The use of dimenhydrinate in conjunction with dexamethasone for induction of parturition in beef cattle

Forty-eight crossbred Chianina cows (3 to 5 years of age), with an expected gestation length of 288 days, were randomly divided into four treatment groups to evaluate the use of dimenhydrinate (an antihistamine agent) in conjunction with dexamethasone (DEX) for inducing parturition in beef cattle. Group (A) received a 20 mg dose of DEX (im) on day 282 of gestation and a carrier vehicle (iv) 24 hours later (day 283); Group (B) was given a carrier vehicle (im) on day 282 and 500 mg of dimenhy-drinate (DMH) diluted in 200 ml of 2.5% dextrose-0.9% saline solution given (iv) on day 283 and Group (C) received 20 mg of DEX (im) on day 282 and 500 mg of DMH in solution (iv) on day 283 of gestation. The remaining 12 cows assigned to Group (D) were not handled and were allowed to calve under natural conditions. The number of cows calving and percent calving within 60 hours after the first injection were: 10(91%), none(0%) and 12(100%) for the DEX, DMH and DEX plus DMH groups, respectively. The mean gestation length of the control cows in Group (D) was 288.6 days. Frequency of dystocia was: 18.2, 8.3, 0 and 0% and retained placentae (>/=24 hours) was: 72.8, 16.6, 33.3 and 0% for DEX, DMH, DEX plus DMH and control groups, respectively. In this study, a 20 mg dose of DEX (im) followed 24 hours later with 500 mg of DMH (iv) was more successful for calving induction than when DEX or DMH was used alone. The combination DEX and DMH treatment induced calving in a shorter interval from treatment (P<.05) and decreased the incidence of retained placentae (P<.01) when compared with those induced following DEX treatment.     

The role of arachidonic acid metabolism in the activities of interleukin 1 and 2

Several investigations have suggested that products of arachidonic acid metabolism have modulatory effects on the development of cellular immunity. In this report we have studied the role of arachidonic acid metabolism in the specific effects of interleukin 1 (IL 1) induction of interleukin 2 (IL 2), and also IL 2 stimulation of proliferation and interferon-gamma (IFN-gamma) production. Utilizing cell lines that are specifically responsive to IL 1 or IL 2, it was found that both interleukins stimulate lipoxygenation of arachidonic acid in their respective target cell. The ability of each interleukin to induce monohydroxyeicosatetraenoic acid (HETE) correlated with the induction of secondary lymphokine secretion. Utilizing selective and partially selective pharmacologic inhibitors of arachidonic acid metabolism, the data suggest that the participation of lipoxygenase activity is required for both IL 1 induction of IL 2 production and IL 2 regulation of proliferation and IFN-gamma secretion. The same requirement for lipoxygenase activity was seen when phorbol myristate acetate (PMA) was used as a secretory stimulant, suggesting a similar mode of action for stimulation-secretory activity between PMA and interleukins. Studies performed with an endogenous inhibitor of 5-lipoxygenase (15-HETE) demonstrated the requirement of this enzyme system for IL 2-dependent proliferation and IFN-gamma production. Although leukotrienes could replace IL 2 for IFN-gamma secretion, they had no effect on IL 2 growth promotion. The results suggest that both IL 1 and IL 2, and PMA, may share the lipoxygenase pathway of arachidonic acid metabolism which is a component of the intracellular signal transduction process that regulates secretory activity and/or cellular proliferation.     

Differential effects of prostaglandin synthetase stimulators on inhibition of cyclooxygenase.

The different effects of prostaglandin synthetase stimulators on inhibition of the cyclooxygenase by structurally distinct classes of nonsteroidal antiinflammatory agents suggest that the enzyme is altered by interaction with these stimulators. Reversible stimulation of prostaglandin synthetase activity by phenols and some other compounds and the relative influence of these stimulators on inhibitors of the cyclooxygenase were determined quantitatively. Two distinct classes of inhibitors were established. The fenamates were relatively weak inhibitors alone but were much more potent in the presence of phenolic compounds. In contrast, ibuprofen, indomethacin, and flurbiprofen were more potent than the fenamates and were reduced in effectiveness by the stimulators, as expected on the basis of two opposing actions. The relative potency of the cyclooxygenase stimulators (phenol greater than norepinephrine greater than tryptophan greater than benzoquinone greater than anisole) paralleled their synergistic action on the fenamates and their antagonist action on the nonfenamates. This correlation suggests that an enzyme alteration which leads to cyclooxygenase stimulation may also result in increased sensitivity to fenamates and decreased sensitivity to the other inhibitors, possibly by altering their capacity to bind.     

