Simon Szwandt - Academia.edu (original) (raw)

Papers by Simon Szwandt

Transactions of the Royal Society of Tropical Medicine and Hygiene, May 1, 1997

The disposition of chlorproguanil/dapsone (one daily dose for 3 d of 1.2 and 2.4 mg/kg respective... more The disposition of chlorproguanil/dapsone (one daily dose for 3 d of 1.2 and 2.4 mg/kg respectively) has been studied in young children with Plasmodium falciparum malaria, to provide data complementary to a clinical trial of this drug combination. Unbound concentrations of chlorcycloguanil (the active metabolite of chlorproguanil) and dapsone in clinical samples have been related to the unbound drug concentrations which produced defined outcomes in tests in vitro of drug efficacy and toxicity. Twelve children with uncomplicated malaria were treated: all cleared parasitaemia within 72 h and made uneventful recoveries, After the first dose of chlorproguanil/dapsone the maximum unbound chlorcycloguanil concentration in clinical samples (19 ng/mL [about 60 KIM]) was 2 orders of magnitude above the 50% inhibitory concentration (X50) value for this drug against the K39 strain of I? fulciparum, while falling 2 orders of magnitude below its IC50 against human bone marrow cells; the maximum unbound dapsone concentration in clinical samples (160 ng/mL [about 645 no]) was lo-fold higher than its IC50 against the K39 strain. However, because of the rapid elimination of chlorproguanil from the body (half-life 12.ti6.3 h), the minimum fractional inhibitory concentrations of unbound chlorcycloguanil/dapsone against the K39 strain were probably exceeded for no more than 6 d. These data, together with the clinical trial, will be helpful in deciding whether current chlorproguanilidapsone doses are optimal for the treatment of falciparum malaria.

Xenobiotica, 1993

1. The effects of malaria infection due to Plasmodium berghei and Escherichia coli endotoxin-indu... more 1. The effects of malaria infection due to Plasmodium berghei and Escherichia coli endotoxin-induced fever on the metabolism of orally-administered caffeine (CA: 10 mg/kg) to its primary metabolites (theobromine (TB), paraxanthine (PX) and theophylline (TH)) were studied in 5-week-old male Wistar rats (n = 5 for each treatment). In separate experiments, the effects of malaria and endotoxin-induced fever on the clearance of i.v.-administered theophylline (TH; 15 mg/kg) were studied in another group of rats. 2. The ratios of CA to the three primary metabolites (TB/CA, PX/CA, PH/CA) determined in a single plasma sample obtained 3 h after CA administration were significantly reduced (p < 0.05) both by malaria and fever compared with control (saline) treatment. The clearance of TH determined from the concentration of TH in a single plasma sample obtained 6 h after TH administration was significantly reduced (p < 0.05) by fever but not malaria (4.0 +/- 0.7 ml/min/kg in controls; 4.2 +/- 0.5 in malaria; 2.4 +/- 0.4 in fever). 3. These results suggest that malaria and fever have different effects on CA and TH metabolism in vivo, probably as a result of different effects on the hepatic isozymes involved.

Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995

Halofantrine, increasingly ,used for treatment of Plasmodium falciparum malaria, is a normally we... more Halofantrine, increasingly ,used for treatment of Plasmodium falciparum malaria, is a normally well-tolerated amino-alcohol with very few side-effects, but torsades de pointes ventricular tachycardia due to halofantrine has been reported in a few patients with a congenital long QT interval (RomanwWard syndrome). We performed a prospective study of the cardiac effect of halofantrine in 20 patients with 48 h ambulatory electrocardiographic (ECG) monitoring; the halofantrine levels in their serum were also determined. Minimal ECG changes were noted, with lengthening of the QT interval without clinical symptoms. This effect was dosedependent and can be very severe in cases of pre-existing cardiopathy; it also occurs in patients without any pre-existing cardiopathy. In order to reduce the likelihood of such incidents, which are admittedly rare, we suggest performing electrocardiography on all patients before initiating treatment with halofantrine.

