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In-vitro drug sensitivity tests were performed on Philippine isolates of Plasmodium falciparum between 1991 and 1993, using the radioisotope microdilution method. The success of the tests varied significantly with the level of parasitaemia, the source of the strains, the period that elapsed before culturing, and the detectable concentrations of antimalarials in the blood. There was a significant positive correlation between the [IC.sub.50] values for chloroquine and artesunate and the level of chloroquine in the blood before testing. In the Philippines the sensitivity profiles of the standard antimalarials chloroquine, quinine, mefloquine, and halofantrine) were less severe than those in other south-east Asian countries. Fairly low [IC.sub.50] values were obtained for the qinghaosu derivatives artemisinin, artemether, arteether and artesunate. There was a positive correlation between quinine, mefloquine, hatofantrine and some of the qinghaosu derivatives, and between the qinghaosu compounds themselves, raising the possibility of either cross-resistance or possible drug associations., Introduction During the early 1960s the resurgence of malaria was accompanied by the worldwide spread of chloroquine resistance from one or two foci in south-east Asia and South America. Compounding [...]

The pharmacokinetics of ornidazole (Tiberal) was studied after intravenous administration of a single 500 mg dose in eight patients with advanced chronic renal failure (ACRF) (creatinine clearance 2-16 ml/min), in seven patients treated by haemodialysis (residual renal creatinine clearance 0-5 ml/min) and in five patients treated by continuous ambulatory peritoneal dialysis (CAPD) (residual renal creatinine clearance 0-6 ml/min). In ACRF patients, the half-life of ornidazole was 10.8 +/- 1.4 h, the total plasma clearance 46.3 +/- 2.3 ml/min and the volume of distribution 0.73 +/- 0.06 l/kg. During haemodialysis, ornidazole was partly removed: the dialyser extraction ratio was 42 +/- 5% and the dialysis clearance 64 +/- 7 ml/min. During CAPD, peritoneal excretion was low: the dialysis clearance was 3.0 +/- 0.4 ml/min and in 48 h 6.0 +/- 1.1% of the administered dose was found in the peritoneal fluids. In these patients, the half-life of ornidazole was 11.8 +/- 0.8 h and total plasma clearance was 48.3 +/- 5.5 ml/min, values which were close to those determined in non dialysed patients. In patients with end-stage renal disease, the half-life of ornidazole is comparable to that of subjects with normal renal function. This is due to the predominantly extra-renal elimination of the drug. Therefore, there is no need to modify the usual dosage of ornidazole for these patients. Because of the large elimination of the drug during haemodialysis it is necessary to administer the drug after the dialysis session. [ABSTRACT FROM AUTHOR]

Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood-brain barrier in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole was assessed in the plasma, cerebrospinal fluid (CSF), and brain in an experimental model of cerebral scedosporiosis in rats receiving or not receiving cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administered to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose, or three doses; 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using ultra-performance liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography UV methods and were documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a noncompartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and brain in all groups studied. The voriconazole C max and area under the curve (AUC) (AUC 0 ≥ 48 hours ) values were significantly higher in plasma than in CSF [CSF/plasma ratio, median (range) = 0.5 (0.39-0.55) for AUC 0 ≥ 48 hours and 0.47 (0.35 and 0.75) for C max ]. Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma, but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together, these results emphasize the impact of cyclosporine on brain voriconazole exposure., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Aims: The objective of the present study was to assess the pharmacokinetics of riluzole in patients with spinal muscular atrophy (SMA)., Methods: Fourteen patients were enrolled in an open-label, nonrandomized and repeat-dose pharmacokinetic study. All participants were assigned to receive 50mg riluzole orally for 5 days. Riluzole plasma concentrations were determined from samples obtained at day 5., Results: The pharmacokinetic analysis demonstrated that a dose of 50mg once a day was sufficient to obtain a daily total exposure [AUC(0,24h)=2257ng ml(-1) h] which was comparable with results obtained in adult healthy volunteers or ALS patients in whom a dose of 50mg twice a day is recommended. The pharmacokinetic simulation demonstrated that the administration of 50mg twice a day could result in higher concentrations, hence reduced safety margin., Conclusion: The dose of 50mg once a day was chosen for the clinical trial evaluating the efficacy of riluzole in SMA patients., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Background: Diet-induced weight reduction promotes a decrease in resting energy expenditure that could partly explain the difficulty in maintaining reduced body mass. Whether this reduction remains after stabilized weight loss is still controversial, and the molecular mechanisms are unknown., Objective: The objective was to investigate the effect of a stabilized 10% weight loss on body composition, metabolic profile, and skeletal muscle gene expression profiling., Design: Obese women were assigned to a 4-wk very-low-calorie diet, a 3-6-wk low-calorie diet, and a 4-wk weight-maintenance program to achieve a 10% weight loss. Resting energy expenditure, body composition, plasma variables, and skeletal muscle transcriptome were compared before weight loss and during stabilized weight reduction., Results: Energy restriction caused an 11% weight loss. Stabilization to the new weight was accompanied by an 11% decrease in the resting metabolic rate normalized to the body cellular mass. A large number of genes were regulated with a narrow range of regulation. The main regulated genes were slow/oxidative fiber markers, which were overexpressed, and the gene encoding the glucose metabolism inhibitor PDK4, which tended to be down-regulated. The knowledge-based approach gene set enrichment analysis showed that a set of genes related to long-term calorie restriction was up-regulated, whereas sets of genes related to insulin, interleukin 6, and ubiquitin-mediated proteolysis were down regulated., Conclusions: Weight loss-induced decreases in resting metabolic rate persist after weight stabilization. Changes in skeletal muscle gene expression indicate a shift toward oxidative metabolism.

Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC50=490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC50 = 8.5-59 microM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC50 = 9.2 microM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.

beta-adrenoceptor antagonists, especially atenolol, reduce perioperative cardiac morbidity. Because there are no data on the bioavailability of atenolol given by nasogastric tube in the postoperative period, we assessed the efficacy of this route of administration in 18 patients scheduled for abdominal surgery. We found a 36% reduction in the area under the atenolol concentration curve and a 46% reduction in the peak concentration of atenolol in the postoperative period compared with preoperative values. In addition, patients had more rapid mean heart rates on the second postoperative day compared with the day before surgery. We conclude that the administration of atenolol via nasogastric tube in the postoperative period does not result in adequate plasma concentrations.

The efficacy and kinetics of the combination chloroquine plus sulfadoxine-pyrimethamine (CQ + SP), given sequentially and simultaneously, were investigated in 32 patients with acute uncomplicated Plasmodium falciparum malaria in Palawan Island, the Philippines. Group 1 with 11 patients received oral CQ 25 mg/kg bw over 3 days followed by a single dose of SP (three tablets 250 mg S + 25 mg P) on Day 4 (CQ0 + SP4). Group 2 with 21 patients received a loading dose of CQ 10 mg/kg plus a single dose of SP three tablets on Day 0, and doses of CQ on Days 1 and 2 (CQ0 + SP0). Patients were followed-up for 28 days until after the clinical and parasitological remission of the disease. Serum samples for CQ, des-ethylchloroquine (DCQ), S and P levels were assayed by high-pressure liquid chromatography with UV and spectrofluorometric detection (HPLC-SF) to determine effective therapeutic concentrations achieved. Parasite and fever clearance times (PCT and FCT) in Group 1 were 48 and 33.5 h, respectively, and 39 and 24 h in Group 2. The parasite elimination half-life (pt1/2) in the CQ + SP0 group was 2.5 h, significantly shorter than the CQ + SP4 group of 5.7 h (P=0.006). Late-treatment failures (R I) were observed in 2/11 patients in Group 1 and in 2/21 patients in Group 2. Serum CQ and DCQ concentrations were effectively adequate. Group 1 pharmacokinetic parameters showed a median maximum concentration (Cmax), area under the curve (AUC) and elimination half-life (t1/2) of 285 ng/ml, 2299 day ng/ml and 5.7 days for CQ, and 89 ng/ml 1845 day ng/ml and 7.3 days for DCQ, respectively. SP was not assayed in Group 1 because of very limited time points. In Group 2, the median Cmax, AUC and t1/2 for CQ and DCQ were at 283 ng/ml 1980 day ng/ml and 5.9 days for CQ and 220 ng/ml, 2680 day ng/ml and 8.5 days for DCQ, respectively. For S and P, the median Cmax, AUC and t1/2 were at 169 microg/ml, 2758 day ng/ml and 10.9 days for sulfadoxine, and 591 ng/ml, 3029 day ng/ml and 2.9 days for pyrimethamine, respectively. Both regimens were well tolerated with a minimum of side-effects, mainly nausea and vomiting. The combination CQ + SP administered simultaneously on Day 0 is more efficacious than when administered sequentially. In the absence of an alternative treatment for acute uncomplicated malaria, this combination is well tolerated, and has an advantage over CQ or SP monotherapy, especially in countries where one drug is still highly effective.

