Intramuscular loading dose of quinine for falciparum malaria: pharmacokinetics and toxicity.

In a study of intramuscular injection of quinine eight adults with moderately severe falciparum malaria resistant to chloroquine were treated with quinine dihydrochloride, being given a loading dose of 20 mg salt (16.7 mg base)/kg followed by three or four eight hourly maintenance doses of 10 mg salt (8.3 mg base)/kg injected into the anterior thigh. All patients responded to treatment. Fever and parasite clearance times (mean (SD) 60 (23) h and 53 (22) h respectively) were comparable with those obtained with intravenous quinine. The mean peak plasma quinine concentration of 11.0 mg/l (34.4 mu mol/l) [corrected] was reached a median of five hours after administration of the loading dose. In all patients plasma quinine concentrations exceeded the high minimum inhibitory concentration for Plasmodium falciparum malaria prevalent in Thailand within four hours of the start of treatment but did not cause toxicity other than mild cinchonism. When intravenous infusion is not possible an intramuscular quinine loading dose is an effective means of starting treatment in patients with moderately severe falciparum malaria who cannot swallow tablets.     

An evaluation of ampicillin pharmacokinetics and toxicity in guinea pigs

Sodium ampicillin was administered subcutaneously to 350-550 g male Dunkin Hartley guinea pigs at doses of 6, 8 and 10 mg/kg tid for 5 days. Over a period of 12 days, the lowest ampicillin dose appeared to be tolerated well. However, significant body weight reduction and mortality occurred with the two higher dosage regimens. Cecal cultures of dead animals confirmed the presence of Clostridium difficile, an organism associated with antibiotic-induced enterotoxemia. Assay of serum collected from ampicillin-treated animals revealed ampicillin concentrations of approximately 10 micrograms/ml at 5 minutes post-dosing which fell precipitously to less than 0.2 micrograms/ml at 60 minutes. Determination of biliary ampicillin levels during the 60 minutes after administration of a single 10 mg/kg SQ dose revealed concentrations ranging from 18 micrograms/ml to 90 micrograms/ml. Estimates of total urinary ampicillin content after a single 10 mg/kg SQ dose were less than 500 micrograms/animal at 7.5 minutes, but increased to greater than 2000 micrograms/animal at 60 minutes after dosing. Results of this study indicated that due to its short serum half-life, sodium ampicillin probably has little systemic therapeutic efficacy in guinea pigs. Because high concentrations of ampicillin accumulated in the urine and bile, the antibiotic probably would have therapeutic efficacy for urinary and intestinal infections. However, its associated toxicity at large doses probably precludes its use. In view of the rapid clearance of ampicillin in guinea pigs in comparison to other species, the pharmacokinetics of other antibiotics, especially those reported to be less toxic for guinea pigs, should be considered.     

Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: an interspecies comparison

This study was undertaken to assess the developmental toxicity and drug distributional and metabolic characteristics of prenatal valproic acid (VPA) exposure in rhesus monkeys. Oral administration of 20-600 mg/kg/day VPA (approximately 1-15 X human therapeutic dose) to 33 animals on variable gestational days (GD) during organogenesis resulted in dose-dependent developmental toxicity manifested as increased embryo/fetal mortality, intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic plasma elimination curves were observed for total and free VPA on the first (GD 21) and last (GD 50) days of treatment in the 100- and 200-mg/kg/day dose groups. VPA exhibited dose-independent elimination kinetics at the plasma concentrations observed in this study. There was no significant change in pharmacokinetic parameters (maternal plasma elimination rate, area under the curve, peak plasma concentration) between the first and last days of treatment at either dose level. Placental transfer studies indicated that embryos were exposed to half the free VPA concentrations present in maternal plasma on GD 37. Comparisons of interspecies sensitivity to VPA-induced developmental toxicity in the mouse, rat, monkey, and man are made.     

Fetal toxicity of cadmium chloride: the pharmacokinetics in the pregnant Wistar rat

The pharmacokinetics of a single subcutaneous injection of 40 mumol/kg CdCl2 in pregnant rats on day 18 were studied during an 18-hour time period. Previous studies demonstrated that this dose of CdCl2 induced fetal death, placental necrosis, and a reduction of uteroplacental blood flow without maternal lethality; direct fetal injections of CdCl2 indicated that the site of toxic action was not in the fetus. Cadmium was rapidly absorbed from the intrascapular subcutaneous depot with the highest blood levels occurring within 5 minutes of injection. The release from the depot appeared to be multiphasic with both rapid and slow absorption components observed in the blood. Uptake of cadmium was greatest in the liver, followed by the placenta, kidney, and pancreas. The best fit to the data was obtained by assuming the existence of two pools of cadmium in the organs: one freely exchangeable with the blood and the other nonexchangeable. Deviations from model predictions were observed for the placenta and adrenals; these deviations are consistent with the concomitant diminished blood flow to these organs. Cadmium uptake by the fetus was also investigated, and the results support the hypothesis that the placenta is relatively impermeable to the toxicant. It is concluded that the rapid and extensive accumulation of cadmium by the placenta may play a role in the development of early placental cellular damage and the eventual induction of fetal death through uteroplacental dysfunction.     

