The role of penicillin G potassium in managing Clostridium perfringens in broiler chickens.

The efficacy of penicillin G potassium (Pot-Pen) administered via drinking water to manage necrotic enteritis (NE) was investigated in a Clostridium perfringens (CP) challenge study using 1600 broiler chickens assigned to one of four treatment groups: nonchallenged, nonmedicated; challenged, nonmedicated; challenged, Pot-Pen 0.2 g/L; challenged, Pot-Pen 0.4 g/L. Overall mortality due to NE was significantly reduced among Pot-Pen-treated pens; mortality due to other causes did not differ among the treatment groups. Among all birds, growth performance parameters were significantly improved among Pot-Pen-treated pens. When considering birds randomly sacrificed 4 days post-Pot-Pen initiation, mean NE lesion scores were greatest among the challenged, nonmedicated pens; only one of 80 randomly sacrificed birds treated with Pot-Pen had NE lesions. Among the nonmedicated control pens, body weight (BW) was significantly greater among birds that did not have NE-associated lesions. When sacrificed birds were stratified by NE lesion score, there were no significant differences in BW among the treatment groups. Results of this study suggest that CP-associated subclinical disease can significantly reduce broiler performance. Furthermore, the positive effects of treatment with Pot-Pen appeared to be associated with the prevention and/or treatment of NE-specific lesions.

Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease.

OBJECTIVES: The present study examined the association of estrogen (E2) and the inflammatory response of endothelium in coronary artery disease (CAD) by measuring circulating cellular adhesion molecules (cCAMs) in subjects with atherosclerosis. BACKGROUND: Atherosclerotic plaque demonstrates features similar to inflammation. Endothelial cell activation by inflammatory cytokines induces expression of cellular adhesion molecules (CAMs), thereby perhaps augmenting leukocyte adhesion and recruitment and subsequent development of atherosclerosis. The incidence of CAD is lower in women; this may be due to the cardioprotective effects of E2. METHODS: Consecutive eligible subjects with CAD admitted for cardiac catheterization were studied. The groups evaluated were men, postmenopausal women receiving E2 replacement therapy (ERT), postmenopausal women not receiving ERT and premenopausal women. Control groups included men and women without CAD. Preprocedural blood samples were drawn from all groups. Measurements of cCAMs, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 were performed by enzyme-linked immunoabsorbant assay. E2 levels were assessed by radioimmunoassay. RESULTS: We observed a statistically significant increase in all cCAMs in men with CAD and postmenopausal women with CAD not receiving ERT compared with postmenopausal women with CAD receiving ERT. Premenopausal women with CAD and postmenopausal women with CAD receiving ERT had a significant increase in VCAM-1 alone compared with the female control group. CONCLUSIONS: A possible mechanism by which E2 exerts one of its cardioprotective effects is by limiting the inflammatory response to injury by modulating the expression of CAMs from the endothelium.

Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group.

BACKGROUND: Prospective studies have shown that doses equivalent to conjugated equine estrogens of 0.625 mg/d or higher are needed to produce a significant increase in bone mineral density of the lumbar spine. OBJECTIVES: To determine the effects of unopposed esterified estrogens on bone mineral density, lipid levels, and endometrial tissue structure, and to relate these effects to changes in plasma estradiol levels. METHODS: Four hundred six postmenopausal women were given calcium, 1000 mg/d, and randomly assigned to receive continuous esterified estrogens (0.3, 0.625, or 1.25 mg/d) or placebo for 24 months. Bone mineral density measurements and endometrial and laboratory assessments were conducted every 6 months; plasma estradiol concentrations were measured after 12, 18, and 24 months. RESULTS: All doses of esterified estrogens produced significant increases in bone mineral density of the lumbar spine compared with baseline and with placebo at 6, 12, 18, and 24 months. Mean plasma estradiol levels increased with esterified estrogens dose, and individual subject bone mineral density changes appeared related to plasma estradiol concentrations. Clinically relevant rates of endometrial hyperplasia were noted only in the groups receiving 0.625 and 1.25 mg of esterified estrogens daily. Lipid changes were dose related and apparent in all groups. CONCLUSIONS: Esterified estrogens at doses from 0.3 to 1.25 mg/d, administered unopposed by progestin, produce a continuum of positive changes on bone and lipids. Plasma estradiol concentrations increased with esterified estrogens dose and were related to positive bone mineral densities. The 0.3-mg dose resulted in positive bone and lipid changes without inducing endometrial hyperplasia.

Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: a two-year study.

