Effect of temperature on serum protein binding characteristics of phenytoin in monotherapy paediatric patients with epilepsy.

OBJECTIVES: To determine the effects of temperature on binding characteristics of phenytoin to serum proteins in paediatric patients with epilepsy. METHOD: Serum samples examined in the study were obtained from 41 paediatric patients (23 male, 18 female) with epilepsy on phenytoin monotherapy. Their age ranged from 1 to 15 years (mean +/- SD, 10;2 +/- 4;0 years). Protein binding of phenytoin was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C) or at a temperature of 37 degrees C. The in vivo binding parameters of phenytoin to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. RESULTS: Significant differences were observed in serum concentrations of unbound phenytoin at the two temperatures (P < 0;05). The mean association constant L/micromol (K) of phenytoin to serum proteins is 0.016 L/micromol at 25 +/- 3 degrees C and 0;009 L/micromol at 37 degrees C, while mean total concentration of binding sites (n(Pt)) seems to be similar between the two temperatures (682 micromol/L for 25 +/- 3 degrees C and 746 micromol/L for 37 degrees C). Significant differences were observed in binding characteristics of phenytoin to serum proteins for the different temperature conditions of ultrafiltration (P < 0;05). CONCLUSION: Our study confirms that binding affinity for phenytoin-serum protein interaction is approximately 44% lower at 37 degrees C than at 25 +/- 3 degrees C and consequently, binding potential (K.n(Pt)) is approximately 38% lower at 37 degrees C than at 25 +/- 3 degrees C.

In vivo binding characteristics of phenytoin to serum proteins in monotherapy pediatric patients with epilepsy.

AIM: The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the pediatric population. Binding parameters of PHT to serum proteins in our study were conducted to compare with in vivo or in vitro binding parameters of PHT to serum proteins in adult subjects reported by other investigators. SUBJECTS AND MATERIALS: Serum samples in the study were obtained from 40 pediatric patients (16 male, 24 female) receiving PHT monotherapy. Their age ranged from 1 to 15 years (9.2 +/- 3.6 years, mean +/- SD). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. RESULTS: The association constant (Ka) was 0.014 l/micromol, while the total concentration of binding sites (n(Pt)) was 747 micromol/l. The number of binding sites per albumin molecule (n) was 1.13, while binding ability (n x Ka) was 0.0161/micromol. The fu was 0.087. The n x Ka is approximately 1.2 times higher in PHT monotherapy adult patients of Pospisil et al. [1992] (i.e. 0.0191 l/micromol) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al. [1978] (i.e. 0.0186 l/micromol) than in our study, while n is similar between the two studies. The fu in our pediatric patients is similar to the unbound serum PHT fraction in adult patients receiving PHT therapy reported by Richens [1979] (i.e. 0.1). CONCLUSION: Our results suggest that there may be small differences in the binding characteristics of PHT to serum proteins between Japanese pediatric and non-Japanese adult subjects. The unbound serum fraction of PHT in pediatric patients with epilepsy can be assumed to be relatively constant in the therapeutic concentration range of PHT.

No gender effect on binding characteristics of phenytoin to serum proteins in monotherapy for adult patients with epilepsy.

The aim of the present study was to determine the gender-related binding characteristics of phenytoin (PHT) to serum proteins in adult patients with epilepsy. Serum samples examined in the study were obtained from 80 adult patients (40 men and 40 women) with epilepsy on PHT monotherapy. Their age ranged from 16 to 64 years (mean [SD], 36.0 [11.7] years). Protein binding of PHT was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C). The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. No significant differences were observed in age and serum concentrations of albumin between male and female patients (p > 0.05), but significant differences were observed in serum concentrations of total and unbound PHT between the two groups (p < 0.05). The mean association constant of PHT to serum proteins is the same value of 0.008 L micromol(-1) between male and female patients, whereas total concentration of binding sites seems to be similar between the two groups (1389 micromol L(-1) for men and 1345 micromol L(-1) for women). No significant differences were observed in binding characteristics of PHT to serum proteins between male and female patients (p > 0.05). Our results show that gender does not have a significant effect on the binding characteristics of PHT to serum proteins in adult patients receiving monotherapy under normal pathophysiologic conditions.

Effect of temperature on binding characteristics of phenytoin to serum proteins in monotherapy adult patients with epilepsy.

