Peter I. Folb

Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients

ABSTRACT Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

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.

Antidiabetic screening and scoring of 11 plants traditionally used in South Africa

AIM To investigate the traditional antidiabetic uses of indigenous or naturalised South African plants using an optimised screening and scoring method. MATERIALS AND METHODS Eleven plant species were screened against Chang liver, 3T3-L1 adipose and C2C12 muscle cells measuring glucose utilisation in all three cell lines and toxicity in the hepatocytes and adipocytes only. A scoring system was devised to aid interpretation of results. RESULTS Catharanthus roseus results correlated with previously reported in vivo results, with best stimulation of glucose utilisation in hepatocytes. Momordica foetida and Momordica balsamina extracts were active in myocytes but only the latter stimulated glucose utilisation in hepatocytes. Brachylaena discolor gave the best overall results, with all plant parts giving high activity scores and negligible toxicity. In vitro toxicity results for Catharanthus roseus, Vinca major, Momordica balsamina and some Sclerocarya birrea extracts raise concern for chronic use. CONCLUSION This screening system increases the likelihood of identifying drug candidates using in vitro antidiabetic screening of crude plant extracts, whilst the scoring system aids data interpretation. ETHNOPHARMACOLOGICAL RELEVANCE The multitude of metabolic steps affected by Type II diabetes offer many drug targets but they complicate in vitro screening to validate traditional uses or find new drug leads from plants.

Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study

BACKGROUND Many patients with malaria of increasing severity cannot take medicines orally, and delay in injectable treatment can be fatal. We aimed to assess the reliability of absorption, antimalarial efficacy, and tolerability of a single rectal dose of artesunate in the initial management of moderately severe falciparum malaria. METHODS 109 children and 35 adults were randomly assigned to rectal artesunate (single dose of about 10 mg/kg) or parenteral quinine treatment (10 mg/kg at 0, 4, and 12 h). The primary endpoint was the proportion of patients with peripheral asexual parasitaemia of less than 60% of that at baseline after 12 h. Secondary endpoints were clinical response and concentrations of drug in plasma. Analysis was by intention-to-treat. FINDINGS All artesunate-treated patients had pharmacodynamic or pharmacokinetic evidence of adequate drug absorption. 80 (92%) of 87 artesunate-treated children had a 12 h parasite density lower than 60% of baseline, compared with three of 22 (14%) receiving quinine (relative risk 0.09 [95% CI 0.04-0.19]; p<0.0001). In adults, parasitaemia at 12 h was lower than 60% of baseline in 26 (96%) of 27 receiving artesunate, compared with three (38%) of eight receiving quinine (relative risk 0.06 [0.01-0.44]; p=0.0009). These differences were greater at 24 h. Clinical response was equivalent with rectal artesunate and parenteral quinine. INTERPRETATION A single rectal dose of artesunate is associated with rapid reduction in parasite density in adults and children with moderately severe malaria, within the initial 24 h of treatment. This option is useful for initiation of treatment in patients unable to take oral medication, particularly where parenteral treatment is unavailable.

The effect of artesunate combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro

The interactions of artesunate with chloroquine, mefloquine, quinine, doxycycline and pyrimethamine were tested in vitro against chloroquine-sensitive (D10) and chloroquine-resistant (RSA11) strains of Plasmodium falciparum. Mefloquine and quinine both showed synergism of artesunate activity against each of the strains, whilst doxycycline showed an additive interaction. Pyrimethamine combinations were antagonistic, and the combination of artesunate with chloroquine was antagonistic against RSA11, and additive against D10. Although weak antagonism in vitro might not indicate any clinical significance, synergism with artesunate may increase the clinical usefulness of either drug, and could potentially be of value in delaying the emergence of resistance.

Combination of tunicamycin with anticancer drugs synergistically enhances their toxicity in multidrug-resistant human ovarian cystadenocarcinoma cells

BackgroundThe pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported. The UWOV2 cell line was derived from a cystadenocarcinoma in a patient refractory to combination chemotherapy with actinomycin D, vincristine (VCR), cis-diaminedichloroplatinum (II) (CDDP) and doxorubicin (DXR). In an attempt to explain drug resistance in this cell line, we examined the effects of TM on their sensitivity to various anticancer drugs, the uptake, efflux and retention of [3H]VCR, and their ability to bind [14C]DXR and [3H]azidopine (AZD), a photoaffinity label of the multidrug transporter, P-glycoprotein (Pgp).ResultsTM effectively decreased the EC50 for DXR, EXR, VCR and CDDP, thus enhancing their cytotoxicity. The antibiotic also prolonged the intracellular retention time of [3H]VCR and increased the binding of both [14C]DXR and [3H]AZD to the cells.ConclusionIt is concluded that the pharmacomodulatory effects of TM in these cells are mediated by global inhibition of protein and glycoprotein synthesis and synergistic interaction with antineoplastic drugs. The ability of TM to enhance the sensitivity of drug resistant tumour cells may have impact on the design and optimization of novel resistance modifiers to improve the efficacy of combination treatment of intractable neoplasms.

