[Large clinical registries for acute aortic dissection: interpretation and comparison of latest results].

Despite the improvements in the diagnosis and management during the past six decades, acute aortic dissection (AAD) remains a life-threatening condition associated with significant morbidity and mortality rates. Due to the relatively rare occurrence of AAD, several clinical registries have been established to gain insights into this lethal disease in a large number of patients, such as the International Registry of Acute Aortic Dissection (IRAD), the German Registry for Acute Aortic Dissection Type A (GERAADA), and the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database Aortic Section. This review aims to interpret and compare the latest results of the IRAD, STS and GERAADA database. It focuses on several controversial and key issues in the diagnosis and management of acute aortic dissection in hope of providing some insights and references for cardiovascular professionals engaged in the care of this deadly disease.

Factors Influencing the Initiation Time of Forensic Psychiatric Assessment of Criminal Cases in Hunan Province.

ABSTRACT: Objective To discuss the related factors influencing the initiation time of forensic psychiatric assessment by analysis of the initiation time of forensic psychiatric assessment of criminal cases in Hunan Province. Methods Related data in assessment files of criminal cases accepted by 8 forensic psychiatric assessment institutions in Hunan Province from January 1, 2011 to December 31, 2016 were extracted. The Logistic regression analysis was used to explore the factors influencing the initiation time of forensic psychiatric assessment. After using property score matching （PSM） to control the influence of confounding factors, the efficiency of public security organs to initiate assessments of suspects with （without） mental disorders and with （without） responsibilities were compared. Results A total of 4 346 cases were included. The Logistic regression analysis suggested that the factors independently related to the initiation time of assessment include： cause of assessment, nationality of the assessed, history of diagnosis and treatment of mental illnesses, history of crimes, history of drug abuse, and status of alcohol consumption before the crime （all P<0.05）. The initiation time of assessment of suspects diagnosed with mental disorder was shorter than those with none （P<0.05）; the initiation time of assessment of suspects without criminal responsibility was shorter than those with responsibility （P<0.05）. After using PSM to control confounding factors, the differences above still existed. Conclusion The cause of assessment, nationality of the assessed, history of diagnosis and treatment of mental illnesses, history of crimes, history of drug abuse, and status of alcohol consumption before the crime are factors that influence the efficiency of public security organs to initiate forensic psychiatric assessments. Under the current assessment initiation mode, forensic psychiatric assessment of suspects who have mental disorders, especially those with no responsibility may be given priority to initiate.

The origin and functional transition of P34.

P34, a storage protein and major soybean allergen, has undergone a functional transition from a cysteine peptidase to a syringolide receptor. An exploration of the evolutionary mechanism of this functional transition is made. To identify homologous genes of P34, syntenic network was constructed using syntenic relationships from the Plant Genome Duplication Database. The collected homologous genes, along with SPE31, a highly homologous protein to P34 from the seeds of Pachyrhizus erosus, were used to construct a phylogenetic tree. The results show that multiple gene duplications, exon shuffling and following granulin domain loss and some critical point mutations are associated with the functional transition. Although some tests suggested the existence of positive selection, the possibility that random fixation under relaxation of purifying selection results in the functional transition is also supported. In addition, the genes Glyma08g12340 and Medtr8g086470 may belong to a new group within the papain family.

Neural-endocrine mechanisms of respiratory syncytial virus-associated asthma in a rat model.

We examined the underlying neural-endocrine mechanisms of asthma associated with respiratory syncytial virus infection. Thirty Sprague-Dawley rats were randomly divided into control group, respiratory syncytial virus (RSV) group, and anti-nerve growth factor (NGF) IgG group. An RSV infection model was established by nasal drip once a week. In the anti-NGF antibody intervention group, each rat was given an intraperitoneal injection of anti-NGF IgG 3 h before RSV infection. Optical microscopy and transmission electron microscopy were used to observe the structural changes in adrenal medulla cells. Changes in adrenaline and norepinephrine in serum were detected by ELISA. NGF expression was assayed by immunohistochemistry. Expression differences in synaptophysin mRNA were detected by RT-PCR. Transmission electron microscopy displayed widened adrenal medulla intercellular spaces, reduced chromaffin particle concentration, and increased mitochondria in the RSV infection group. At the same time, NGF expression was increased in the RSV infection group significantly. In addition, the adrenaline concentration was significantly decreased compared with the control and anti-NGF antibody groups. Synaptophysin mRNA expression was significantly increased in the RSV infection and anti-NGF antibody groups. However, compared with the RSV infection group, synaptophysin mRNA expression was significantly decreased in the anti-NGF antibody group. We conclude that RSV infection could induce adrenal medulla cell differentiation to nerve cells by over-expression of NGF, resulting in the decreased endocrine function found in asthma progression.

