Zulmi W

Impact of CYP2D6 Genetic Polymorphism on Tramadol Pharmacokinetics and Pharmacodynamics

AbstractBackground and objective: Tramadol is metabolized by the highly polymorphic enzyme cytochrome P450 (CYP)2D6. Patients with different CYP2D6 genotypes may respond differently to tramadol in terms of pain relief and adverse events. In this study, we compare the pharmacokinetics and effects of tramadol in Malaysian patients with different genotypes to establish the pharmacokinetic-pharmacodynamic relationship of tramadol. Study design and setting: All patients received an intravenous dose of tramadol 100mg as their first postoperative analgesic. Blood was sampled at 0 minutes and subsequently at 15 and 30 minutes, 1, 2, 4, 8, 16, 20, and 24 hours for serum tramadol and analyzed by high-performance liquid chromatography (HPLC). Patients were genotyped for CYP2D6*1, *3, *4, *5, *9, *10, and *17 alleles and duplication of the gene by means of an allele-specific PCR. Pain was measured using the Visual Analog Scales, and adverse effects were recorded. Results: About half of the patients had the wild-type allele (CYP2D6*1), with the ‘Asian’ CYP2D6* 10 allele accounting for most of the rest (40%). None of the genotypes predicted poor metabolism. Twenty-seven percent of the patients were intermediate metabolizers (IM) and 2.9% were ultra-rapid (UM) metabolizers; the remaining 70% were extensive metabolizers (EM). The mean total clearance (CL) predicted by the model was lower (19 L/h) and the half-life longer (5.9 hours) than those reported in Western populations. This may due to the high frequency of the CYP2D6*10 allele amongst Malaysian patients. The UM and EM groups had 2.6- and 1.3-times faster CL, respectively, than the IM. CL was 16, 18, 23, and 42 L/h while mean half-lives were 7.1, 6.8, 5.6, and 3.8 hours among the IM, EM1, EM2, and UM groups, respectively. However, the analgesic effects of tramadol were not measured adequately among the postoperative patients to establish its full therapeutic effects. There were significant differences in the adverse-effect profiles amongst the various genotype groups, with the IM group experiencing more adverse effects than the EM, and the EM having more adverse effects than the UM. Conclusion: CYP2D6 activity may play an important role in determining the pharmacokinetics of tramadol and in predicting its adverse effects. If these results can be confirmed in a larger population, genotyping may be an important tool in determining the dose of tramadol.

Tumour volume and lung metastasis in patients with osteosarcoma

Purpose. To assess the association between tumour volume and occurrence of lung metastasis in patients with osteosarcoma and to determine the cut-off value. Methods. Records of 70 patients with histopathologically confirmed primary osteosarcoma in the extremities who had magnetic resonance imaging and computed tomography of the thorax less than one month before treatment were reviewed, with reference to the official report of tumour dimensions and lung metastasis by radiologists. The status of lung metastasis was assessed. Tumour volume was measured using the formula for an ellipsoidal mass. Results. Of the 70 patients with osteosarcoma, 33 (47%) had evidence of lung metastasis. Tumour volume was directly associated with occurrence of lung metastasis (p=0.048). The proportion having lung metastasis when the primary tumour volume exceeded 371 cm3 was 69%, compared to 34% in those with smaller tumours. Conclusion. Larger tumours are more likely to correlate with lung metastasis. Both features are predictive of patient survival and prognosis.

Prognostic factors and survival rate of osteosarcoma: A single-institution study

Osteosarcoma is a highly malignant primary bone tumor. The study aim to evaluate the prognostic factors influencing the survival rate in our center.

Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms

Background and objective:  Although the kinetic behaviour of tramadol has been described, the present study is the first to our knowledge, to report specifically on the population pharmacokinetic modelling of tramadol hydrochloride.

Residual nonunion following vascularised fibular graft treatment for congenital pseudarthrosis of the tibia: a report of two cases

Resection and reconstruction using a vascularised fibular graft is a viable alternative treatment for congenital pseudarthrosis of the tibia, although distal junctional nonunion and residual deformity are known complications that are difficult to treat. We illustrate 2 cases in which bony union was achieved following a technique using fibular grafting and intramedullary nailing, without additional bone grafting. This technique was feasible because of hypertrophy of the fibular graft.

The Outcomes of Salvage Surgery for Vascular Injury in The Extremities: A Special Consideration For Delayed Revascularization