The effects of temperature on binding characteristics of phenytoin (PHT) to serum proteins were determined in adult patients with epilepsy. Serum samples examined in the study were obtained from 47 adult patients (29 men, 18 women) with epilepsy on PHT monotherapy. Ages ranged from 18 to 64 years (mean [SD], 36.8 [12.1] years). Protein binding of PHT was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C) or at a temperature of 37 degrees C. The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. Significant differences were observed in serum concentrations of unbound PHT between paired data (P <.05). The mean association constants (K) of PHT to serum proteins are 0.009 L micromol(-1) at 25 +/- 3 degrees C and 0.003 L micromol(-1) at 37 degrees C, whereas mean total concentrations of binding sites [n(Pt)] are 1215 micromol L(-1) for 25 +/- 3 degrees C and 2263 micromol L(-1) for 37 degrees C. Significant differences were observed in binding characteristics of PHT to serum proteins between the data determined in different conditions of ultrafiltration (P <.05). Our study confirms that binding affinity for PHT-serum protein interaction is approximately 67% lower at 37 degrees C than at 25 +/- 3 degrees C, and, consequently, binding potential [K.n(Pt)] is approximately 38% lower at 37 degrees C than at 25 +/- 3 degrees C.

In vivo binding characteristics of phenytoin to serum proteins in monotherapy for adults with epilepsy.

The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the adults. Binding parameters of PHT to serum proteins in our study were compared with in vivo or in vitro binding parameters of PHT to serum proteins reported by other investigators. Serum samples in the study were obtained from 36 adult patients (17 men, 19 women) receiving PHT monotherapy. A total of 43 steady-state concentrations were analyzed in the study. Patients' age ranged from 16 to 73 years (mean [SD], 42.9 [14.7] years). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. The association constant (K) was 0.014 L x micromol(-1), whereas the total concentration of binding sites (n(Pt)) was 754 micromol x L(-1). The number of binding sites per albumin molecule (n) was 1.16, whereas binding ability (n.K) was 0.016 L x micromol(-1). The fu was 0.087. The n.K is approximately 1.2 times higher in PHT monotherapy patients of Pospísil and Perlík (ie, 0.0191 L x micromol(-1)) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al (ie, 0.0186 L x micromol(-1)) than in our study, whereas n is similar between the two studies. The fu in our patients is similar to the unbound serum PHT fraction in patients receiving PHT therapy reported by Richens (ie, 0.1). Our results suggest that there may be small differences in the binding affinity of PHT to serum proteins between in vivo and in vitro studies. The unbound serum fraction of PHT in epileptic patients can be assumed to be relatively constant in the therapeutic concentration range of PHT.

Temperature effect on serum protein binding kinetics of phenytoin in monotherapy patients with epilepsy.

The effects of temperature on the binding kinetics of phenytoin (PHT) to serum proteins were determined in patients with epilepsy. Serum samples examined in the study were obtained from 59 patients (31 male, 28 female) with epilepsy on PHT monotherapy. Their age ranged from 3 to 64 years (mean (SD), 23.3 (16.3) years). Protein binding of PHT was evaluated by ultrafiltration under current routine laboratory conditions (25 +/- 3 degrees C) or at a temperature of 37 degrees C. The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. Significant differences were observed in serum concentrations of unbound PHT between paired data (P < 0.05). The mean association constant (K) of PHT to serum proteins is 0.011 microM-1 at 25 +/- 3 degrees C and 0.006 microM-1 at 37 degrees C, while mean total concentration of binding sites (n(Pt)) is 1002 microM for 25 +/- 3 degrees C and 1112 microM for 37 degrees C. Significant differences were observed in the binding kinetics of PHT to serum proteins for the different temperature conditions of ultrafiltration (P < 0.05). Our study confirms that binding affinity for PHT-serum protein interaction is approximately 45% lower at 37 degrees C than at 25 +/- 3 degrees C and consequently, binding potential (K.n(Pt)) is approximately 39% lower at 37 degrees C than at 25 +/- 3 degrees C.

Serum protein binding kinetics of phenytoin in monotherapy patients.

OBJECTIVES: To determine the binding characteristics of phenytoin to serum proteins in the Japanese population and to compare these with those reported by other investigators. METHOD: Serum samples examined in the study were obtained from 72 patients (35 males, 37 females) receiving phenytoin monotherapy. The patients' ages ranged from 1 to 73 years (1-15 years, 36 subjects; 16-44 years, 20 subjects; 45-64 years, 13 subjects; > or = 65 years, 3 subjects). RESULTS: The in vivo population binding parameters of phenytoin to serum proteins and theoretical minimal unbound serum phenytoin fraction (fu) were determined using the Scatchard equation. The association constant (K) was 0.020 1/micromol, while the total concentration of binding sites (n(Pt) was 556 micromol/l. The number of binding sites per albumin molecule (n) was 0.85, while binding ability (n.K) was 0.017 l/micromol. The fu was 0.083. The n.K is approximately 1.1 times higher in patients of Pospísil et al. (26) (i.e. 0.0191 l/micromol) than in all our patients. The association constant is approximately 1.1 times higher in our study than in the in vitro study of Monks et al. (23) (i.e. 0-0186 l/micromol), while n is similar between the two studies. The fu in our patients is similar to the unbound serum phenytoin fraction in adult patients receiving phenytoin therapy reported by Richens (2) (i.e. 0.1). CONCLUSION: Our results suggest that there may be small differences in the binding characteristics of phenytoin to serum proteins between Japanese and non-Japanese subjects. The unbound serum fraction of phenytoin in our patients with epilepsy can be assumed to be relatively constant in the therapeutic concentration range of phenytoin.

