Effect of minoxidil on platelet function and the synthesis of prostaglandins in platelets.

At the 12.5 micrograms level, minoxidil prevents the irreversible aggregation of platelets by 2 x 10(-6) mol/L adenosine diphosphate (ADP). Levels of minoxidil greater than 12.5 micrograms cause a reversal of primary aggregation by 2 x 10(-6) mol/L ADP. Aggregation of platelets in response to 125 micrograms of arachidonic acid is measurably reduced by 12.5 micrograms of minoxidil and totally suppressed by 30 micrograms. Concurrent with the inhibition of platelet aggregation, increasing concentrations of minoxidil cause a gradual reduction in the synthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2). In the presence of 100 micrograms of minoxidil, PGE2 is reduced from a control value of 87.7 +/- 2.2 pg/ml to 23.9 +/- 3.2 pg/ml. At this level of minoxidil, TxB2 drops from 105 +/- 3.3 ng/ml to 10.5 +/- 2.6 ng/ml. The effect of minoxidil on platelet aggregation is not associated with increased cyclic adenosine monophosphate synthesis. All data support the conclusion that minoxidil functions (in platelet metabolism) primarily as a cyclooxygenase inhibitor.

Effects of hypothyroidism and short-term aging on whole blood thromboxane and arterial prostacyclin synthesis.

Hypothyroidism results in decreased platelet aggregation and has unique effects on the development of atherosclerosis and angina pectoris. Because prostacyclin and thromboxane A2 profoundly influence platelet function and vascular tone and are thought to be important in the development of atherosclerosis and angina pectoris, we studied the effects of hypothyroidism in rats on the in vitro elaboration of prostacyclin passively by aortic tissue and of thromboxane A2 by thrombin-stimulated whole blood. Hypothyroidism induced by iodine 131 (given at age 7 weeks) persistently caused a mild decrease in platelet count (P less than 0.01) and 30% decrease in immunoreactive thromboxane B2 (the hydrolysis product of thromboxane A2) generation per platelet (P less than 0.01) compared with age-matched euthyroid rats. Between 20 and 23 weeks of age immunoreactive 6-ketoprostaglandin F1 alpha (the hydrolysis product of prostacyclin) generation decreased by 30% in euthyroid rats. In hypothyroid rats less than 23 weeks of age, 6-ketoprostaglandin F1 alpha production was the same as that of age-matched euthyroid rats. With further aging, 6-ketoprostaglandin F1 alpha production did not decrease as it did in euthyroid rats. Hypothyroid rats more than 20 weeks old had, therefore, significantly greater 6-ketoprostaglandin F1 alpha production than age-matched euthyroid rats (P less than 0.005). L-Thyroxine given daily for 28 days to 23-week-old hypothyroid rats caused a rapid increase in platelet count and a delayed normalization of the thromboxane synthetic abnormality. 6-Ketoprostaglandin F1 alpha production transiently increased in response to L-thyroxine, but decreased to the euthyroid level after 28 days of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemoperfusion of phencyclidine in the dog.

Experiments were conducted to determine whether charcoal hemoperfusion (HP) would be useful in severe phencyclidine (PCP) overdose. Dogs were given a single 5 mg/kg injection of PCP. In 6 experiments HP for 2.5 hours was done; and in 6 control experiments, the extracorporeal circuit contained no HP cartridge. The number of seizures, symptoms, duration of coma, and PCP concentrations in the tissues of HP dogs were not different from control. PCP clearance by HP was 67 +/- 16.5 ml/min. PCP recovery by HP was 2.25 +/- 0.25 mg (2.0% of the administered dose). Urinary excretion of PCP was 1.33 +/- 0.46 mg (1.2% of the dose). Volume of distribution of PCP was 21.8 +/- 1.7 L/kg. Due to the high volume of distribution, high lipid solubility and low plasma levels of PCP, HP was not effective in managing PCP overdose in the dog.

Effect of orally administered magnesium hydroxide in experimental iron intoxication.