OBJECTIVE: To determine the relationships among bone mineral density changes, bone marker changes, and plasma estrogens in postmenopausal women receiving estrogen replacement therapy. DESIGN: A total of 406 postmenopausal women received 1,000 mg calcium and continuous esterified estrogens (0.3 mg, 0.625 mg, or 1.25 mg) or placebo daily for up to 24 months. Bone mineral density and bone marker measurements were determined at 6-month intervals; plasma estrogens were measured in a subset after 12, 18, and 24 months. RESULTS: Esterified estrogens produced significant increases in bone mineral density (lumbar spine, hip) compared with baseline and placebo at 6, 12, 18, and 24 months. Bone markers decreased from baseline with all esterified estrogen doses relative to placebo. Bone marker changes at 6 months correlated negatively with bone mineral density changes at 24 months (correlation coefficient range = -0.122 to -0.439). The strongest correlation was noted for spine bone mineral density changes and serum osteocalcin. Mean plasma estrogen levels increased with esterified estrogen dose, and bone mineral density changes correlated positively with plasma estrogen levels. Positive bone mineral density changes were noted in treatment groups with plasma estradiol levels at and above 25 pg/mL. CONCLUSIONS: Esterified estrogens, at doses from 0.3 mg to 1.25 mg/day, unopposed by progestin, increase bone mineral density of the spine and hip in postmenopausal women. These bone mineral density changes correlated significantly with bone marker changes at 6 months and with plasma estrogens at 12, 18, or 24 months. Data variability minimizes the predictive value of the bone marker changes in monitoring individual therapy.

Terminology and core curricula in natural family planning.

PIP: 22 physician-providers who serve natural family planning (NFP) programs, mostly in the private sector, gathered to formulate a standard terminology for the field. The Billings and sympto-thermal methods are the 2 methods taught by this group. The sypto-thermal method helps a woman predict ovulation by detecting changes in her cervical mucus and in the cervix itself. Ovulation is confirmed by monitoring the temperature shift as well as by observing the cessation of mucus buildup, closing of the cervix, and firmness of the os. Those women using the Billings ovulation method predict fertility by the appearance of the cervical mucus, its sensation, color, and elasticity. Sperm will only survive if the cervical mucus is of the fertile type. It is also helpful to recognize mucus patterns of anovulation during breastfeeding, weaning, and premenopause. Use-effective rates which only reflect pregnancy are inadequate in evaluating NFP. A series of definitions are presented which in the future will help to analyze NFP data to accurately reflect NFP effectiveness. The terms included are: total pregnancies, planned pregnancy rate, pregnancy avoidance, method effectiveness rate, method-related pregnancies, informed choice pregnancies, teaching-related pregnancies, and unresolved pregnancies. All NPF teaching programs include instruction in basic reproductive physiology and in the recognition of the fertile phase. The cervical mucus factor is emphasized in ovulation method groups while thermal and other parameters are given equal weight in the sympto-thermal groups. It is the intent of NPF to teach couples to distinguish the fertile phase by using the fertility markers and to have them integrate this information into their sexual decision making. Success is dependent on teacher skill and the ability to inspire confidence in the method. Recognition of the mucus patterns of ovulation and anovulation are crucial in assessing infertility. All family providers under Title 10 must by law offer either NFP instruction or referrals to sites which do. A directory of non-Title 10 providers of NFP Services is available for $4.00 from the Human Life and NFP Foundation, 205 South Patrick Street, Alexandria, Virginia, 22314.^ieng

Anti-hypertensive effects of intravenous compared with oral captopril.

Twenty mild to moderate hypertensive subjects (11 men, 9 women, mean age 54.3 years, range 39-65 years) were studied to determine whether an intravenous form of captopril could be as safe and efficacious as an oral form and to estimate the time course of anti-hypertensive action over a wide dose range (100-fold) of i.v. doses versus oral captopril and placebo. Each subject demonstrated supine diastolic blood pressure (DBP) < or = 90 mm Hg following prospective ACE inhibitor monotherapy, with return of supine DBP to within 95-110 mm Hg 4 weeks after ACE inhibitor discontinuation. These subjects were then admitted to an inpatient unit for six 24 h periods; an initial acclimation period followed by five single doses of i.v. captopril (1.25, 12.5 and 125 mg) or placebo given as a 20 min infusion and oral captopril (25 mg) or placebo in a double-blind, double-dummy crossover study. Each dose was separated by 48 h. All 20 patients completed the study with no clinically significant adverse events. Captopril at doses of 125 mg i.v., 12.5 mg i.v. and 25 mg orally produced similar BP reductions over the 12 h postdose interval, and were more effective in lowering BP than intravenous captopril 1.25 mg or placebo. The 125 mg intravenous captopril dose was no more effective overall in BP reduction than the 12.5 mg i.v. and 25 mg oral doses and was associated with a greater incidence of adverse events. Treatment with 12.5 mg i.v. captopril is safe and comparable to 25 mg oral therapy.