Abstract A seven years retrospective study was performed in 45 consecutive vascular injuries in the extremities to investigate the pattern of injuries, managements and outcomes. Motor-vehicle accidents were the leading cause of injuries (80%), followed by industrial injuries (11.1%) and iatrogenic injuries (4.4%). Popliteal and brachial artery injuries were commonly involved (20%). Fifteen (33.3%) patients had fractures, dislocation or fracture dislocation around the knee joint and 6 (13.3%) patients had soft tissue injuries without fracture. Traumatic arterial transection accounted for 34 (75.6%) cases, followed by laceration in 7 (15.6%) and 9 (6.7%) contusions. Associated nerve injuries were seen in 8 (17.8 %) patients using intra-operative findings as the gold standard, both conventional angiogram (CA) and computerized tomography angiogram (CTA) had 100% specificity and 100% sensitivity in determining the site of arterial injuries. The mean ischemic time was 25.31 hours (4 - 278 hours). Thirty-three (73.3 %) patients were treated more than 6 hours after injury and 6 patients underwent revascularization after 24 hours; all had good collateral circulation without distal pulses or evidence of ischemic neurological deficit. The mean ischemic time in 39 patients who underwent revascularization within 24 hours was 13.2 hours. Delayed amputation was performed in 5 patients (11.1%). Of the 6 patients who underwent delayed revascularization, one patient had early amputation, one -had delayed amputation following infection and multiple flap procedures while the rest of the patients’ limbs survived. Joint stiffness was noted in 10 patients (22.2%) involving the knee joint, elbow and shoulder in two patients each. Infection was also noted in 5 patients (11.1%) with two of them were due to infected implants. Other complications encountered included nonunion (2 patients, 4.4%), delayed union (1 patient, 2.2%),limb length discrepancy (1 patient, 2.2%), hematoma (1 patient, 2.2%) and leaking anastomosis in one patient (2.2%). Volkmann’s ischemic contracture occurred in 3 (6.7%) patients. There was no complication noted in 8 (17.8%) patients Three patients (6.7%) died of whom two were not due to vascular causes. We conclude that early detection and revascularization of traumatic vascular injuries is important but delayed revascularization also produced acceptable results.

Soft Tissue Reconstruction following Hemipelvectomy: Eight-Year Experience and Literature Review

Background and Objectives. Hemipelvectomy is a major surgical procedure that associates with significant morbidity, functional impairment, and psychological and body image problem. Reconstruction of the defect is a challenged since a large amount of composite tissues are needed. We would like to share our eight-year experience with massive pelvic resection and reconstruction. Methods. A retrospective analysis of all cases of hemipelvectomy was conducted in our institution over eight-year period with particular attention given to the reconstruction choices and associated complications. Results. Thirteen patients were included with median age of 39 years (range 13–78) of which all had advanced tumour with stage IIb (54%) and Stage III (46%). External hemipelvectomy was performed in all cases, and resultant defects were reconstructed with variety type of flaps. These include fillet thigh flaps, regional pedicle flaps of different designs, and free flap. Conclusions. Massive pelvic tumour is rarely encountered in our population but can be seen across all age groups and usually due to late presentation. The defects should be reconstructed using local or regional flaps, incorporating the muscle component to enhance flap perfusion. The tissue should be harvested from the amputated limb, as it can limit the donor site morbidity.

Early Functional Outcome of Resection and Endoprosthesis Replacement for Primary Tumor around the Knee

Abstract We evaluated functional outcomes for patients who underwent surgery for resection and endoprosthesis replacement for primary tumours around the knee. We used the Musculoskeletal Tumour Society Scoring System (MSTS) for functional evaluations to compare differences between distal femur (DF) and proximal tibia (PT) placements. The study sample included 34 cases of distal femur and 20 cases of proximal tibia endoprosthesis replacement. Primary tumours were classified as follows: 33 osteosarcoma, 20 stage III giant cell tumour (GCT) and one case of mesenchymal chondrosarcoma. The mean MSTS score for both DF and PT endoprosthesis together was 21.13 (70.43%), and The MSTS scores for DF was 21.94 (73.13%) and PT was 19.75 (65.83%) Infection developed in 7 cases and 5 of which were PT endoprosthesis cases. Three deep infections required early, two-stage revision and resulted in poor MSTS scores. We conclude that endoprosthesis replacement for primary bone tumours had early good to excellent functional outcome. There were no differences in functional outcomes when comparing distal femur endoprostheses with proximal tibia endoprostheses. Key Words functional outcome, bone tumour, knee, and endoprosthesis

Outcome of Surgical Treatment of Pelvic Osteosarcoma: Hospital Universiti Sains Malaysia Experience

Abstract We reviewed the surgical treatment and outcomes of 13 patients with pelvic osteosarcoma treated in our centre in the past decade. The study sample included 9 males and 4 females with a mean age of 28.1 years. Four patients had ileal lesions, five had acetabulum lesions, one had a ischiopubis lesion, and three had involvement of the whole hemipelvis. Seven patients presented with distant metastases at diagnosis. Limb salvage was performed in 6 patients and amputation in 7. In 60% of cases in the limb salvage surgery group, we attempted wide resection with positive microscopic margin compared to only 16.7% in the amputation group. Local recurrence was higher in the limb salvage group. Overall survival was 18 months for mean follow up of 14.8 months. Median survival was 19 months in the limb salvage group compared to 9 months in amputation group. The outcome of surgical treatment of pelvic osteosarcoma remains poor despite advancements in musculoskeletal oncology treatment. Key Words Pelvic osteosarcoma, limb salvage surgery, hemipelvectomy, margins, oncologic outcomes