Traumatic internal carotid artery occlusion--case report.

A 20-year-old male was admitted comatose immediately after a motorcycle accident. Initial computed tomography demonstrated traumatic subarachnoid hemorrhage, and the diagnosis of traumatic internal carotid artery occlusion was established by angiography. Conservative management improved his symptoms, but eventually he died from delayed traumatic apoplexy. Traumatic internal carotid artery occlusion is relatively rare, but is serious and requires early diagnosis and treatment. For patients with severe head trauma and vascular occlusion, anticoagulants are contraindicated, and frequent follow-up angiography is recommended.

An applicability study on a CT-guided stereotactic technique for functional neurosurgery.

When a CT-guided stereotactic technique for functional neurosurgery is adopted, extremely precise targeting is needed to obtain satisfactory surgical results. In this study the authors have investigated the accuracy of the target points determined by CT-guided techniques and compared with those of conventional roentgenographically controlled stereotactic procedures. Stereotactic surgery, employing the Brown-Roberts-Wells (BRW) system, was performed contemporarily 26 times in 23 patients, that is, 9 times in 8 patients for functional neurosurgery using with the roentgenographic method, and 17 times in 15 patients with the CT-guided method only for intracranial neoplasm biopsy. As a result, there were no problems of accuracy of determining the target points by CT-guided stereotactic surgery with the BRW system. When applying this technique for functional neurosurgery, it should be pointed out that there could be a discrepancy within 2 mm from the conventional target determination.

[Problems on recurrence after removal of teratoma in pineal region--an experience of recurrence of pineal teratoma 4 years after tumor removal].

A case of teratoma in the pineal region which recurred 4 years after the first tumor removal was reported in this paper. When the patient was 5 years old, she, complained of headache and vomiting, and visited our hospital. As a heterogeneous mass with no enhancement effect was found in the pineal region by CT scan, she was admitted on November 9, 1976. There was no abnormalities on physical examination but neurological examination revealed slight disturbance of conjugate upward gaze (Parinaud's sign). Left vertebral angiogram demonstrated posterior superior displacement of posterior choroidal artery and downward displacement of Rosenthal vein, but early venous filling and tumor stain were not seen. Under preoperative diagnosis of a teratoma in the pineal region, the first operation (left occipital craniotomy and total removal of the tumor) was performed on November 24, 1975. Microscopic examinations revealed that the removed tumor was a mature teratoma in the pineal region. Postoperative course was uneventful and discharged on December 20, 1975. The follow-up study was continued at outside clinic after discharge. There was no signs of recurrence until 3 years after the first operation, but on January, 1981 (4 years after the first operation), she suffered from severe headache and vomiting again and re-admitted to our hospital on February 3, 1981. There was no remarkable neurological deficits except for the mild intracranial hypertensive sign and no changes of findings on angiogram. But CT findings were markedly characteristic. It revealed a heterogenous mass with remarkable enhancement effect in the pineal region and ventricular enlargement. Because a mixed type (teratomatous and germinomatous) of pineal tumors was suspected from the CT findings, irradiation was done after V-P shunt. The tumor was reduced to half size after the first course of 2000 rads irradiation, but there is no more reduction of the size of the tumor following the second course of 2000 rads (total 4000 rads) irradiation. Against the residual tumor, tumor removal was performed on June 2, 1981. Microscopically, the most part of the resected tumor showed fibrous changes caused by irradiation and partially teratomatous compartment. From this result (radiosensitivity and histology) the authors assumed that the recurred tumor could be a mixed type (germinoma and teratoma) of pineal tumor. Postoperative course was uneventful except for a transient disturbance of conjugate upward gaze and she was discharged on June 25, 1981. And now, there is no signs of recurrence 12 months after the second operation. Conclusively, it will be stressed that we should continue follow-up study the case even after total removal of teratoma, especially in the pineal region. Moreover, it was considered that there is a possibility of the changes of the histological features on recurrence of the pineal teratoma. When germinomatous compartment is suspected, irradiation is the first choice and then microsurgical operation should be done against residual tumor.