Dehydroepiandrosterone (DHEA; 50 and 25 mg) and placebo tablets were orally administered daily to 24 healthy aging men and women (67.8 +/- 4.3 yr) for 8 days according to a balanced incomplete block design. Nine blood tests on both the first and eighth days allowed the measurement of DHEA, its sulfate DHEAS, and metabolites: testosterone, 5alpha-androstan-3alpha,17beta-diol glucuronide, estradiol, and estrone. Relatively low background levels of DHEA(S) were observed, and with the reestablishment of "young" levels, four important results were obtained. 1) Blood DHEA had an apparent terminal half-life of more than 20 h, the same order of magnitude as that of blood DHEAS, a result explainable by back-hydrolysis of the large amount of DHEAS formed after oral administration of DHEA, a mechanism providing long-lived unconjugated DHEA and metabolites. 2) The metabolic conversion of DHEAS to DHEA was significantly greater in women than in men. 3) No accumulation of steroids was observed. 4) No worrying transformation to androgen and estrogen was recorded; indeed, the limited increased estradiol in aged women could be predicted to be beneficial. These results suggested that daily oral administration of DHEA (25/50 mg) is safe in elderly subjects. The 50-mg dose was chosen for a 1 yr, double blind, placebo-controlled trial of daily oral administration of DHEA in 60- to 80-yr-old individuals (DHEAge).

Objective: To determine whether diarrhea and intestinal malabsorption during HIV infection alter oral ganciclovir systemic exposure., Methods: We studied the oral disposition of ganciclovir in 42 HIV-infected patients stratified into three groups: A (n = 15), HIV (stage A and B); B (n = 13), AIDS (stage C); and C (n = 14), AIDS with chronic diarrhea and wasting syndrome (10% or more weight loss). Each patient was evaluated for nutritional (body mass index, serum albumin and transferrin), immunologic (CD4 count, plasma viral load) and intestinal status (D-xylose test, fecal fat and nitrogen excretion, and intestinal permeability). Following an overnight fast, 1 g oral ganciclovir was given to patients. Six blood samples were collected over 24 hours. Serum was analyzed for ganciclovir by high performance liquid chromatography. Drug disposition was characterized using a population pharmacokinetic approach., Results: Mean intestinal permeability increased as HIV disease progressed (0. 05, 0.1, and 0.2 for groups A, B, and C, respectively). Average weight-adjusted maximum concentration (Cmax) in group C was twofold more than that in group A and B patients (12.5 versus 6 and 6.4 ng/ml/kg), and average area under the curve (AUC0-infinity) was threefold greater in group C patients (193 versus 59 and 65 ng. hour/ml/kg in groups A and B, respectively). Mean oral clearance was threefold lower in group C (96 versus 258 and 212 L/hour in groups A and B, respectively)., Conclusion: Because systemic exposure of oral ganciclovir is enhanced in AIDS patients with diarrhea and wasting syndrome, oral ganciclovir therapy may benefit these patients.

We investigated human immunodeficiency virus (HIV) type 1 RNA, proviral DNA, and antiretroviral drug-resistant variants in cervicovaginal secretions of HIV-1-infected women receiving antiretroviral therapy. The prevalence of detectable HIV-1 RNA in genital secretions was inversely related to the number of antiretroviral drugs taken by the patients. Proviral DNA was detected in approximately half of all samples of cervicovaginal secretions from HIV-1-infected women, regardless of the presence or absence of HIV-1 RNA in cervicovaginal secretions and of the antiretroviral regimen. In cervicovaginal secretions of most women with persisting genital viral replication, HIV variants exhibiting mutations associated with drug resistance against protease and reverse-transcriptase pol genes were found. Our observations indicate that antiretroviral therapy is not effective in purging the female genital tract of cell-associated provirus and that antiretroviral drugs that penetrate the female genital tract at suboptimal concentrations exert a potent selective pressure on genital HIV variants when local replication of free HIV-1 RNA persists.