Transactions of the Royal Society of Tropical Medicine and Hygiene, 1997

Journal of the International AIDS Society, 2012

Journal of Pharmaceutical and Biomedical Analysis, 2012

Within the drug discovery environment, the key process in optimising the chemistry of a structura... more Within the drug discovery environment, the key process in optimising the chemistry of a structural series toward a potential drug candidate is the design, make and test cycle, in which the primary screens consist of a number of in vitro assays, including metabolic stability, cytochrome P450 inhibition, and time-dependent inhibition assays. These assays are often carried out using multiple drug compounds with chemically diverse structural features, often in a 96 well-plate format for maximum time-efficiency, and are supported using rapid liquid chromatographic (LC) sample introduction with a tandem mass spectrometry (MS/MS) selected reaction monitoring (SRM) endpoint, taking around 6.5 h per plate. To provide a faster time-to-decision at this critical point, there exists a requirement for higher sample throughput and a robust, well-characterized analytical alternative. This paper presents a detailed evaluation of laser diode thermal desorption (LDTD), a relatively new ambient sample ionization technique, for compound screening assays. By systematic modification of typical LDTD instrumentation and workflow, and providing deeper understanding around overcoming a number of key issues, this work establishes LDTD as a practical, rapid alternative to conventional LC-MS/MS in drug discovery, without need for extensive sample preparation or expensive, scope-limiting internal standards. Analysis of both the five and three cytochrome P450 competitive inhibition assay samples by LDTD gave improved sample throughput (0.75 h per plate) and provided comparable data quality as the IC 50 values obtained were within 3 fold of those calculated from the LC-MS/MS data. Additionally when applied generically to a chemically diverse library of over 250 proprietary compounds from the AstraZeneca design, make and test cycle, LDTD demonstrated a success rate of 98%.

Journal of Infection, 1998

Therapeutic failure is common in the treatmeot of toxoplamni¢ encephalitis in AIDS patients recei... more Therapeutic failure is common in the treatmeot of toxoplamni¢ encephalitis in AIDS patients receiving the synergistic combination pyrimethamine with sulfadiazine. It has been suggested that some cases of treatment-failure may result ~om low plasma levels of pytirnnthamine due to low oral bionvailability z. We have developad a safe and practical formulation of pyrimethamine for intra venous administration 2, and have characterised its pharmaeokinati~ in healthy volunteers. The dosage regimen was predetexmin~ by pharmaeokinetic modelling of oral and intramuscular data obtained from previous ~udies Ia. Eight male subjects entered the study, each receiving an infusion ofp~ sulphate (ling (of the base )/kg body weight; diluted to 50mL in 0.9% saline over 2 hours). Blood was drawn pre-dose and at 30, 60 minutes [to charactefise the rise towards peak concentration; 65, 70, 75, 80, 85, and 90 minutes [ to charaetetise the distribution phase land at 2, 4, 6, 8, 12, 24, 48,72,96, 120, 168 and 336 hours [to eharacterisethe elimination phaso ]. No adverse events were observed during the infusion or follow up. summarisas results available to date :

Journal of Antimicrobial Chemotherapy, 1995

We have characterized the disposition of pyrimethamine in 20 adults with advanced AIDS. After the... more We have characterized the disposition of pyrimethamine in 20 adults with advanced AIDS. After the first dose, the area under concentration versus time curves (corrected for dose-size) varied 13-fold. This marked variation in drug levels was also noted during accumulation towards steady-state: pyrimethamine levels were consistently below the suggested lower end of the therapeutic range (750 mg/L) in three severely ill patients with perturbed consciousness (two of whom received the drug by nasogastric tube). Possible mechanisms for these observations are discussed. Pyrimethamine levels may be an important determinant of the rate of response to treatment by AIDS patients with toxoplasmosis: therapeutic drug monitoring may have a role.

Antimicrobial Agents and Chemotherapy, 2000

A proportion of patients with AIDS and toxoplasmic encephalitis (TE) sustain low plasma pyrimetha... more A proportion of patients with AIDS and toxoplasmic encephalitis (TE) sustain low plasma pyrimethamine concentrations during oral treatment, possibly because of incomplete and variable bioavailability. We wanted to develop a safe, practicable intravenous (i.v.) formulation of pyrimethamine and characterize its disposition in healthy volunteers. A neutral, aqueous, sterile solution of pyrimethamine was produced and presented in sealed glass ampoules. Pyrimethamine (1 mg/kg) was given to eight healthy male volunteers by i.v. infusion over 2 h, and blood was sampled over a 2 week period. Pyrimethamine levels in plasma were measured by highperformance liquid chromatography. The drug was well tolerated by all volunteers, and there were no changes in vital signs, electrocardiogram, hematology, or biochemical parameters. The maximum pyrimethamine concentration of 2,089 ؎ 565 ng ml ؊1 (mean ؎ standard deviation) was achieved shortly after the end of the infusion; thereafter, concentrations declined in a log-linear manner, with a half-life of 140 ؎ 31 h.

Antimicrobial Agents and Chemotherapy, 1995

The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combinat... more The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethaminesulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.