Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer.

BACKGROUND: Neutropenia is common in patients receiving myelotoxic chemotherapy. Pegfilgrastim, a sustained-duration filgrastim is a once-per-cycle therapy for prophylactic neutrophil support. PATIENTS AND METHODS: Women, treated with four cycles of doxorubicin/docetaxel chemotherapy every 21 days, received pegfilgrastim or filgrastim 24 h after chemotherapy as a single subcutaneous injection per chemotherapy cycle (pegfilgrastim 30, 60 or 100 microg/kg) or daily subcutaneous injections (filgrastim 5 microg/kg/day). Safety, efficacy and pharmacokinetics were analyzed. RESULTS: The incidence of grade 4 neutropenia in cycle 1 was 95, 90 and 74%, in patients who received pegfilgrastim 30, 60 and 100 microg/kg, respectively, and 76% in patients who received filgrastim. Mean duration of grade 4 neutropenia in cycle 1 was 2.7,2 and 1.3 days for doses of pegfilgrastim, and 1.6 days for filgrastim. The pharmacokinetics of pegfilgrastim were non-linear and dependent on both dose and neutrophil count. Pegfilgrastim serum concentration was sustained until the neutrophil nadir occurred then declined rapidly as neutrophils started to recover, consistent with a self-regulating neutrophil-mediated clearance mechanism. The safety profiles of pegfilgrastim and filgrastim were similar. CONCLUSIONS: A single subcutaneous injection of pegfilgrastim 100 microg/kg provided neutrophil support and a safety profile comparable to daily subcutaneous injections of filgrastim during multiple chemotherapy cycles.

Ginger: an ethnomedical, chemical and pharmacological review.

Powerful medicinal properties have been recorded for Zingiber officinale, commonly known as ginger. All of these medicinal activities have been compiled with 99 references to the present status of the plant in the literature. Volatile components and the presence of trace metals are included. In addition, details of individual medicinal activities are given and the molecular structures of identified organic metabolites and their synthesis are described.

Chronotoxicity as related to chronobiology.

This review focuses primarily on the complexities of chronotoxicity and chronopharmacology (time-of-day effects on the metabolism of environmental chemicals and therapeutic agents as related to chronobiology). The nature of the melatonin signal may modify the function of the hepatic endoplasmic reticulum resulting in variations in the metabolism of xenobiotic chemicals. Concepts are explored for modification of exposure limits and/or Threshold Limit Values (TLVs) of industrial chemicals in risk assessment and health effects of workers on rotating shifts. The TLVs of chemicals may be changed during work shift schedules to minimize adverse health effects among workers.

The effect of nutrition on chemical toxicity.

The toxicity of chemicals, and of reactive oxygen species (ROS), are both affected by nutrition and diet. Calorific excess (continuous feeding), or deficiency (fasting), may increase production of ROS, which are also formed by interaction of toxic chemicals with cytochromes P450 (CYP2E or futile cycling). Both ROS (GSH reductase and peroxidase) and toxic chemicals (S-transferases) are detoxified by GSH enzymes; ROS are scavenged by a system comprising GSH, ascorbic acid and tocopherols, which may be regenerated by NADPH. Dietary protein is necessary for GSH or enzyme replacement, lipids are required for polyunsaturated fatty acids (PUFAs) and prostanoid biosynthesis, lipotropes and phospholipids for synthesis of endoplasmic reticulum, and folate is needed for dug metabolizing activity. Among required minerals, Se is necessary as the essential component of the antioxidant enzyme, glutathione peroxidase. Other dietary factors considered are the natural toxicants, gossypol, lathyrogens, glucosinolates, and saponins, and toxicants from food spoilage, food intoxication and food processing.

Vicia faba as a bioindicator of oil pollution.