We have previously shown that ferrous and ferric ions readily for complexes with magnesium hydroxide [Mg(OH)2] thus reducing the absorption of iron salts from the gastrointestinal tract. The present study answers the following question: what is the optimal dose, time of administration, optimal limit of effectiveness, and potential hazard of this form of therapy. Adult mongrel dogs were administered ferrous sulfate [FeSO4] tablets at a dosage of 650 mg/lb of body weight. Either 30 or 60 minutes later, the dogs were given Mg(OH)2 at either 5 or l0 times the dose of elemental iron. Serum iron concentrations in all animals given Mg(OH)2 were significantly lower (p less than 0.05) than those of control animals. No significant differences were observed regardless of dose or time of administration of Mg(OH)2. Although serum Mg++ concentrations were significantly elevated (p less than 0.05) om all treated animals 4 and 6 hr post iron, no clinical manifestations of hypermagnesemia were observed. These studies demonstrate the effectiveness of Mg(OH)2 in the management of experimental iron intoxication and warrant a controlled clinical trial in humans.

Decreased absorption of propoxyphene by activated charcoal.

In 1968 we first suggested that activated charcoal (AC) should be administered in the emergency treatment of propoxyphene overdosage. The dramatic increase in recent years of deaths involving propoxyphene has prompted us to again evaluate the efficacy of AC in preventing absorption of propoxyphene from the GI tract. Male rats (100-125 g) were administered propoxyphene hydrochloride (P-HCl, 350 mg/kg) or propoxyphene napsylate (P-N, 825 mg/kg) either dissolved or suspended in 5% acacia in H2O. After 30 min the rats were administered either AC at 10 times the drug dose or water. Surviving rats were sacrificed at 1, 2, 4, 8, 12, and 24 h; the brain, liver, and both kidneys were removed intact, weighed, and stored at -70 degrees C. After lyophilization, the tissues were analyzed for propoxyphene and its metabolite, norpropoxyphene, by GLC. There were significantly less deaths in rats that received P-HCl + AC or P-N + AC than rats that received either P-HCl or P-N alone (9 vs 19, p less than .01 and 5 vs 10, p less than .05 respectively). Tissue levels of propoxyphene and norpropoxyphene were similarly significantly reduced. These studies provide further evidence of the efficacy of AC in propoxyphene overdosage.

A stable parenteral solution of apomorphine.

A sterile, stable apomorphine preparation suitable for parenteral use was prepared by dissolving 0.3% w/v powdered apomorphine hydrochloride in 1% reduced l-ascorbic acid. The solution was then sterilized by filtration through a 0.22 -micrometer Millipore filter, the air in the vial was replaced by nitrogen, and the vials were sealed and stored at 5 degrees C in the dark. Under these conditions the apomorphine solutions remained water-clear and retained their potency for at least 1 year following preparation.

Decreased alpha-adrenergic receptors in newborn platelets: cause of abnormal response to epinephrine.

Platelets of newborn infants fail to aggregate or release adenosine diphosphate in response to epinephrine. Because epinephrine-induced aggregation is an alpha-adrenergic event, we considered the possibility that newborn platelets possess fewer alpha-adrenergic receptors than do those of adults. Therefore we compared the specific binding of the alpha-adrenergic antagonist, [3H]-dihydroergocryptine (DHE), in intact washed platelets prepared from paired samples of maternal and cord platelet-rich plasma. Newborn platelets demonstrated normal kinetics of [3H]-DHE binding and normal affinity for [3H]-DHE. Scatchard analysis of [3H]-DHE binding indicated a single class of binding sites that exhibited a high affinity for the radioligand (Kd = 10 nM). Maternal platelets were found to bind approximately 2-fold more [3H]-DHE than newborn platelets (3.70 +/- 0.28 vs. 1.74 +/- 0.17 fmol/10(7) platelets) at saturation. This corresponds to 223 +/- 17 vs. 105 +/- 11 binding sites per platelet (p less than 0.001). Repeat washing of newborn platelets did not yield increased [3H]-DHE binding suggesting the binding sites had not previously been masked by elevated circulating levels of catecholamines in venous cord blood. When control platelets were incubated with concentrations of [3H]-DHE that half-saturated the alpha-adrenergic receptors, diminution of platelet function comparable to that seen in newborn platelets was observed. Since maternal and newborn platelets are similar size, it appears that a deficiency of alpha-adrenergic receptors may account for the diminished response of newborn platelets to epinephrine.