Association of MHC class-III gene polymorphisms with ER-positive breast cancer in Chinese Han population.

Polymorphisms of the major histocompatibility complex (MHC) have been linked to many diseases, especially autoimmune disorders. Previous studies have shown that genetic variants in MHC class III are associated with breast cancer. To determine if there is an association between MHC class III and breast cancer risk in the Chinese Han population, we carried out a hospital-based case-control study in Guangdong and Jiangsu Provinces, including 216 histologically confirmed breast cancer patients and 216 healthy controls. Nine SNP markers distributed in the class III-coding region were detected using the Sequenom MassARRAY(®) iPLEX System. Deviation from Hardy-Weinberg equilibrium was observed for seven SNPs. There was no significant association between these seven SNP variants and breast cancer in these Chinese women (unconditional logistic regression analysis). However, chr6_31697494 at BAT2, one of the seven SNPs, was found to be significantly associated with both ER- and PR-positive breast cancer. In addition, both chr6_31911109 at C6orf48 and chr6_31975605 at ZBTB12, another two of the seven SNPs, show relevance with ER-positive breast cancer. In conclusion, this is the first evidence that genetic polymorphisms in the MHC class III region are significantly associated with ER-positive breast cancer in the Han Chinese population.

[Controversies and progress in adjuvant chemotherapy for patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy].

Colorectal cancer is one of the most common malignant tumors worldwide. Surgical resection is the most important and decisive method in the treatment of rectal cancer. Total mesorectal excision (TME) has greatly reduced the local recurrence rate of middle and low rectal cancer. However, local recurrence and distant metastasis remain the leading cause of death in patients with rectal cancer. 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy has been widely accepted in locally advanced rectal cancer and was recommended by various clinical practice guidelines as the standard treatment option. Tumors often achieve satisfactory reduced stage after neoadjuvant radiotherapy, and some patients even achieve pathological complete regression, which brings much controversies to the choice of adjuvant chemotherapy. This article intends to introduce evidence-based evidences for adjuvant chemotherapy for rectal cancer, impact of current neoadjuvant models on choice of adjuvant chemotherapy strategies, controversies and considerations for adjuvant chemotherapy in the context of neoadjuvant radiotherapy.

Long non-coding RNA DILC as a potentially useful biomarker for the diagnosis and prognosis of colorectal cancer.

OBJECTIVE: LncRNA downregulated in liver cancer stem cells (lnc-DILC) has been implicated as a tumor suppressor in colorectal cancer (CRC). However, the clinical significance of lnc-DILC in CRC patients has not been investigated. In this study, we aimed to explore the diagnostic and prognostic value of lnc-DILC in CRC patients. PATIENTS AND METHODS: The expression of lnc-DILC was measured in 174 paired CRC tissues and adjacent normal tissues using Real Time-Polymerase Chain Reaction (RT-PCR). The correlation of lnc-DILC expression with clinicopathological factors was statistically analyzed by the Chi-square test. Besides, overall survival analysis was carried out with the Kaplan-Meier curve with the log-rank test. Univariate and multivariate analyses were performed to explore the prognostic significance of lnc-DILC expression. RESULTS: We found that lnc-DILC expression was downregulated in CRC tissues compared to their adjacent normal tissues (p<0.01). ROC analyses showed that lnc-DILC levels were reliable in distinguishing patients with CRC from normal colorectal tissues. Then, down-regulation of lnc-DILC was positively associated with aggressive clinical characteristics, including depth of invasion (p=0.018) and advanced TNM stage (p=0.009). Moreover, the Kaplan-Meier analysis demonstrated that overexpression of lnc-DILC was associated with poorer overall survival (p=0.0205) and disease-free survival (p<0.001). Finally, multivariate analyses confirmed that expression of lnc-DILC was an independent prognostic factor in CRC. CONCLUSIONS: Our results firstly suggested that lnc-DILC could be a favorable indicator of prognosis in CRC.