Subcutaneous recombinant gamma interferon in cancer patients: toxicity,pharmacokinetics, and immunomodulatory effects

Summary Recombinant gamma interferon (r-IFN) was administered s. c. daily to 26 patients with advanced cancer. Patients were assigned to one of six doses: 0.5, 1, 2, 4, 6, or 8 million units (MU)/m² per d. The major toxicities were an influenza-like syndrome and fever, seen in all patients. Dose limiting toxicity occurred in 4 of 4 patients treated at 8 MU/m². One patient with nodular poorly differentiated lymphocytic lymphoma had a mixed response, and two patients with renal cell cancer have had stabilization of disease for >10 and >12 months. Pharmacokinetic analysis, by radioimmunoassay, revealed mean serum r-IFN concentrations up to 17 ng/ml, with maximal serum levels noted 6 to 13 h after injection. In vivo immunomodulation was assessed by natural killer (NK) cytotoxicity, monocyte activation as determined by cell surface expression of HLA-Dr, and peripheral blood mononuclear cell phenotype analysis by flow cytometry. The mean T₄/T₈ ratio increased from 2.1 pretreatment to 4.1 after 24 h of treatment, but returned to baseline after 7 and 28 days of treatment. Augmentation of NK function was noted after 7 days of treatment. Monocyte cell surface expression of HLA-Dr increased after 28 days of treatment at the three lowest doses. In conclusion, daily s. c. r-IFN can be easily administered on an outpatient basis with minimal local skin toxicity, results in prolonged serum levels, and is associated with immunological changes of potential antitumor significance. Further study of the in vivo immunomodulatory effects induced by r-IFN is indicated to help define the optimal treatment regimen.Recipient of a Clinical Investigator Award CA 01030 from the National Cancer Institute, NIH, DHHS. Supported by the Clinical Research Division of the Schering Corporation. A portion of this work was conducted at the Clinical Research Center of the University of Washington, supported by the NIH Grant RR-37. Additional support provided by the National Cancer Institute Grant CA 09515     

In silico evaluation of pharmacokinetics and acute toxicity of withanolides in Ashawagandha

Ashwagandha is a medicinal plant used in traditional Asian medicines as an adaptogen to promote both physical and mental health. Withanolides are the major bioactive phytochemicals in Ashwagandha; they are a group of naturally occurring C₂₈-steroidal lactones with an ergostane-based skeleton. Despite the broad use of Ashwagandha, data on the pharmacokinetic and toxicological properties of withanolides remain scarce. Here, 75 withanolides in Ashwagandha were identified in journal publications, databases, and monographs. In silico quantitative structure-activity relationship (QSAR) models were used to evaluate the physicochemical and pharmacokinetic properties as well as the acute toxicity of withanolides. Withanolides had high molecular weight and pKa, low aqueous solubility, and high lipophilicity. QSAR models also predicted high effective human jejunal permeability and plasma protein binding, tissue partitioning, extensive metabolism, hepatic uptake, and renal excretion for certain withanolides. In addition, two thirds of the withanolides evaluated had predicted median lethal dose (LD₅₀) under 100 mg/kg after oral administration in rats. These in silico results could be used to guide further testing and confirmed by in vitro and in vivo studies.     

Interferon and Interferon Inducers in Protozoal Infections

Several interferon inducers (Newcastle disease virus, statolon, and poly rI:poly rC) as well as exogenous mouse interferon protect mice from sporozoite-induced Plasmodium berghei malaria, as long as they are administered before the end of the preerythrocytic phase of development of the parasite. The protective effect of the interferon inducers was related to their interferon-inducing effect; the protective effect of the interferon preparations was related to the interferon titer of the preparations, and it exhibited other attributes of interferon such as species specificity. In contrast to sporozoite-induced infection, blood forms-induced P. berghei malaria was only weakly susceptible to the protective effect of interferon inducers. This difference may provide an approach to study the mechanism of protection. The growth in cell cultures of another intracellular protozoon, Toxoplasma gondii, is also inhibited by interferon (22). The fact that P. berghei and T. gondii (as well as another group of intracellular parasites susceptible to interferon, the Chlamydia) have their own ribosomes raises questions, concerning the role of host cell ribosomes in the host cell-parasite relationship of these intracellular parasites and in the mechanism of interferon action against them, that can be approached experimentally. The possibility of therapeutic or prophylactic application of interferon or of its inducers to certain protozoal diseases of man and of other animals is still remote, but it has to be considered for long range planning.     