The role of anticoagulation in acute myocardial infarction.

The rule of anticoagulation therapy in the setting of an acute myocardial infarction has been debated for decades. The role of such therapy in reducing mortality, preventing deep venous thrombosis and pulmonary emboli, and in reducing the frequency of left ventricular thrombus formation and subsequent systemic embolization is discussed.

Isolation, identification, and synthesis of the major sulpiride metabolite in primates.

The major metabolite of sulpiride, N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-sulfamoyl-2-anisamide (I), in the monkey is N-[(1-ethyl-5-oxo-2-pyrrolidinyl)methyl]-5-sulfamoyl-2-anisamide (II). It is also a metabolite in other laboratory animal species and possibly at very low levels in humans. Treatment of the urine from a monkey dosed orally with 14C-I by dry column chromatography and high-pressure liquid chromatography (HPLC) produced the major metabolite in pure form. Characterization of the purified 14C-radiolabeled metabolite by proton NMR, TLC, HPLC, and chemical ionization mass spectroscopy, along with subsequent comparison of a synthetically prepared sample, gave unequivocal structural confirmation.

Stereospecific determinations of (+/- )-DU-124884 and its metabolites (+/- )-KC-9048 in human plasma by liquid chromatography.

(+)-DU-124884 is a 5-HT1-like receptor agonist under investigation for drug development. A sensitive, stereospecific LC method was developed for the analysis of (+)-DU-124884, its optical isomer (-)-DU-124884 and their N-dealkylated metabolites, (+/- )-KC-9048, in human plasma. A plasma sample was treated with triethylamine in methanol and the proteins were precipitated by acetonitrile. The supernatant was evaporated to dryness under nitrogen. The analytes and internal standard (acebutolol) formed diastereomers with (S)-(+)-1-(1-naphthyl)ethyl isocyanate immediately. The diastereomers formed were extracted into diethyl ether. They were completely resolved from each other and from matrix peaks on a Microsorb silica column with a mobile phase of methanol-chloroform-hexane (8:12:80, v/v/v) in a run time of 26 min. Detection was by fluorescence with excitation wavelength at 320 nm and emission wavelength at 440 nm. The linearity range is 0.1-200 ng ml-1 (r > 0.99). The limit of quantitation is 0.1 ng ml-1 and the detection limit is 0.02 ng ml-1 (signal-to-noise ratio = 3). The interday precision and accuracy of quality control samples were 5.5-7.6% RSD (relative standard deviation) and 0 to+4% bias for (+)-DU-124884, 5.5-7.9% RSD and 0 to +4% bias for (-)-DU-124884, 4.5-6.5% RSD and -7 to 0% bias for (+)-KC-9048 and 4.5-7.5% RSD and -7 to 0% bias for (-)-KC-9048. Consistent recovery from different lots of human plasma, parallelism of the method, stabilities of on-system, reinjection, bench-top, freeze-thaw cycles and sample storage were established.

Carotid endarterectomy: current indications for surgery.

The study of carotid artery occlusive disease interventions can be divided clinically into the treatment of asymptomatic and symptomatic diseases. Clinical trials that have studied or are currently studying asymptomatic disease include: the Carotid Artery Stenosis with Asymptomatic Narrowing Operation Versus Aspirin study; the Mayo Asymptomatic Carotid Endarterectomy trial; Veterans Administration Cooperative Trial on Asymptomatic Carotid Stenosis; and the Asymptomatic Carotid Atherosclerosis Study. Trials for the treatment of symptomatic disease include: the North American Symptomatic Carotid Endarterectomy Trial; the European Carotid Surgery Trial; and the Veterans Administration Cooperative Study. In the earliest trials conducted to study asymptomatic disease medical therapy was slightly favored; on close scrutiny these studies were flawed and the findings appeared to be equivocal. The more scientific and appropriate trial, which was ended due to ethical concerns, revealed a clear advantage in patients who underwent surgery for greater than 60% stenosis and when the surgical center demonstrated less than 3% surgical risks. All trials studying symptomatic disease found a significant decrease in subsequent stroke when surgical intervention was performed. It is now judged that patients with greater than 50% stenosis receive significant benefit. In this paper the authors review the data from all of these studies. They also review data for special circumstances, such as critical stenosis and patients with symptomatic and asymptomatic Hollenhorst plaques. It is their opinion that these data have allowed surgeons to make much more educated decisions when considering the treatment of patients with carotid artery occlusive disease.