Neonatal platelet function: a membrane-related phenomenon?

Synthesis of prostaglandin endoperoxides was evaluated in paired maternal and cord blood samples. Platelets from mothers and neonates aggregated normally in response to arachidonic acid (AA). Cyclooxygenase activity was evaluated by monitoring the incorporation of radioactivity into prostaglandin endoperoxide metabolites after incubation with 1-14C-AA. Thin layer radiochromatograms of methylated incubation products revealed three main peaks corresponding to 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid, 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT), and 8-(1-hydroxy-3-oxoproply)-9,12-L-dihydroxy-5,10-heptadecadienoic acid (TXB2). Maternal and neonatal platelets incorporated similar amounts of radioactivity into HHT and TXB2. Radioimmunoassay for TXB2 in thrombin-clotted PRP revealed no significant differences between maternal and neonatal platelets. Since these metabolites are derived from cyclic endoperoxides formed by the action of cyclooxygenase on AA, we conclude that prostaglandin endoperoxide synthesis is fully developed in neonatal platelets. Mutual correction of collagen-induced platelet aggregation and ADP release was observed when equal volumes of neonatal and aspirin-treated adult platelet-rich plasma were mixed. Therefore, since neonatal platelets contain normal amounts of storage pool nucleotides, we also conclude that the defective secondary aggregation and release seen in neonatal platelets is caused by a failure in the release of AA from membrane phospholipids upon stimulation with collagen or epinephrine.

Activated charcoal adsorbs aflatoxin B1.

Activated charcoal was demonstrated to adsorb aflatoxin B1 in an efficient manner in vitro at a neutral pH. One mg aflatoxin was adsorbed by 100mg activated charcoal. The complex appeared to be quite stable. Destruction of the aflatoxin by alkaline conditions was confirmed, and a large measure of destruction was also noted at acid pH. Implications of the adsorption phenomenon include prevention of systemic absorption.

Aspirin in pregnancy: maternal and fetal effects.

Recent surveys of prenatal drug consumption indicate that aspirin is the most frequently consumed drug in pregnancy. Over the past several years, numerous reports have suggested a possible association between prenatal aspirin ingestion and adverse effects in the pregnant woman and her developing fetus. This review summarizes the available experimental animal and human epidemiological data on the possible teratogenicity of aspirin, its effects on fetal lethality, its effects on the duration of pregnancy and parturition, and its ability to alter hemostatic mechanisms in both the mother and newborn. From an analysis of the data, it appears that, although direct conclusive evidence of adverse effects in humans is lacking, a potential hazard does exist and thus "the indiscriminate use of aspirin during pregnancy is contraindicated."

Newborn platelet dysfunction: a storage pool and release defect.

Per cent aggregation, release and content of adenine nucleotides, and specific radioactivity were evaluated in citrated platelet-rich plasma (PRP) prepared from paired samples of maternal and cord blood. Platelets of newborn infants aggregated normally in response to highdose ADP (20 muM), strong collagen suspensions, and thrombin; however, when compared with PRP from the mothers or from normal adults, per cent aggregation in response to lower concentrations of ADP (2 muM), weak collagen, and part particularly epinephrine was markedly reduced. Nucleotide release after stimulation of the newborns' PRP with the latter two inducers was also impaired. ATP and ADP content of the newborns' platelets was also significantly less than that of their mothers or of normal adults, but specific activity was normal. The data suggest that the impairment of ADP release in the platelets of newborn infants is due to decreased sensitivity to external stimuli. Since metabolic ATP is necessary for the platelet release reaction, it is postulated that the platelet dysfunction results from a lack of metabolic ATP.