Multidetector computed tomography angiography in the evaluation of potential living donors for liver transplantation: single-center experience in China.

OBJECTIVE: To evaluate relevant arterial, hepatic, and portal venous anatomy using multidetector computed tomography (CT) angiography in potential living liver donors at a single liver transplantation center in China. METHODS: One hundred two consecutive potential liver donors underwent CT angiography in the arterial, portal, and hepatic venous phases with a 16-row CT scanner. All source and reconstructed images were evaluated for hepatic vasculature anatomy by an experienced radiologist and a surgeon in consensus. The anatomic variants of arterial system, portal venous system, and hepatic veins were characterized according to the classification system of Michels, Akgul, and Nakamura respectively. In 42 donors of right hepatic lobectomy, CT findings were compared with the results of surgery. RESULTS: Of 102 candidates, 63 had type I, 8 type II, 12 type III, 3 type IV, 11 type V, 2 type VI, 2 type VIII, and 1 type IX hepatic arterial anatomy. According to the classification of the portal venous system created by Akgul, type A was seen in 81 subjects. Type B, type C, and type E were revealed in 15, 4, and 2 subjects, respectively. According to the classification of the right hepatic drainage pattern by Nakamura, type 1 drainage was seen in 71 subjects (69.6%), type 2 in 22 candidates (21.6%), and type 3 in 9 subjects (8.8%). Forty five right inferior hepatic veins were identified in 41 potential donors, and 68.9% of these veins were larger than 5 mm in diameter. CT angiography findings were confirmed in all donors who underwent operations. CONCLUSIONS: Multidetector CT angiography can successfully show the relevant hepatic vascular anatomy in potential liver donors.

Protective effects of fentanyl preconditioning on cardiomyocyte apoptosis induced by ischemia-reperfusion in rats.

We aimed to study the effect of fentanyl (Fen) preconditioning on cardiomyocyte apoptosis induced by ischemia-reperfusion (I/R) in rats. A total of 120 Sprague Dawley male rats (age: 3 months) were randomly divided into: sham operation group (S group), I/R group, normal saline I/R group (NS group), and fentanyl low, middle, and high dose groups (Fen1: 2 µg/kg; Fen2: 4 µg/kg; Fen3: 6 µg/kg). Heart rate (HR), mean arterial pressure (MAP), left ventricular developed pressure (LVDP), ±dp/dtmax, malondialdehyde (MDA), superoxide dismutase (SOD) activity, creatine phosphokinase-MB (CK-MB), and cardiac troponin-I (cTnI) were measured. Myocardial ischemic (MI) area, total apoptotic myocardial cells, and protein and mRNA expressions of B-cell lymphoma 2 (Bcl-2) and Bax were detected. HR and MAP were higher, while LVDP and ±dp/dtmax were close to the base value in the Fen groups compared to those in the I/R group. Decreased MDA concentration and CK-MB value and increased SOD activity were found in the Fen groups compared to the I/R group, while cTnI concentration was significantly lower in the Fen1 and Fen2 groups (all P<0.05). Myocardial damage was less in the Fen groups compared to the I/R group and the MI areas and apoptotic indexes were significantly lower in the Fen1 and Fen2 groups (all P<0.05). Furthermore, significantly increased protein and mRNA expressions of Bcl-2, and decreased protein and mRNA expressions of Bax were found in the Fen groups compared to the I/R group (all P<0.05). Fentanyl preconditioning may suppress cardiomyocyte apoptosis induced by I/R in rats by regulating Bcl-2 and Bax.

Sivelestat sodium hydrate attenuates acute lung injury by decreasing systemic inflammation in a rat model of severe burns.