Effects of glycosaminoglycan polysulfate treatment on soundness, hyaluronic acid content of synovial fluid and proteoglycan aggregate in articular cartilage of lame boars.

Eighteen lame boars were equally assigned to two treatment groups based on initial bodyweight and leg soundness. The boars were injected intramuscularly with an aqueous solution of glycosaminoglycan polysulfate or saline on day 0, 5, 10, 15, 20 and 25 and killed on day 27. The glycosaminoglycan polysulfate treatment significantly (P less than 0.05) improved leg soundness score, and resulted in an increase (P less than 0.06) in the hyaluronic acid concentration of the cubitus joint synovial fluid, and an increase (P less than 0.05) in the proportion of aggregated proteoglycans in the articular cartilage of the medial femoral condyle. Feed intake, growth rate and articular cartilage soundness score for the cubitus and stifle joints were not significantly (P greater than 0.10) affected by the treatment.

Relative effectiveness of methionine hydroxy analog compared to DL-methionine in broiler chickens.

Two broiler experiments were conducted to assess the relative bioefficacy of liquid DL-Met hydroxy analog-free acid (MHA-FA) and DL-Met (DLM). Exponential regression analysis was used to determine biological efficacy based on body weight, feed conversion, and carcass responses to dietary Met source. In Trial 1, four graded inclusion levels of DLM and liquid MHA-FA (0.06, 0.12, 0.18, and 0.24%) were each added to a basal diet that met the nutrient and energy requirements of broiler chickens, with the exception of Met + Cys. In four additional treatments, diluted DLM (65%) was added at the same supplementation levels as pure DLM and liquid MHA-FA. In the 42-d trial, broilers responded significantly (P < 0.05) to the supplements. Regression analysis revealed that liquid MHA-FA was 68% (weight gain), 67% (feed conversion), 62% (carcass yield), and 64% (breast meat yield) as efficacious as pure DLM on an as-fed basis. Responses to liquid MHA-FA and diluted DLM were very similar at corresponding supplementation levels. Diluted DLM as an internal standard confirmed that exponential regression analysis was a statistically valid technique for determination of the relative efficacy of nutrient sources. In Trial 2, five graded inclusion levels of each DLM (0.040, 0.091, 0.152, 0.222, and 0.303%) and liquid MHA-FA (0.045, 0.102, 0.170, 0.250, and 0.350%) were added to a basal diet limiting in Met + Cys but adequate in all other nutrients and energy. Liquid MHA-FA was 72% (weight gain), 51% (feed conversion), 48% (carcass yield), and 60% (breast yield) as efficacious as DLM on a weight-for-weight basis.

Efficacy of DL-methionine hydroxy analog free acid and DL-methionine as methionine sources for pigs.

Two experiments were conducted to evaluate the efficacy of dietary DL-methionine hydroxy analog-free acid (MHA-FA, 88%) compared with DL-methionine (DLM, 99%) as Met sources in pigs. In Exp. 1, a total of 245 crossbred pigs (initial BW of 6.4 kg [SD = 0.5]) were allotted to 7 treatments in 7 replicates for an experimental period of 28 d. The basal diet (BD) was formulated to contain 17.5% CP and 0.21% Met. Dietary treatments included 1) BD, 2) BD + 0.030% DLM, 3) BD + 0.060% DLM, 4) BD + 0.090% DLM, 5) BD + 0.034% MHA-FA, 6) BD + 0.068% MHA-FA, and 7) BD + 0.103% MHA-FA; the MHA-FA was supplemented on an equimolar basis to the DLM. Because of a nonlinear response, exponential regression analysis was used to evaluate the responses, and a comparison of the equations was then made to determine the relative effectiveness of the 2 Met sources. With increases in dietary Met, weight gain increased (P < 0.05). Compared with DLM on a product-to-product (wt/wt) basis, the relative effectiveness of MHA-FA was calculated to be 73% for increasing weight gain and 54% for decreasing the feed:gain. In Exp. 2, a total of 30 weanling barrows [initial BW of 16.8 kg (SD = 2.8)] were used in a metabolism study to evaluate the relative value of MHA-FA to DLM. The BD was formulated to contain 16.9% CP and 0.21% Met. Dietary treatments included 1) BD, 2) BD + 0.030% DLM, 3) BD + 0.060% DLM, 4) BD + 0.046% MHA-FA, and 5) BD + 0.092% MHA-FA; the MHA-FA levels were chosen based on a pre-experiment estimate of bioequivalence in an attempt to provide approximately equal pig responses. There was no difference in fecal N output among the treatments; however, urine N linearly decreased with increasing concentrations of both sources (P = 0.034 for DLM, and P = 0.007 for MHA-FA), which resulted in a linear increase in retained N for both DLM (P = 0.012) and MHA-FA (P = 0.005). In addition, N retention (% of intake) linearly increased with increasing level of DLM (P = 0.014) and MHA-FA (P = 0.007). Using a slope-ratio procedure for comparison of the responses from the 2 sources, the relative biological equivalence value of MHA-FA to DLM in this experiment was 64.2% based on percent N retention and 66.3% based on the grams of N retained per day. Based on the results from both experiments, these data indicated that the mean relative bioequivalence of MHA-FA to DLM was 64% on a product-to-product (wt/wt) basis or 73% on an equimolar basis.

