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Biomedical subjects

P I Folb

Publications and source records attributed to P I Folb.

At least 19 recordsLinked to original sources
PubMed2000

Validation of population pharmacokinetic parameters of phenytoin using the parallel Michaelis-Menten and first-order elimination model.

This study was conducted to assess whether the parallel Michaelis-Menten and first-order elimination (MM+FO) model fitted the data better than the Michaelis-Menten (MM) model, and to validate the MM+FO model and its parameter estimates. The models were fitted to 853 steady state dose: serum concentration pairs obtained in 332 adults with epilepsy using nonlinear mixed-effects modeling (NONMEM). The MM+FO model fitted the data better than the MM model. The validity of the pharmacokinetic models and the estimated population parameter values was tested using the naive prediction method. The estimation and validation of the pharmacokinetic parameters were undertaken in two separate patient groups (cross-validation) obtained by splitting the data set. Patients were randomly allocated to two equally matched groups (groups 1 and 2). The predictive performance was assessed using 770 paired predicted versus actual dose or measured serum concentrations. The population pharmacokinetic parameters estimated by NONMEM in group 1 were validated in group 2 and vice versa. When predicting steady state serum concentration, the MM+FO model was clearly superior to the MM model (mean bias of 0.91 and 8.13 mg/L, respectively).

Adolescent↗
PubMed2000

Developing a national system for dealing with adverse events following immunization.

Although vaccines are among the safest of pharmaceuticals, the occasional severe adverse event or cluster of adverse events associated with their use may rapidly become a serious threat to public health. It is essential that national monitoring and reporting systems for vaccine safety are efficient and adequately coordinated with those that conventionally deal with non-vaccine pharmaceuticals. Equally important is the need for an enlightened and informed national system to be in place to deal with public concerns and rapid evaluation of the risk to public safety when adverse events occur. Described in this article is the outcome of efforts by the WHO Global Training Network to describe a simple national system for dealing with vaccine safety and with emergencies as they arise. The goals of a training programme designed to help develop such a system are also outlined.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

Erythropoietin production in anemia associated with experimental cancer.

Serum erythropoietin (EPO) concentrations reportedly are depressed in patients with chronic disorders such as cancer, rheumatoid arthritis, and acquired immunodeficiency syndrome. We evaluated serum EPO levels in mice with tumors and found that the EPO response was appropriate for the associated anemia during the major part of the disease process. The levels of the hormone increased as the anemia worsened in association with progression of the disease. The increased EPO levels were comparable to those of controls with a similar degree of experimentally induced anemia. Only during the terminal stages of cancer, when the animals were severely cachectic, were serum EPO concentrations lower than in controls with a similar degree of anemia. These findings suggest that a blunted EPO response in experimental cancer occurs only in association with advanced disease.

Anemia, Hemolytic↗
PubMed1999

Optimization of phenytoin therapy in adults with epilepsy in the Western Cape, South Africa.

OBJECTIVE: To assess the extent to which adults with epilepsy were optimized and individualized on phenytoin monotherapy in the Western Cape, South Africa and to estimate the average optimized dose and serum phenytoin concentration, and the therapeutic range for this patient group. METHODS: Patients were considered to be optimized on phenytoin if they were seizure-free or the best compromise was achieved between seizure reduction and side-effects. RESULTS: 538 (233 black and 305 coloured) adult people with epilepsy were treated at nine epilepsy clinics as outpatients. Of these patients, 332 (226 male and 106 female, 149 black and 183 coloured) were included in the data analysis as they were considered to have reliable phenytoin levels. Phenytoin doses and steady-state serum concentrations were predicted using the Michaelis-Menten equation. Patients attended a clinical pharmacokinetic service for 7.7+/-5.3 (range 1-22) months. The average optimized dose was 305.8 (range 100-500) mg/day and the average optimized level was 62.7+/-23.9 (range 15-133) micromol/l. Most patients (61.9%) were optimized in the therapeutic range 40-79 micromol/l; 21.1% were optimized above and 17% below this range. In 1.6% of patients serum concentrations above 120 micromol/l were required. Dosage adjustments were made in 47.0% of patients, increased in 31.9% and reduced in 15.1%. CONCLUSION: These findings indicate that many patients (47%) attending outpatient clinics were not optimized on phenytoin therapy.

Adolescent↗
PubMed1999

Factors influencing the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa.

The influence of various covariates (including weight, race, smoking, gender, age, mild-to-moderate alcohol intake, and body surface area) on the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa was investigated. The parameters were the maximum metabolic rate (Vm) and the Michaelis-Menten (MM) constant (Km) of phenytoin. The study population comprised 332 black and colored epileptic patients (note: "black" refers to indigenous people of South Africa, who speak one of the Bantu languages as their native language; "colored" refers to people considered to be of mixed race, classified as such by the apartheid former government of South Africa). The influence of covariates on Vm and Km estimates was determined using nonlinear mixed-effects modeling (NONMEM). Parameter models describing the factors that could potentially influence Vm and Km were tested using the Michaelis-Menten parallel MM and first-order elimination models, to which 853 steady state dose-to-serum concentration pairs were fitted. The results indicated that body weight, smoking, race, and age (65 years or older), in descending order of importance, significantly influenced Vm (p < 0.05). Although a significant difference (p = 0.03) in Km was found between black and colored patients, incorporating the influence of race in Km in the final regression model did not improve the fit of the model to the data, which indicated that the variability in Km was accounted for by Vm. The scaling factors for smoking, colored patients and age (65 years or older) in Vm were 1.16, 1.10, and 0.88, respectively. These factors should be taken into account when adjusting phenytoin dose.