OBJECTIVE: Patients with severe burns often develop acute lung injury (ALI), systemic inflammatory response syndrome (SIRS) often complicates with ALI. Sivelestat sodium hydrate is an effective drug against ALI. However, the mechanisms of this beneficial effect are still poorly understood. In the current study, we evaluate the effects of sivelestat sodium hydrate on systemic and local inflammatory parameters (neutrophil elastase [NE], interleukin [IL]-8, matrix metalloproteinase [MMP] 2 and 9) in a rat model of severe burns and ALI. And to analyze the correlations between expression of NE and IL-8 and acute lung injury. MATERIALS AND METHODS: 48 Sprague-Dawley (SD) rats were divided into 3 groups: normal control group, severe burns injury group and severe burns treated with sivelestat sodium hydrate group (SSI). The lung water content and PaO2 were detected in each group. Pathological manifestations in each group were observed for pathology scoring in SD rats with acute lung injury. ELISA was used for detecting expression of NE and IL-8 in serum and BAL specimens of SD rats in each group. RT-PCR was used to detect mRNA expression of NE and IL-8 in lung tissues of each group. Western blotting was used for detecting protein expression of MMP-2 and MMP-9 in lung tissues of each group. SPSS 18.0 was used for statistical analysis. RESULTS: The PaO2 was significantly increased after sivelestat sodium hydrate intravenous injection. Pathological score and water content of lung tissue were significantly decreased in SSI group compared with severe burns injury group, slightly higher than that normal control group. NE and IL-8 levels significantly decreased in serum, BAL and lung tissue specimens after sivelestat sodium hydrate intravenous injection; Expression of MMP-2 and MMP-9 were significantly up-regulated in severe burns group and showed no significantly changed after sivelestat sodium hydrate intravenous injection. CONCLUSIONS: In a rat model of severe burns and ALI, administration of sivelestat sodium hydrate improved symptoms of ALI and significantly decreased inflammatory parameters NE and IL-8.

Aromatization and hydrolysis of norethisterone-3-oxime in rabbit.

Two pharmacologically active metabolites, norethisterone (NET) and ethinylestradiol (EE2), were detected by HPLC and HPLC-RIA methods in rabbit plasma following single i.v. and i.g. administration at a dose of 1 mg/20 microCi/kg of [3H]norethisterone-3-oxime (NETO). Approximately 48% (i.v. injection) and 91% (i.g. administration) of the NETO dose were hydrolyzed to NET. Although only 0.35% of the NETO dose was aromatized to EE2, due to its high estrogenic potency, EE2 might contribute to the overall pharmacological pattern of NETO in the rabbit.

Isolation and characterization of three inhibitors of thymidine incorporation into bovine fetal liver cells.

During the isolation and purification of erythroid cell-stimulating factors from fetal tissues and blood, we found that they were almost invariably contaminated with substances that inhibited thymidine incorporation into erythroid cells of fetal bovine liver. We have isolated and partially sequenced three of these inhibitory factors. The first one was a 46-kDa heparin-binding protein from fetal bovine serum with 80% sequence identity with human apolipoprotein H (apo H). Although human apo H had no inhibitory activity on thymidine incorporation, the bovine apo H-like protein inhibited thymidine incorporation with an ID50 of 36 nM. It probably belongs to a group of heparin-binding apolipoproteins such as apo B and E, which have been reported to inhibit hematopoietic cells. The second inhibitor isolated from fetal bovine serum was clearly cytotoxic at a concentration of 1 nM. This 11-kDa peptide seems to be structurally related to the anaphylatoxins. The third inhibitor was isolated from human fetal intestine. The amino-terminal sequence of this protein was nearly identical to the amino-terminal sequence of human phospholipase A2 isolated from pancreas or lung. Bovine liver erythroid cell membranes are particularly sensitive to phospholipases. Since the synthesis and secretion of phospholipase A2 has been reported to be under the control of interleukin-1 or tumor necrosis factor in different cells, it is possible that this enzyme may be secreted locally and play an important role in tissue remodeling during injury or fetal development.

Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.