Excitable channel currents and gating times in the presence of anticonvulsants ethosuximide and valproate.

The effects of the anticonvulsants ethosuximide and valproate on the excitable Na and K channels of the squid giant axon are evaluated and compared. The drugs are highly specific in their effects on channel gating and ion permeability with regard to the membrane side of application. Both drugs when applied internally affect Na activation gating in ways that lead to the conclusion that they do not act as channel blockers. However, external ethosuximide is clearly a voltage-independent Na channel blocker with no effect on channel gating. On the K channel, ethosuximide appears to have a mixed action affecting both gating and the ion flux through open channels. However, valproate slows K channel gating without effect on the flux through open channels. The dose-response curve of the effects has a shape similar to that for ethanol. The implications for paroxysmal discharge and synchronous impulse generation are discussed in a preliminary way.

Lyme myocarditis presenting as fascicular tachycardia with underlying complete heart block.

A case of Lyme myocarditis manifest as a fascicular tachycardia is presented. Subtle findings of heart block in the presence of preserved ventricular function led to the correct diagnosis in this otherwise healthy patient. Treatment with ceftriaxone resolved both abnormalities.

Physiologic assessment of ostial left circumflex coronary artery disease using a Doppler guidewire before and after rotational atherectomy facilitated angioplasty.

Intravascular Doppler assessment of coronary flow velocity has demonstrated the physiologic significance of intermediate stenoses and the success of coronary interventions. We describe a patient where Doppler evaluation confirmed the significance of an intermediate left circumflex ostial stenosis. We also describe the Doppler flow velocity characteristics after successful rotational atherectomy facilitated angioplasty.

Direct determination of substituted azepinoindole enantiomers in rat plasma using silica stationary phase and beta-cyclodextrin as a mobile phase additive.

DU 124884 is a racemic serotonin receptor agonist in an early stage of drug development. DU 124884 and its potential N-desmethyl metabolite, KC 9048, both contain a single chiral center. A direct enantioselective HPLC assay was developed and validated to quantify DU 124884 and KC 9048 in rat plasma. The drug and metabolite enantiomers were extracted from plasma and separated using silica stationary phase with an aqueous mobile phase containing beta-cyclodextrin (beta-CD), triethylamine, and 2-methyl-2-propanol. A variable wavelength detector was used to monitor absorbance at 231 nm. The assay calibration range was from 100 to 5000 ng/mL. Quality control sample precision (< or = 9% RSD) and accuracy (+/-10% error) were satisfactory for all four analytes (n = 12). The method was used to assess drug exposure during a pilot toxicology study in rats. Toxicokinetic study animals were dosed subcutaneously for 15 days at 0, 2.5, 10, and 40 mg of DU 124884.HCl kg-1 day-1. Blood was collected on the last day of dosing between 22 min and 4 h and 13 min after the last dose. The samples showed (+/-)-DU 124884 isomer ratios ranging from 1.1 to 1.3. These data suggest that DU 124884 undergoes stereoselective metabolism in rats. Levels of the N-desmethyl metabolite enantiomers were < 100 ng/mL.

Metabolism of sulpiride in man and rhesus monkeys.

The metabolism of 14C-carbonyl-sulpiride (form A) and of 14C-3, 4 pyrrolidine-sulpiride (form B) was studied in the rhesus monkey and man. In the monkey, the metabolites in both the urine and the bile were the same with form A and form B: 60-80% sulpiride, 10-30% 5-oxopyrrolidine sulpiride and 3-8% an unidentified metabolite (ME-X). In four human volunteers given a single oral dose of either 108 mg form A or 100 mg form B, more than 95% of the 14C recovered in the urine and feces was unchanged sulpiride. Sulpiride levels in plasma reached maximum in 3 hr and ranged from 232 to 403 ng/ml. The plasma t1/2 was 8.3 hr. Pharmacokinetic analyses indicated little or no biliary excretion of sulpiride in man.