In 1990, the Gulf War caused an unprecedented environmental catastrophe. More than 700 oil wells were set on fire, emitting thousands of tons of oxides of nitrogen, sulfur, soot and oil mist at high temperatures. The blazing oil wells and lakes were the major cause of environmental pollution, damaging flora and fauna throughout Kuwait and the surrounding region. We set up this study in order to investigate whether Vicia faba could be used as a bioindicator of oil pollution. Growth parameters of Vicia faba, such as levels of photosynthetic pigments, proteins, free amino acids, phenols, sugars, biomass, moisture and fatty acids, were studied. Levels of total reducible sugars, phenols, proteins, free amino acids and proline were found to be higher in plants grown in hydrocarbon-polluted soil, compared to those grown in control soil. However, biomass, moisture, pheophytin, the 435/415 nm ratio for chlorophylls and the chlorophyll a/carotenoid ratio, were higher in the plants grown in control soil than those grown in polluted soil. Our results indicate that Vicia faba can be used as a bioindicator of pollution and a ratio of the fatty acid C(20:1)/C(18:1) is an important index of environmental oil pollution.

Changes by progesterone derivatives in fatty acids from phosphatidylcholine and phosphatidylethanolamine fractions in rat liver endoplasmic reticulum.

The effects of two progesterone metabolites on fatty acid composition of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) from total liver and liver microsomes were studied in female rats. 16 alpha-Hydroxyprogesterone significantly increased the amount of fatty acids esterified to PC and PE fractions in total liver and liver microsomes. Both saturated and unsaturated fatty acyl components were enhanced. In contrast, 5 beta-pregnan-3 alpha-ol-20-one caused a reduction of fatty acids bound to PC and PE fractions from total liver and liver microsomes. Pregnanolone decreased both saturated and unsaturated fatty acids. Changes in specific fatty acids occurred in palmitic and stearic acids among saturated components, and palmitoleic, oleic, linoleic, eicosatrienoic, arachidonic and docosahexenoic acids among unsaturated ones. The unsaturated: saturated fatty acid ratio was raised by 16-alpha-hydroxyprogesterone and lowered by 5 beta-pregnan-3 alpha-ol-20-one in all phospholipid fractions. The induction of drug metabolizing enzymes by 16 alpha-hydroxyprogesterone may be related to an enhanced synthesis of microsomal phospholipids containing unsaturated fatty acids, particularly arachidonic and docosahexenoic acids. In contrast, the inhibition of drug metabolism by 5 beta-pregnan-3 alpha-ol-20-one is associated with reduced formation of unsaturated fatty acyl side chains.

Effect of environmental pollutants on hepatocellular function in rats: 3-methylcholanthrene and Aroclor-1254.

Environmental pollutants, Aroclor-1254 (PCB) and 3-methylcholanthrene (MC), were employed in this study to investigate some aspects of the induction of hepatic drug metabolism in rats. PCB and MC treatments increased 7-ethoxyresorufin and 7-ethoxycoumarin O-deethylase activities related to cytochrome P-448. Cytochrome P-450 reductase activity was increased by PCB while no effect was observed by MC treatment. Pretreatment with PCB resulted in approximately 50% increase in the phospholipid content of the microsomes whereas MC caused no change. Liver microsomal cholesterol content was decreased while triglycerides were increased by PCB. The ratio between saturated and unsaturated fatty acids (saturation index) decreased in the total microsomes and phospholipids with PCB treatment, whereas MC did not alter the ratio, except that the major effect of MC was observed in the acyl derivatives of microsomal phosphatidylethanolamine. It is proposed that the uniaxial rotation and mobility of hemoproteins may be restricted by an increase in the saturation index of the membrane, while a decreased index may facilitate contact with reductases for electron transfer by enhanced membrane fluidity. The decreased saturation index after treatment with MC may play a role in carcinogenicity by triggering induction of free radicals.

Modulation of bile acids induced by paraquat in rabbits.