The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20 &mgr;g/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.

Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate with anti-HIV activity demonstrated in vitro and in pilot phase I studies. To assess its safety, efficacy and pharmacokinetics, we conducted a multicenter, randomized, double-blind, placebo-controlled trial of FZD monotherapy in 72 HIV-infected patients who had not previously received antiretroviral therapy. In each dosage group (200 mg daily, 400 mg daily, 200 mg twice daily, 800 mg daily, 400 mg twice daily, and 600 mg twice daily), 12 patients were randomized to receive in a 10:2 ratio either FZD or a placebo for 4 weeks. Overall, FZD was well tolerated in all dosage groups; only 1 patient discontinued the drug, because of a moderate rise in aminotransaminase activity. HIV viral load fell in all the patients who were receiving FZD, except in the 200 mg daily group. The largest decrease (-0.67 log10) was observed in the 600 mg twice daily group. The plasma half-life was significantly longer (approximately 3.8 hours) than that of the parent drug ZDV. Exposure to ZDV, as reflected by the area under the time-concentration curve, was much lower after FZD than after ZDV administration. FZD thus appears to be as effective as and potentially better tolerated than ZDV during short-term administration and has the advantage of once daily intake.

Suicide gene therapy based on ganciclovir (GCV) metabolism by transgene herpes simplex thymidine kinase (HSV-1 TK) has been used to selectively kill proliferating cells in clinical settings such as cancer, vascular restenosis, and immunological disorders. We investigated whether encapsulation of ganciclovir (GCV) into liposomes would improve its efficacy, especially against hepatic tumors. Large unilamellar liposomes containing GCV were prepared by reversed-phase evaporation. Pharmacokinetic studies in rats showed that, compared with free GCV, the intravenous injection of liposome-encapsulated GCV (lip-GCV) led to a faster decrease in GCV plasma concentrations, but higher liver-blood ratios. After treatment of syngeneic HSV-1 TK+ liver metastases in rats, histologically active tumors were found in 95% of the transplanted lesions when physiological saline had been given and in 50% when free GCV had been given at 90.2 microM/kg twice daily. This dose is known to be insufficient for the eradication of HSV-1 TK+ tumors. In contrast, only 5% viable tumors were found in rats receiving lip-GCV at this same concentration. Average tumor volumes were 19 +/- 15, 7 +/- 9, and <1 mm3 for the control, free GCV, and lip-GCV groups, respectively. GCV-related toxicity was no longer observed. The results demonstrate that liposomal encapsulation of GCV is feasible and significantly enhances its efficacy against HSV-1 TK+ hepatic tumors.

Despite extensive surgery for glioblastoma, residual tumor cells always lead to relapse. Gene therapy based on retrovirus-mediated gene transfer of herpes simplex virus type 1 thymidine kinase (HSV-1 TK), which specifically sensitizes dividing cells to ganciclovir (GCV) toxicity, may help eradicate such cells. During glioblastoma surgery, HSV-1 TK retroviral vector-producing cells (M11) were injected into the surgical cavity margins after tumor debulking. After a 7-day transduction period, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based relapse-free survival at month 4 and by overall survival. Twelve patients with recurrent glioblastoma were treated without serious adverse events related to M11 cell administration or GCV. Quality of life was not negatively influenced by this treatment. Overall median survival was 206 days, with 25% of the patients surviving longer than 12 months. At 4 months after treatment, 4 of 12 patients had no recurrence; their median overall survival was 528 days, compared with 194 days for patients with recurrence (p=0.03 by the log rank test). One patient is still free of detectable recurrence, steroid free and independent, 2.8 years after treatment. Thus, brain injections of M11 retroviral vector-producing cells for glioblastoma HSV-1 TK gene therapy were well tolerated and associated with significant therapeutic responses. These results warrant further development of this therapeutic strategy in brain tumor, including recurrent glioblastoma.