintenance results in a significant reduction in methadone plasma concentrations mediated by enzyme induction. It is important to distinguish efavirenz neurological effects which were observed between days 1-5 of therapy from symptoms of methadone withdrawal which occurred from day 8 onwards. The dose of methadone was adjusted by increments of 10 mg to counteract the efavirenz inducing effect.

Zidovudine phosphorylation determined sequentially over 12 months in human immunodeficiency virus-infected patients with or without previous exposure to antiretroviral agents.

We sought to determine whether the intracellular activation of zidovudine (ZDV) varied over time and with previous antiretroviral exposure in human immunodeficiency virus-infected individuals and to examine whether there is an association between virological responses and intracellular phosphorylation. A total of 23 patients (12 treatment naïve, 11 previously treated with ZDV) who commenced ZDV as part of dual nucleoside therapy were prospectively monitored for 12 months or until withdrawal from the study. No association was observed between virological responses at 2 weeks and 3 months and ZDV phosphorylation. The mean intracellular concentrations of ZDV mono-, di-, and triphosphates did not change significantly over time or with previous ZDV exposure. The rate of formation of total ZDV phosphates was increased in patients with CD4 counts <100 cells/mm(3). Previous reports from in vitro cell culture experiments or cross-sectional cohort studies suggesting alterations of ZDV phosphorylation over time are not confirmed by this longitudinal study.

Pharmacokinetics of zidovudine phosphorylation in human immunodeficiency virus-positive thai patients and healthy volunteers.

We assessed the pharmacokinetics of zidovudine (ZDV) in plasma and intracellular ZDV phosphate anabolites in peripheral blood mononuclear cells in Thai human immunodeficiency virus (HIV) type 1-infected patients and healthy volunteers. The plasma ZDV area under the concentration-time curve from 0 to 6 h (AUC(0-6)) was similar in patients and healthy volunteers (32.77 and 22.77 micromol/liter. h, respectively; confidence interval, -3.37 to 19. 92). Although the concentration of ZDV triphosphate (ZDVTP) was similar in the two groups, the ZDV monophosphate (ZDVMP) AUC(0-6) was significantly greater in HIV patients (1.12 pmol/10(6) cells) than in healthy volunteers (0.15 pmol/10(6) cells). In agreement with previously published data obtained with Caucasians, the significant difference in intracellular phosphorylation in Thai volunteers and HIV patients is primarily due to ZDVMP. Comparing the data from this study with the data obtained with Caucasians suggests no marked ethnic differences in ZDV phosphorylation.

Therapeutic drug monitoring of antiretrovirals in human immunodeficiency virus infection.

The era of antiviral therapy directed against HIV-1 has now entered its second decade. In the twelve years since the FDA approved the first antiretroviral drug zidovudine there have been a number of seminal developments that have revolutionized the approach to therapy. These advances converged to change the treatment paradigm from one of therapeutic nihilism to that of cautious optimism. First, several trials demonstrated that combination therapy of nucleoside reverse transcriptase inhibitors (NRTIs) is superior to monotherapy in extending survival and delaying disease progression. Second, the concept of virologic latency in asymptomatic HIV-infected patients was revised. Mathematic modelling demonstrated that there is an ongoing high level of virus production driving a rapid turnover of CD4 cells at all stages of infection. Hence it was concluded that the aim of antiretroviral therapy (ART) should be to "hit early and hit hard." Third, significant advances in molecular virology facilitated the development of quantitative methods to measure the circulating HIV plasma RNA. HIV viral load has been shown to be a sensitive predictor of disease progression and a valuable marker of response to therapy. However, none of these developments would have translated into improved patient care without the advent of two new classes of drugs-the protease inhibitors (PIs) and the nonnucleoside reverse transcriptase inhibitors (NNRTIs).

Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients.

OBJECTIVE: The most important hepatic enzyme involved in the metabolism of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy volunteers. In this study we investigated the kinetics of SQV when administered alone and in combination with RIT in HIV-infected patients. DESIGN: SQV pharmacokinetics were determined in seven patients who had advanced HIV disease. Steady-state SQV profiles were obtained on two occasions following treatment with SQV 600 mg three times daily alone and when administered with RIT 300 mg twice daily. METHODS: Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h post-dosing. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored at -80 degrees C until analysis using high performance liquid chromatography. RESULTS: For patients treated with SQV alone there was a 12-fold variability in the area under the SQV concentration-time curve (AUC0-8h) ranging from 293 to 3446 ng.h/ml. When combined with RIT there was a marked increase in the maximum plasma concentration of SQV [median (range), 146 (57-702) versus 4795 (1420-15810) ng/ml; approximately 95% confidence interval (CI), 2988-6819; P = 0.0006, Mann-Whitney U test]. The AUC0-8h for SQV was also significantly increased in the presence of RIT [median (range), 470 (29-3446) versus 27,458 (7357-108,001) ng.h/ml; approximately 95% CI, 16,628-35,111; P = 0.0006]. CONCLUSIONS: For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.

The effect of zidovudine dose on the formation of intracellular phosphorylated metabolites.

OBJECTIVES: Zidovudine (ZDV) requires intracellular phosphorylation to ZDV triphosphate (ZDV-TP) prior to the inhibition of HIV replication. The effect of ZDV dose on the formation of intracellular phosphorylated metabolites may help define the optimum daily dose of ZDV, which is still unknown. DESIGN AND METHODS: The plasma and intracellular phosphorylated metabolite concentrations of ZDV were determined over a 12 h period following oral administration of 100 and 300 mg ZDV to 10 HIV-seropositive patients at steady state during two dosing regimens (i.e., 100 mg three times daily and 300 mg twice daily). The intracellular ZDV phosphates, ZDV monophosphate (ZDV-MP), ZDV diphosphate (ZDV-DP) and ZDV-TP were measured in peripheral blood mononuclear cells using a combination of high-performance liquid chromatography and radioimmunoassay. RESULTS: There was a greater than threefold increase in maximum plasma concentration (Cmax) following 300 mg ZDV when compared with 100 mg ZDV (mean +/- SD, 2.59 +/- 0.52 versus 0.70 +/- 0.14 mumol/l). The area under the concentration time curve (AUC0-12 h) was also significantly increased (4.59 +/- 0.79 versus 1.42 +/- 0.51 mumol/l x h) following 300 mg ZDV dose. For total intracellular ZDV phosphate metabolites the AUC0-12 h was doubled (7.64 +/- 3.67 versus 3.71 +/- 1.83 pmol/10(6) cells x h) in patients taking 300 mg ZDV compared with 100 mg. The AUC0-12 h for ZDV-MP was significantly increased at the higher dose (6.47 +/- 3.14 versus 2.77 +/- 1.70 pmol/10(6) cells x h), whereas the active moiety ZDV-TP was variable and not significantly different (0.42 +/- 0.42 versus 0.61 +/- 0.81 pmol/10(6) cells x h) following 100 and 300 mg ZDV. CONCLUSIONS: Administration of 100 mg ZDV orally produces significantly less of the potentially toxic metabolite, ZDV-MP, and comparative, although variable, concentrations of the active metabolite ZDV-TP when compared with 300 mg ZDV orally. This finding supports clinical data indicating the efficacy of low-dose (300 mg daily) ZDV. The measurement of intracellular phosphorylated metabolites advances our understanding of the clinical pharmacology of ZDV.