Rabbit bile was examined for changes in composition induced by paraquat. Paraquat was administered intraperitoneally and changes in bile components were monitored by high performance liquid chromatography. Alterations in the ratios of total glycine/taurine conjugated bile acids (TGC/TTC), cholic acid/deoxycholic acid (CA/DC), cholic acid/chenodeoxycholic acid (CA/CDC) and cholic acid/cholesterol (CA/CH) were measured as an index of paraquat toxicity. A statistically significant increase in the ratio of TGC/TTC was observed, while CA/DC, CA/CDC and CA/CH showed a decrease. Phospholipids, protein, sugar, bilirubin, beta-carotene, vitamin A and vitamin E in the bile and serum of the experimental animals were also monitored. In bile, the levels of cholesterol, phospholipids, protein, sugar, and total bile acids increased while the levels of the antioxidants beta-carotene, vitamin A and vitamin E decreased. A decrease in the bilirubin content of the bile was also observed. These modifications may be useful clinically for assessment of paraquat toxicity.

Venous thromboembolism and high grade gliomas.

A retrospective study was done to determine the incidence of and the risk factors predisposing to clinical venous thromboembolism (VTE) in patients treated for high grade gliomas. Medical records of 68 consecutive patients diagnosed and treated at Saint Francis Hospital and Medical Center from January 1986 to June 1991 were reviewed. The follow up was to time of death or at least 6 months (up to December 1991). All clinically suspected episodes of VTE were confirmed by objective tests. Sixteen episodes of VTE were detected in 13 patients for an overall episode rate of 23.5%. Administration of chemotherapy (p = 0.027, two tailed Fisher exact test) and presence of paresis (p = 0.031, two tailed Fisher exact test) were statistically significant risk factors for the development of VTE. Thrombotic events were more likely to occur in the paretic limb and this difference was statistically significant (p = 0.00049, chi square test, with Yates correction). No major bleeding complications were seen in the nine episodes treated with long term anticoagulation. We conclude that venous thromboembolic complications are frequently encountered in patients being treated for high grade gliomas and the presence of paresis and the administration of chemotherapy increases the risk of such complications.

Thrombosis in patients with cancer.

The relationship between cancer and abnormalities of blood coagulation has been recognized for well over a century. Deep venous thrombosis of the lower extremities is most common, but pulmonary embolism, upper extremity vein thrombosis, disseminated intravascular coagulation, and other, more unusual, clinical events may occur. Chemotherapy also has been linked to thrombotic episodes. Anticoagulant therapy is appropriate in many patients with venous or arterial thrombosis. Prophylaxis of venous thrombosis is particularly important in hospitalized cancer patients who are at bed rest or undergoing surgery.

Modification of liver and serum enzymes by paraquat treatment in rabbits.

Paraquat (PQ) is known to cause progressive interstitial fibrosis in the lungs. Previous investigations have indicated that PQ acts by lipid peroxidation of the membrane. However, there are few reports on the action of PQ on hepatic enzymes. This work was carried out to investigate the modulation of various hepatic enzymes by PQ in rabbits. Paraquat was administered at a dose of 3, 6 or 12 mg/kg b. wt/day intraperitoneally to male rabbits for different periods of time. Administration of paraquat resulted in a significant decrease in plasma activities of transaminase enzymes, alkaline phosphatase and liver transketolase. No significant change was found in the activities of plasma and hepatic lactate dehydrogenase and alkaline phosphatase. A marked increase in blood glucose was noticed 48 hours after paraquat administration.

Effects of cervical adjustments on lateral-flexion passive end-range asymmetry and on blood pressure, heart rate and plasma catecholamine levels.