Recent Developments in Aluminium Toxicology

SummaryAluminium is now recognised as an important toxin causing considerable morbidity and mortality, particularly in patients with chronic renal failure. Diseases that have been associated with aluminium include dialysis dementia, renal osteodystrophy and Alzheimer’s disease. Aluminium also has an effect on red blood cells, parathyroid glands and chromosomes.Accumulation of aluminium in the body tends to occur when the gastrointestinal barrier is circumvented. This has been identified as a problem during dialysis or intravenous fluid administration. Renal functional impairment results in decreased aluminium excretion and promotes accumulation of the element in the body.Many sources have been shown to be contaminated with aluminium. These include the water used for dialysis; medicines containing aluminium, such as aluminium-containing phosphate binding gels; total parenteral nutrition solutions; processed human serum albumin; intravenous fluids in infants; and other environmental and industrial sources.The management of aluminium toxicity involves the identification of these contaminated sources and subsequent removal of the element. This includes regular monitoring of water used in dialysis. The use of aluminium-containing phosphate binding gels in patients with compromised renal function should be reviewed and alternatives sought. The development of effective aluminium-free phosphate binders is desirable. Once a patient has aluminium toxicity, desferrioxamine (deferoxamine) has been shown to be an effective agent in its chelation and removal.

Colchicine Therapy in Primary Amyloidosis of the Bladder: A Case Report

A patient with diffuse localized amyloidosis of the bladder was considered for cystectomy because of intractable gross hematuria. Oral colchicine (2 mg. daily) was commenced and 4 years later the patient was asymptomatic with minimal evidence of amyloidosis cystoscopically.

Pharmacokinetics of ranitidine in patients with chronic renal failure.

SummaryThe pharmacokinetic behaviour of a single oral 150 mg ranitidine dose was studied in six patients with severe chronic renal failure (CRF) (creatinine clearance 2–18 ml/min) and compared to that in ten patients with duodenal ulceration but normal renal function (N) (creatinine clearance 69–125 ml/min). Although the maximum concentrations (Cmax) were significantly higher in CRF group when compared to N group (p<0.025) there was no difference in the time taken to reach Cmax (tmax). The area under the curve (AUC) was also significantly larger in the CRF group (p<0.001) than in the N group. Within the CRF group there was a large variation in Cmax (CV = 38%) and AUC (46%) which may reflect variable bioavailability of ranitidine. The terminal elimination rate constant (β) was significantly smaller (p<0.001) in CRF group when compared with N group resulting in a median t1/2 for the CRF group of 7.3 h, 2.4 times that of N group. The recovery of unchanged ranitidine in the urine was significantly less in CRF group (p<0.001) despite a great interindividual variation in both groups. A significant linear relationship betweenβ and creatinine clearance was shown (r=0.81p<0.001). The results indicate that ranitidine elimination is appreciably reduced in renal failure. It is tentatively suggested that the standard 150 mg dose should be halved while keeping the dose interval unchanged at twelve hours in patients with severe renal failure (creatinine clearance less than 30 ml/min).

Efficacy of Artemisia afra phytotherapy in experimental tuberculosis.

Artemisia afra [Jacq] (Asteraceae) phytotherapy is widely used for its medicinal properties in traditional practices. In this study we investigated whether extracts of A. afra are capable of controlling mycobacterial replication. For Mycobacterium aurum cultured in the presence of aqueous-, methanol- and dichloromethane (DCM) extracts of A. afra we found that bacterial replication was inhibited by the dichloromethane extract only. Activity of the DCM extract was confirmed in dose-dependent studies against both M. aurum and M. tuberculosis with an IC(50) =270 microg/ml and IC(50) = 290microg/ml, respectively. Fractionation of the DCM extract and evaluation of its efficacy in vitro found that most of the antimycobacterial activity was associated with isolate fraction C8 that contained several sesquiterpene lactones, the most prominent of which are Artemin and Arsubin. Evaluation of the bactericidal efficacy in vitro showed that isolate fraction C8 reduced replication of M. aurum and M. tuberculosis in a dose-dependent manner with IC(50) =1.9 microg/ml and IC(50) = 2.0 microg/ml, respectively, and an MIC = 10 microg/ml. Further, isolate fraction C8 and the DCM extract was administered to M. tuberculosis-infected mice at a tolerated dose of 1000 microg/kg for up to 26 weeks and mycobacterial burdens compared to untreated-, INH/RIF treated- and aqueous-extract-treated animals to assess its bactericidal activity in vivo. Bacterial replication remained unaffected during treatment with either isolate fraction C8 or the DCM extract resulting in pulmonary and splenic bacilli burdens comparable to that of untreated mice. In contrast, INH/RIF treatment cleared M. tuberculosis infection after only 8 weeks to undetectable levels. Interestingly, treatment of M. tuberculosis-infected mice with aqueous extract of A. afra regulated pulmonary inflammation during early infection notwithstanding its inability to inhibit mycobacterial growth. This study clearly demonstrates that A. afra contains in vitro anti-mycobacterial activity, modulates pulmonary inflammation in early mycobacterial infection, and that the mouse experimental tuberculosis model may serve as a useful assay for evaluating the utility of phytotherapy.