Adolescent↗
PubMed1998

Role for the plasmodium falciparum digestive vacuole in chloroquine resistance.

We have developed a method for the isolation of pure and intact Plasmodium falciparum digestive vacuoles capable of ATP-dependent chloroquine (CQ) accumulation in vitro. The method is rapid and reliable, and it produces a high yield of vacuoles (20%). CQ accumulation in isolated vacuoles was found to be ATP-, Mg2+-, and temperature-dependent. We then investigated the CQ-accumulating capabilities of vacuoles isolated from CQ-resistant (CQR) and CQ-sensitive (CQS) parasites. At external CQ concentrations of 100 and 250 nM, vacuoles isolated from two CQS strains (D10 and RSA3) (Vm: 380-424 fmol/10(6) vacuoles/hr) accumulated significantly more CQ (approximately 3 times) than those isolated from three (FAC8, RSA11, and RSA15) of the four CQ-resistant strains of P. falciparum tested (Vmax: 127-156 fmol/10(6) vacuoles/hr) (P < or = 0.05). We propose that the low level of CQ accumulation observed in vacuoles isolated from most of the CQ-resistant parasites tested contributes to the decreased CQ accumulation seen in these strains and, hence, to CQ resistance. Although it is often suggested that the digestive vacuole of the P. falciparum parasite is involved in the mechanism of CQ resistance, to our knowledge this is the first direct confirmation.

Adenosine Triphosphate↗
PubMed1998

The role of oxygen free radicals in isoniazid-induced hepatotoxicity.

Isoniazid and its metabolites acetylisoniazid, hydrazine and monoacetylhydrazine were investigated for generation of oxygen free radicals during incubation with rat liver slices. Lipid peroxidation was assessed by the thiobarbituric acid reactive substances test using malonaldehyde as the external standard, while hepatotoxicity was assessed by histopathology studies. Malonaldehyde formed in liver slices after 10 hours of incubation with the drugs was 1.28 +/- 0.24 nmol/mg for isoniazid (control 1.12 +/- 0.17 nmol/mg); 0.88 +/- 0.45 nmol/mg for acetylisoniazid (control 0.84 +/- 0.42 nmol/mg); 1.43 +/- 0.14 nmol/mg for monoacetylhydrazine (control 1.10 +/- 0.12 nmol/mg) and 1.36 +/- 0.02 nmol/mg for hydrazine (control 1.13 +/- 0.04 nmol/mg). Histologically, all slices exhibited hepatic necrosis by 4 hours. However, hydrazine-induced hepatotoxicity was characterized by nuclear hyperchromatsia, karyolysis and karyohexis while monoacetylhydrazine exhibited hydropic karyomegaly only. Isoniazid and acetylisoniazid cytotoxicity exhibited a mixture of the above features such that it could be attributed to the two metabolites, hydrazine and monoacetylhydrazine. In conclusion, there was no evidence implicating oxygen free radicals in isoniazid-induced hepatotoxicity; however, the histopathology findings indicate a need for a review of our knowledge on pathognomonic features of isoniazid hepatotoxicity.

Animals↗
PubMed1998

Benefits of a clinical pharmacokinetic service in optimising phenytoin use in the western Cape.

OBJECTIVES: To study the benefits of a clinical pharmacokinetic service in optimising phenytoin use in the Western Cape. DESIGN: Assessment of the response to treatment was based on the number of seizures during the 3 months before entering the study (first baseline period), 3 months after entering the study (second baseline period) and 3 months before the termination of the study (test period). Patients kept a seizure diary throughout the study. The Michaelis-Menten model was used to calculate doses and predict steady-state serum concentrations. SETTING: Nine epilepsy clinics. SUBJECTS: One hundred and ninety-five (113 black and 82 coloured) compliant people with epilepsy receiving generic phenytoin monotherapy. OUTCOME MEASURES: Reduction in seizure frequency and adverse effects. RESULTS: A reduction in seizure frequency (64.8% compared with pre-optimisation) was experienced by 64.9% of patients. Mean seizure frequency was reduced from 3.39 to 1.18 per month. Reductions in seizure frequency of 100% and more than 50% were reported by 39.2% and 58.7% of patients, respectively. Adverse effects of phenytoin were reduced from 20.5% at the first visit to 3.2% at the last visit. CONCLUSION: The clinical pharmacokinetic dosing service for phenytoin applied in this study contributed significantly to the success of epilepsy management.