Cellular Alteration by Interferon: a Virus-Free System for Assaying Interferon

A system is described for assaying mouse interferon without using a viral "challenge" agent. Interferon-treated L cells were destroyed by exposure to polyriboinosinic.polyribocytidylic acid [poly(I).poly(C)], and the amount of destruction was dependent on both the concentration of interferon to which the cells were exposed and the amount of poly(I).poly(C) used as the "challenge" material. If the amount of poly(I).poly(C) was constant, the concentration of interferon could be determined by quantitating cell destruction 6 hr after addition of the double-stranded ribonucleic acid. In addition to eliminating the necessity for employing infectious virus for interferon assays, this system has the advantages of being quicker, easier, and more sensitive than other interferon assays. The sensitivity of the assay is related directly to the amount of poly(I).poly(C) applied to the cells, with each fivefold increase of poly(I).poly(C) giving about a fivefold increase of sensitivity.     

Poxviruses: Interfering with Interferon

Interferon (IFN) is an important innate defense against virus infection and many viruses have consequently evolved ways to interfere with the action of IFN. The poxviruses are an excellent example and devote at least four proteins to this task. Two function within the infected cell to block the action of IFN-induced antiviral proteins, and two are secreted to capture type I and type II IFNs before they can bind to cellular IFN receptors. The vaccinia virus IFN receptors have a surprisingly broad species specificity that may aid virus replication in several species and provide clues about the enigmatic origin of vaccinia virus.     

Interferon and Interferon Inducers in the Treatment of Malignancies

The mechanism of the antitumor action of polyinosinic-polycytidylic acid is probably multifaceted. The compound induces the synthesis of interferon, and interferon probably is active against some tumors. Poly I:poly C alters protein and RNA synthesis in tissue culture. It specifically inhibits such macromolecule synthesis in tumors in vivo, while having less inhibitory action on synthesis in normal organs, or it may actually enhance. Finally, poly I:poly C strongly enhances graft vs. host rejection mechanisms, which may play a role in the rejection of some tumors.     

Radiosensitization, pharmacokinetics, and toxicity of a 2-nitroimidazole nucleoside (RA-263)

A 2-nitroimidazole nucleoside, 1-(2',3'-dideoxy-alpha-D-erythro-hex-2'-enopyranosyl)-2-nitroimida zole (RA-263), has been investigated for its radiosensitization, pharmacokinetics, and toxicity properties. The in vitro radiosensitization tests against hypoxic Chinese hamster (V-79) cells demonstrated that RA-263 was a more potent radiosensitizer than misonidazole and at 2 mM concentration approached the oxic curve. Significant in vitro radiosensitization activity was also observed in EMT6 mammary tumor cells. The in vitro cytotoxicity data suggested that RA-263 is considerably more toxic to hypoxic cells than misonidazole. The increased cytotoxicity may be related to its higher depletion of nonprotein thiols (NPSH) than misonidazole. The combined effects of radiosensitization and hypoxic cell toxicity were measured by preincubation of the V-79 cells for 4 h under hypoxic conditions before irradiation. The results demonstrated a synergistic response by causing a significant decrease in the extrapolation number with loss of shoulder of the radiation survival curves. The in vivo radiosensitization experiments conducted by the in vivo-in vitro cloning assay with the EMT6 mammary tumor indicate that RA-263 is an effective sensitizer. Pharmacokinetic data suggested that RA-263 was eliminated from plasma by a rapid alpha phase and a slower beta phase with T 1/2 of 36 and 72 min, respectively. The concentration in the brain was approximately one-sixth of tumor concentration, suggesting that RA-263 is excluded from the CNS. Moreover, RA-263 was two times less toxic than misonidazole on equimolar basis by acute LD50 tests. This agent was also significantly less mutagenic than misonidazole in a strain of Escherichia coli.     

干扰素及其基因工程

1　概述Ｚｓｓａｃｓ和Ｌｉｎｄｅｎｍａｎｎ于 185 7年首先发现受到病毒感染的细胞能产生一种物质 ,可以保护其它细胞抗御多种病毒的感染 ,并命名为干扰素。现定义为 :由干扰素诱导剂作用于活细胞后 ,由活细胞产生的一种蛋白质 ,当它再作用于其他细胞时 ,使其它细胞立即获得抗病毒和抗肿瘤等多方面的免疫力。病毒、细菌、立克次图 1　干扰素的作用机制氏体、真菌以及原虫等都能诱导细胞产生干扰素。细菌的内毒素、外毒素、放线菌素Ｄ(ａｃｔｉｎｏｍｙｃｉｎＤ)等也能诱导产生干扰素。人工合成的物质如聚次黄嘌呤核苷酸 (聚肌苷酸 ) :聚胞…