The biomechanical and physiological effects of a single, unilateral lower cervical spinal adjustment delivered to the most restricted side of cervical lateral-flexion passive end-range were examined. Only healthy, asymptomatic male subjects who exhibited goniometrically verified lateral-flexion passive range of motion asymmetries of 10 degrees or greater on the morning of the experiment were chosen for the study. Posttreatment goniometric measurements revealed that in sham-adjusted controls, mean lateral-flexion asymmetries had not changed significantly during the 4-hr time period examined. However, in subjects who received lower cervical adjustments, dramatic ameliorations of asymmetry magnitude were observed which persisted throughout the entire 4-hr posttreatment time period. On the other hand, in the face of this rather robust biomechanical effect, heart rate and blood pressure measurements obtained at -60 and -15 min prior to treatments, and at 5, 30, 60, 120 and 240 min following treatments, revealed no significant differences between adjusted and sham-adjusted subjects at any of the time periods examined. Consistent with this, analysis of the plasma concentrations of norepinephrine, epinephrine and dopamine in serial blood samples collected at these same times also failed to reveal significant differences between treatment groups at any of the time periods examined. The results of this investigation indicate that lower cervical adjustments are capable, at least in asymptomatic subjects, of inducing relatively robust biomechanical effects related to passive cervical end-range capability without simultaneously inducing significant alterations in the overall activity of the sympathetic nervous system.

Using anticoagulants safely. Guidelines for therapeutic and prophylactic regimens.

Heparin and warfarin sodium (Coumadin, Panwarfin, Sofarin) are used most often to treat acute and recurrent venous thromboembolic disease, arterial disease, valvular heart disease, and atrial fibrillation. These agents along with dextran, pneumatic compression devices, and gradient stockings are also used to prevent deep venous thrombosis and pulmonary embolism in patients at high risk (eg, those with venous stasis, lower limb or spinal cord trauma, clotting abnormalities). Anticoagulation therapy is monitored by maintaining the activated partial thromboplastin time and the prothrombin time in the therapeutic range.

Identification of Some Prostanoids in Aloe vera Extracts.

Screening of extracts from ALOE VERA revealed the presence of endogenous arachidonic acid, a potential precursor for the prostanoids synthesis. The presence of endogenous cyclooxygenase, in the plant extracts, was established by radiometric assay. Relatively high proportions of PGE (2) and TXB (2) and low proportions of other prostaglandins were identified in the plant extract when incubated with [ (14)C]-arachidonic acid. Other lipids present in this plant were examined and a high percentage of phosphatidylcholine and cholesterol was established. Possible importance of prostaglandins formed endogenously by the plant is discussed.

Spinal manipulation and beta-endorphin: a controlled study of the effect of a spinal manipulation on plasma beta-endorphin levels in normal males.

The role of spinal manipulation in the relief of pain is becoming clearer and more demonstrable as time passes. One approach to this study is the effect of manipulation on the neurochemical mechanisms of antinociception. Chief among these is beta-endorphin, which has been found to produce a wide range of beneficial effects, especially analgesia. The intent of our study was to demonstrate the effect of spinal manipulation on plasma beta-endorphin levels. Three groups of male subjects were randomly created: the experimental, sham and control groups. All three groups were screened for symptomatology, present use of medications and the present use of innocuous stimulants, such as nicotine and caffeine. A standard protocol involving a 20-min pretest resting period, an intervention and a 40-min test period ensued. The experimental group received a manipulation in the region of the cervical spine; the placebo group received a sham maneuver with no dynamic thrust; the control group received no intervention. Samples were taken by venipuncture at -20, -5, +5, +10 and +30 min. The data were analyzed by repeated measures analysis of variance and by Scheffe's post-hoc multiple comparison tests. Plasma beta-endorphin levels were assessed by radioimmune assay technique (according to the method described by Harber and Sutton in 1984). The results of our study demonstrated a small, but statistically significant, increase in serum beta-endorphin levels in the experimental group at the 5-min postintervention point. The levels in the placebo and control groups demonstrated a steady decrease that was distinct from the response in the experimental group.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional responses of the rat hepatic endoplasmic reticulum to treatment proposed as a model for cholestasis.