The neurotoxicity of beta-arteether (AE) is related to drug accumulation in blood due to slow and prolonged absorption from the intramuscular injection sites. In this efficacy and toxicity study of AE, the traditional sesame oil vehicle was replaced with cremophore to decrease the accumulation and toxicity of AE. Dihydroartemisinin (DQHS), a more toxic and active metabolite of AE, was also analyzed. When administered at a daily dosage of 25 mg/kg for seven days, blood accumulation of AE with sesame oil (AESO) was used had a 7.5-fold higher area under the curve (AUC) (on last versus first day dosing), while AE with cremophore (AECM) had only a 1.8-fold higher AUC. Although the accumulation of AECM was greatly reduced, its total exposure level (46.29 microg x h/ml) was 2.7-fold higher than with AESO (16.92 microg x h/ml) due to a higher bioavailability of AECM (74.5%) compared with AESO (20.3%). Total exposure time (calculated at over the minimal detected neurotoxicity level of 41.32 ng/ml) of AECM was 103 hours during the whole treatment period (192 hours), which was more than one-third (37%) less than with AESO (162 hours). Similar pharmacokinetic results were also shown with the active metabolite, DQHS. Anorexia and gastrointestinal toxicity with AESO were significantly more severe than with AECM (P < 0.001). Histopathologic examination of the brain demonstrated neurotoxic changes; the AESO rat group was significantly more severe than the AECM rat group. The brain injury scores with AECM were mild to moderate (2.3-3.0), and with AESO they were moderate to severe (3.0-4.7) on day 7 and day 10, respectively. In addition, the results of a 50% cure dose (CD50) against Plasmodium berghei in mice were 34.1 mg/kg for AESO and 14.2 mg/kg for AECM, indicating a significant higher efficacy was found in the AECM animals. Toxicity and efficacy of DQHS were also dependent on its exposure time and level, which was the same as its parent drug (AE). In conclusion, following the seven-day treatment in rats, AE and DQHS exposure time and level varied based on the vehicle used. The extension of drug exposure time and the low peak level of AE and DQHS were more associated with severe neurotoxicity and lower antimalarial efficacy, whereas the high level and short exposure time of AE and DQHS resulted in higher efficacy and milder toxicity.

Pharmacology and toxicology of artelinic acid: preclinical investigations on pharmacokinetics, metabolism, protein and red blood cell binding, and acute and anorectic toxicities.

The pharmacokinetics, metabolism, protein binding, red blood cell (RBC) binding, stability in vitro, and acute and anorectic toxicity of artelinic acid (ARTL) were investigated in various animal species and human blood samples. Absorption and distribution following 10 mg/kg intramuscular or oral administration in dogs and rats were very rapid with t1/2 0.12-0.54; there were also a high AUC (11,262 ng/h/mL) and Vss (9.5 L/kg), low CL (15 mL/min/kg) and long elimination time (t1/2 = 2.6 h), compared with rat data. Oral bioavailability of ARTL was 79.7% in dogs and 30.1% in rats. The conversion of ARTL to dihydroartemisinin (DART) in dogs (0.1-0.5% of total dose) after 3 routes of administration (intravenous, intramuscular and oral) was 10-fold lower than that in rats. In rats dosed with [14C]ARTL, unchanged ARTL accounted for less than 13% of the total radioactivity after all 3 administration routes, suggesting that ARTL was extensively biotransformed. The half-lives of total radioactivity (21-49 h) in urine were much longer than that of unchanged ARTL in plasma (1.4-3.7 h), indicating that some long-lasting metabolites of ARTL were formed in rats. The mass balance data showed that 77-83% of total radioactivity was recovered in urine and faeces. High binding capacity (79-95%) and low binding affinity (1.1-9.3 x 10-7 M) of ARTL were measured in rat, rabbit, dog, monkey and human plasma. The RBC/plasma ratios of [14C]ARTL were 0.35 and 0.44 for dog and human plasma, respectively. ARTL was much more stable than artesunic acid (ARTS) in rat and dog plasma, and both ARTL and ARTS were more stable in dog plasma than in rat plasma in vitro. The 50% lethal dose (LD50) of ARTL in rats was about 535 mg/kg. Multiple intramuscular dosing for 7 d of 50 mg/kg/d of ARTL caused mild anorectic toxicity compared to ARTS in rats. In contrast to 4 other artemisinin derivatives, ARTL seems to be a good antimalarial candidate as it has the highest plasma concentration, the highest binding capacities in RBC, the highest oral bioavailability, the longest elimination half-life, the lowest metabolism rate and the lowest toxicity at equivalent dose levels.

Analysis of anti-implantational action of norethisterone-3-oxime.