Effects of indomethacin on moloney sarcoma virus-induced tumors

Chronic administration of indomethacin to weanling (20 day old) BALB/c mice inoculated with Moloney sarcoma virus (MSV) delayed the onset of the tumor and suppressed the tumor growth. As expected, the prostaglandin (PG) levels associated with the MSV-injected leg muscle of the indomethacin treated mice were greatly depressed when compared to the elevated PG content associated with the tumors of MSV injected control mice. There was no effect of indomethacin on the cyclic AMP or cyclic GMP levels.The elevated levels of PG and cyclic AMP associated with the tumor were found to parallel the tumor growth.Administration of antilymphocyte serum (ALS) to the mice at the time of MSV inoculation resulted in accelerated and enhanced tumor growth. Indomethacin treatment of these mice similarly suppressed the tumor growth, but less dramatically.     

A Multi-Center,Randomized, Controlled,Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury

Objective

Acute kidney injury (AKI) is a highly morbid condition in critically ill patients that is associated with high mortality. Previous clinical studies have demonstrated the safety and efficacy of the Selective Cytopheretic Device (SCD) in the treatment of AKI requiring continuous renal replacement therapy in the intensive care unit (ICU).

Design, Setting, Patients

A randomized, controlled trial of 134 ICU patients with AKI, 69 received continuous renal replacement therapy (CRRT) alone and 65 received SCD therapy.

Results

No significant difference in 60-day mortality was observed between the treated (27/69; 39%) and control patients (21/59; 36%, with six patients lost to follow up) in the intention to treat (ITT) analysis. Of the 19 SCD subjects (CRRT+SCD) and 31 control subjects (CRRT alone) who maintained a post-filter ionized calcium (iCa) level in the protocol’s recommended range (≤ 0.4mmol/L) for greater or equal to 90% of the therapy time, 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the CRRT alone group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD treated versus control CRRT alone patients maintained for ≥ 90% of the treatment in the protocol’s recommended (r) iCa target range of ≤ 0.4 mmol/L with values of, 0% (0/16) and 25% (4/16), respectively (P = 0.10). When the riCa treated and control subgroups were compared for a composite index of 60 day mortality and dialysis dependency, the percentage of SCD treated subjects was 16% versus 58% in the control subjects (p<0.01). The incidence of serious adverse events did not differ between the treated (45/69; 65%) and control groups (40/65; 63%; p = 0·86).

Conclusion

SCD therapy may improve mortality and reduce dialysis dependency in a tightly controlled regional hypocalcaemic environment in the perfusion circuit.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01400893","term_id":"NCT01400893"}}NCT01400893 http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01400893","term_id":"NCT01400893"}}NCT01400893     

Substituted 2-aminopyridines as inhibitors of nitric oxide synthases

A series of substituted 2-aminopyridines was prepared and evaluated as inhibitors of human nitric oxide synthases (NOS). 4,6-Disubstitution enhanced both potency and specificity for the inducible NOS with the most potent compound having an IC50 of 28 nM.     

Lipoxygenase pathways of macrophages

Resident mouse peritoneal macrophages when exposed to zymosan during the first day of cell culture synthesize and secrete large amounts of prostaglandin E2 and leukotriene (LT) C4, the respective products of cyclooxygenase- and 5-lipoxygenase-catalyzed oxygenations of arachidonic acid. Under these conditions of cell stimulation only small amounts of hydroxyeicosatetraenoic acids (HETEs) are concomitantly produced. However, exogenously added arachidonic acid is metabolized to large amounts of 12- and 15-HETE. No LTC4 is formed under these conditions. Inasmuch as 12- and 15-HETE have been shown to modulate certain lymphocyte responses, further study of the regulation of their production by macrophages is warranted.