Concurrent treatments of cobalt chloride (CoCl2) and phenobarbital (PB), alone or in combination with lithocholic acid (LCA), were administered to rats for 7 days to assess whether or not a hypoactive hypertrophic smooth endoplasmic reticulum (HHSER) could be induced, as well as investigating the potential role of HHSER in the pathogenesis of cholestasis. LCA given alone slightly reduced hepatic triglycerides, significantly elevated plasma triglycerides and decreased microsomal glucose-6-phosphatase (G6P-ase) activity. PB administered alone significantly increased hepatic phospholipids and microsomal protein, phospholipid and cytochrome P-450 contents, as well as microsomal aminopyrine-N-demethylase (APDM-ase) activity. Functional indicators of liver impairment were associated primarily with CoCl2 treatment, whether given alone or in combination with PB + LCA. These signs included significantly reduced hepatic triglycerides, and increased plasma triglycerides associated with enhanced release of hepatic VLDL-triglycerides, as well as significantly decreased microsomal G6P-ase activity and/or reduced APDM-ase activity and cytochrome P-450 content. Elevated plasma bilirubin levels, and aspartate and alanine aminotransferase activities were also evident with concurrent CoCl2 + PB + LCA treatments. Combined CoCl2 + PB treatments, with or without LCA, caused significant increases in microsomal protein and phospholipid, and decreased activity of the rough endoplasmic reticulum (RER) marker G6P-ase, but no changes in cytochrome P-450 levels and no marked alterations in the activity of the SER marker APDM-ase. The data indicated that simultaneous CoCl2 and PB treatments, whether given alone or in combination with LCA, caused a functional impairment of the RER, and did not induce HHSER membranes.

Intrahepatic cholestasis as a side-effect of drug therapy.

Drug-induced hepatotoxicity causes 2-5% of hospitalization for jaundice; in the elderly this figure is close to 20%. The liver is particularly susceptible to drug damage because its blood supply delivers drugs in higher concentrations, and because of its role in metabolizing drugs. This article reviews the morphological, biochemical and clinical features of intrahepatic cholestasis, outlining the hypotheses for this frequent side-effect of drug therapy.

Phospholipids in the developing rat liver: fatty acid content and composition.

Fatty acid content and composition of hepatic phospholipids was studied in rats during the fetal and postnatal period of development. Total phospholipid fatty acid content showed increases related to age including an elevation of saturated fatty acids such as myristic, stearic arachidic and lignoceric acids. Palmitic acid was unchanged in females and only slightly altered in males. Unsaturated fatty acids from total phospholipids were discretely increased, including linoleic, linolenic, arachidonic, eicosapentaenoic, docosapentaenoic and docosahexaenoic acids. Total fatty acid content of phosphatidylcholine and phosphatidylethanolamine fractions were also increased in relation to age in both sexes. The unsaturated components, however, showed a larger proportional increase. Major acyl components involved in these age-related changes were significantly increased, including linolenic and arachidonic acids; palmitic and docosahexaenoic acids were decreased. These data indicate that in rat hepatic phospholipids a selective increase in unsaturated fatty acids predominated during development with profound influences in the subcellular distribution of these moieties.

Fatty acid content and composition of phospholipids from the endoplasmic reticulum in developing rat liver.

The development of enzyme functions of the endoplasmic reticulum in the neonatal rat liver is associated with the formation of membrane-bound phospholipids. This study examined the distribution of fatty acid moieties in isolated endoplasmic reticulum membranes of liver after birth and postnatal development. The content of microsomal phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and lysophosphatidylcholine was raised throughout the postnatal to the adult animal. Acyl components were also increased, especially unsaturated fatty acids such as arachidonic, docosapentaenoic and docosahexaenoic acids. Conversely, saturated components were reduced during maturation, such as palmitic and stearic acids. This work demonstrated that the ontogenesis of the hepatic endoplasmic reticulum correlated with the selectively increased production of discrete phospholipid moieties containing greater amounts of unsaturated fatty acids. Thus, during development, phospholipids are not only required for structural membrane assembly but also display a determining role in the organization of enzyme activity for xenobiotic biotransformation.