Ambulatory Care Facilities↗
PubMed1996

Erythropoiesis and erythropoietin synthesis during aseptic acute inflammation.

Erythropoietin (Epo) production during acute inflammation induced by s. c. turpentine administration in experimental Long-Evans rats increased in response to reduced erythropoiesis. A close correlation was found between decreased haematocrit (Hct) and increased levels of tumour necrosis factor-alpha (TNF alpha) in this experimental system. The Epo response was not different between rats with acute inflammation and anaemia and control animals with a comparable degree of anaemia. It is concluded that Epo is not an acute phase reactant, and that the Epo response in acute experimental inflammation in rats is explained by the associated development of anaemia.

Acute Disease↗
PubMed1996

Cytokine-mediated inhibition of erythropoietin synthesis by dexamethasone.

The effect of inflammatory cytokines on the in-vitro synthesis of erythropoietin by HepG2 cells was evaluated. Monocyte-conditioned medium, and the cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha all reduced synthesis of erythropoietin. The steroidal anti-inflammatory drug, dexamethasone, did not affect cytokine-mediated erythropoietin inhibition. Dexamethasone did cause a reduction in the secretion of erythropoietin inhibitory cytokines from monocytes. These results point to a possible therapeutic approach in the treatment of anaemia caused by suppression of erythropoietin synthesis by monocytic cytokines.

Anti-Inflammatory Agents↗
PubMed1995

Blunted erythropoietin response to anaemia in tuberculosis.

The precise cause of the anaemia that is commonly associated with severe pulmonary tuberculosis (PTB) has not been elucidated. The role of erythropoietin (Epo), the central hormone regulating red cell formation, still awaits clarification. We therefore determined serum Epo levels in patients with PTB; group 1, haemoglobin less than 110 g/L, group 2, haemoglobin greater than 110 g/L; group 3, controls, consisted of matched individuals with uncomplicated iron deficiency; group 4, healthy volunteers. Peripheral blood monocytes were obtained from patients with PTB and the controls, cultured, and the supernatant fluid (SNF) harvested. Tumour necrosis factor alpha (TNF alpha) levels were determined in the SNF, which were then added in various dilutions to a hepatocellular carcinoma cell line (HepG2) capable of regulated EPO synthesis in vitro. The influence of this cytokine was defined by the addition of specific neutralising anti-TNF alpha antibodies in this assay system. Patients in group 1 had significantly lower Epo levels (54 + 11 mU/mL) compared with those in group 3 (142 +/- 41 mU/mL) (p < 0.01). Monocyte supernatants from patients in the anaemic PTB group had markedly elevated TNF alpha levels and significantly suppressed Epo output by HepG2 cells in vitro (p < 0.01). This inhibition was consistently abrogated by anti-TNF alpha antibodies. Serum Epo levels were inappropriately low in untreated PTB patients when compared with corresponding haemoglobin levels in iron deficient controls. This blunted response could be ascribed to release of TNF alpha or other cytokines by activated monocytes.

Anemia↗
PubMed1995

Oxidative stress during antituberculous therapy in young and elderly patients.

Using allantoin (ATN) as a marker for reactive oxygen species (ROS), oxidative stress during antituberculous (anti-TB) therapy was compared in 10 young and 9 elderly patients. Before treatment, ATN plasma concentrations in patients were similar to that of volunteers. Administration of a combination of isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) increased plasma ATN in both groups of patients. ATN concentrations (M +/- SE) at six hours were higher (P < 0.05) in elderly than in young patients on day one, 8.22 +/- 1.50 vs 1.89 +/- 0.98 microgram/mL); day 30, (5.85 +/- 0.82 vs 0.87 +/- 0.57 microgram/mL; and day 90, (4.84 +/- 1.24 vs 0.52 +/- 0.50 microgram/mL). Because total amount of ATN excreted was similar in both groups on the three occasions, more ATN was formed in elderly than young patients. In conclusion, there was more oxidative stress in elderly than young patients. It is thereby suggested that Anti-TB drugs induce formation of ROS and elderly patients are at a greater risk of toxicity probably because of poor antioxidant mechanisms.

Adult↗
PubMed1994

Comprehensive assay for pyrazinamide, rifampicin and isoniazid with its hydrazine metabolites in human plasma by column liquid chromatography.

A comprehensive assay for determination of pyrazinamide (PZA), rifampicin (RIF), isoniazid (INH) and hydrazine metabolites is described. The method involves organic solvent extraction of PZA and RIF, followed by derivatization of INH, monoacetylhydrazine (mHYD) and hydrazine (HYD) with salicylaldehyde and extraction with diethyl ether. Acetylisoniazid (acINH) and diacetylhydrazine (dHYD) were hydrolyzed to INH and mHYD, respectively, and processed as above. Using a gradient solvent programmer, PZA and RIF were analyzed on a C8 (5 microns) column at 248 nm, while INH and metabolites were analyzed on a C18 (5 microns) ODS2 column at 280 nm.

Chromatography, High Pressure Liquid↗