Mature rabbits received norethisterone-3-oxime (NETO) 2 mg/kg/day from day 2 through day 4 of pregnancy by gavage. Control rabbits were given vehicle. All animals were sacrificed on day 5. The oviducts were removed and sections stained with HE. Morphological changes were evaluated. The outer and inner diameters of tubes, and the thickness of circular muscle layers were measured. The layers of the circular muscle cells and the mean thickness occupied by the cytoplasmic mass of the muscle cells were estimated. The fertilized ova flushed out from the oviduct were stained together with the section of ampullary-isthmic junction (AIJ) and isthmus by PAS. The intensity of the staining was observed microscopically and quantified with a microspectrophotometer. NETO treatment led to tortuosity of oviducts showing hyperplasia of epithelial cells and a mucosal edema. The circular muscle layer was thickened but no increase in the number of muscle cells was observed, indicating muscular contraction. Dilatated and congested capillaries appeared in the muscular and subserous layers. All these manifestations were so prominent that the lumen of AIJ and isthmus portion were significantly narrowed as shown by a decreased percentage of inner diameter to outer diameter at AIJ and isthmus. The amount of mucin secreted into the lumen was decreased, but there was an accumulation of mucin in the epithelial cells. The above-mentioned morphological changes lead to the suggestion that the anti-implantational action of NETO is exhibited by its effect on the oviduct in rabbits. Most probably, the action is mainly related to the estrogenic and anti-progestational activity of NETO.

A modified method of UDS detection in vitro suitable for screening the DNA-damaging effects of chemicals.

The UDS induced in cultured FL cells by exposure to chemicals was measured as hydroxyurea-resistant incorporation of 3H-TdR in the acid-insoluble fraction of the 14C-TdR-prelabelled cells synchronized by the combination of arginine starvation and pretreatment with hydroxyurea. The level of UDS is represented by the ratios of 3H/14C radioactivities which are measures of specific activities of 3H. Two direct-acting alkylating agents, MMS and MNNG, a cross-linking agent, mitomycin C, and 3 procarcinogens, B(a)P, AFB1 and cyclophosphamide elicited UDS in the absence or presence of the liver-metabolizing system. Three chemicals of unknown carcinogenicity were also able to induce UDS in this assay system, i.e., bis-(O,O-diethylphosphinothioyl)-disulphide, 4-chlorophenoxy acetic acid (sodium salt) and caramelized malt sugar. With the exception of 4-chlorophenoxy acetic acid, they were also active in the Ames test.

Genotoxic activity of caramel on Salmonella and cultured mammalian cells.

The genetic activity of 2 commercial caramel preparations, manufactured either by heating the malt sugar solution directly (non-ammoniated caramel) or by heating it with ammonia (ammoniated caramel) was studied in the Salmonella mutagenicity test and UDS assay in cultured mammalian cells. The non-ammoniated caramel was found to be mutagenic to S. typhimurium TA100, while the ammoniated one was genetically active in all the tester strains used, namely TA100, TA97 and TA98. It was also demonstrated that non-ammoniated caramel was capable of inducing UDS in cultured human amnion FL cells, but for the ammoniated one, no such activity was observed. Furthermore, based on the results obtained in the DNA synthesis inhibition assay, it was suggested that the DNA synthesis inhibition seen in our experiments with the ammoniated caramel was probably not of DNA damage in origin. These data indicate that the mutagenic fractions formed during ammoniated and non-ammoniated caramelization were quite different.

The effects of media properties on the horseradish peroxidase-catalyzed fluorogenic reaction.

The effects of media properties including buffers, acidity, solvents and surfactant on horseradish peroxidase-catalyzed fluorogenic reaction were investigated. The results showed that the so-called non-fluorescent hydrogen donors were in fact fluorescent. There existed an acid-base equilibrium in the fluorescent dimer product. For p -hydroxyphenylpropionic acid, a pK(a) value of 8.0 for the product was obtained from its titration curve. The product fluorescence increased with higher pH, however, a longer time was needed to reach the reaction equilibrium due to the pH mismatch problem. Cationic micelles cetyltrimethylammonium bromide and cetyltrimethylammonium chloride could reduce the pH mismatch and offered a way to further increase the determination sensitivity. Finally, a micelle-enhanced flow-injection analysis of horseradish peroxidase is suggested.

The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats.

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.