Features on Computed Tomography That Correlate With Acute Appendicitis.

Background: The purpose of this study is to investigate the relevant findings in adult patients admitted to Cabell Huntington Hospital who were diagnosed with acute appendicitis. Methods: Patients who had the postoperative diagnosis of acute appendicitis and a preoperative computed tomography (CT) scan from January 2011 through December 2016 were included in this retrospective chart review. Results: There were 592 patients. A thick, edematous appendix was the most common CT finding in acute appendicitis. The average diameter was 12.6 mm. The wall thickness correlated to the diameter of the appendix (P < 0.001). For comparison, we reviewed the CT scans of 50 trauma patients who had normal abdominal CT scans. The average diameter of a normal appendix was 4.9 mm (SD 1.139) with a range of 4-7 mm. Interestingly, the admission white blood cell count (P = 0.0372) as well as the thickness of the appendix (P < 0.0001) were strongly associated with increased length of stay. Conclusions: An appendiceal diameter greater than 9 mm should be considered abnormal and associated with acute appendicitis. Appendiceal size, white blood cell count, and age correlate with length of stay. Early antibiotics and early surgical intervention may decrease length of stay.

Novel gp91(phox) homologues in vascular smooth muscle cells : nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways.

Emerging evidence indicates that reactive oxygen species are important regulators of vascular function. Although NAD(P)H oxidases have been implicated as major sources of superoxide in the vessel wall, the molecular identity of these proteins remains unclear. We recently cloned nox1 (formerly mox-1), a member of a new family of gp91(phox) homologues, and showed that it is expressed in proliferating vascular smooth muscle cells (VSMCs). In this study, we examined the expression of three nox family members, nox1, nox4, and gp91(phox), in VSMCs, their regulation by angiotensin II (Ang II), and their role in redox-sensitive signaling. We found that both nox1 and nox4 are expressed to a much higher degree than gp91(phox) in VSMCS: Although serum, platelet-derived growth factor (PDGF), and Ang II downregulated nox4, they markedly upregulated nox1, suggesting that this enzyme may account for the delayed phase of superoxide production in these cells. Furthermore, an adenovirus expressing antisense nox1 mRNA completely inhibited the early phase of superoxide production induced by Ang II or PDGF and significantly decreased activation of the redox-sensitive signaling molecules p38 mitogen-activated protein kinase and Akt by Ang II. In contrast, redox-independent pathways induced by PDGF or Ang II were unaffected. These data support a role for nox1 in redox signaling in VSMCs and provide insight into the molecular identity of the VSMC NAD(P)H oxidase and its potentially critical role in vascular disease.

Iodine-123 phenylpentadecanoic acid and single photon emission computed tomography in identifying left ventricular regional metabolic abnormalities in patients with coronary heart disease: comparison with thallium-201 myocardial tomography.

Iodine-123 phenylpentadecanoic acid (IPPA) is a synthetic long chain fatty acid with myocardial kinetics similar to palmitate. Two hypotheses were tested in this study. The first hypothesis was that IPPA imaging with single photon emission computed tomography (SPECT) is useful in the identification of patients with coronary artery disease. Fourteen normal volunteers (aged 27 +/- 2 years) and 33 patients (aged 54 +/- 11 years) with stable symptomatic coronary artery disease and at least one major coronary artery with luminal diameter narrowing greater than or equal to 70% were studied with symptom-limited maximal exercise testing. The IPPA (6 to 8 mCi) was injected 1 min before the termination of exercise, and tomographic imaging was performed beginning at 9 min and repeated at 40 min after the injection of IPPA. Nine of the normal volunteers and 13 of the patients had a second examination performed at rest on another day. Using the limits of normal as 2 SD from the normal mean values, 27 of the 33 patients with coronary artery disease demonstrated abnormalities in either the initial distribution or the clearance of IPPA, or both. Nineteen of the 33 patients had a maximal variation of activity distribution of greater than or equal to 25% on the 9 min IPPA images. Twenty-two of the 33 patients had a maximal variation in IPPA washout greater than 17% and 17 had a washout rate less than or equal to 2%. There was good agreement between the location of significant coronary artery stenoses and abnormalities in the initial distribution and clearance of IPPA. The second hypothesis tested was that IPPA imaging is as or more sensitive and, therefore, complementary to thallium-201 imaging in the identification of exercise-induced ischemia in patients. Twenty-five of the 33 patients underwent both thallium-201 and IPPA tomographic imaging after symptom-limited maximal exercise testing. The amount of exercise performed by each patient during both studies was similar. Twenty-one of the 25 patients had abnormal IPPA tomographic studies, whereas 18 had abnormal thallium-201 tomographic studies (p = NS). The results of this study suggest the following conclusions: 1) iodine-123 phenylpentadecanoic acid imaging using single photon emission computed tomography and exercise provides a sensitive and relatively noninvasive method for identifying abnormalities in myocardial metabolism associated with significant coronary artery stenoses, and 2) iodine-123 phenylpentadecanoic acid is at least as sensitive as thallium-201 for this purpose using tomographic imaging and exercise testing.

Tomographic gated blood pool radionuclide ventriculography: analysis of wall motion and left ventricular volumes in patients with coronary artery disease.

The use of planar radionuclide ventriculography to evaluate global and segmental ventricular function is limited by the superimposition of structures in some projections and the gross segmental resolution of the planar technique. Preliminary reports have suggested the feasibility of tomographic gated radionuclide ventriculography with rotating detector systems. This study tested the hypotheses that 1) tomographic radionuclide ventriculography detects segmental dysfunction at rest not identified with multiview planar studies and single plane contrast ventriculography, and 2) ventricular volumes and ejection fraction calculated from these studies provide data similar to those obtained with angiography and planar radionuclide ventriculography. Gated blood pool tomograms were acquired over 180 degrees at 15 frames per cardiac cycle during the initial 90% of the cardiac cycle. Compared with the multiview planar technique tomographic ventriculography showed an increased sensitivity for detecting left ventricular segments with significant coronary artery stenosis (97 versus 74%, p less than 0.025) without any loss in specificity. Compared with both planar radionuclide and contrast ventriculography, tomographic radionuclide ventriculography also detected more noninfarcted left ventricular segments supplied by stenosed coronary arteries (81 versus 39 and 32%, respectively, p less than 0.01). Tomographic radionuclide ventriculographic measurements of left ventricular volumes and ejection fraction showed close correlations with angiographic and planar radionuclide determinations. Gated blood pool tomography is a sensitive method for the evaluation of segmental wall motion and an accurate method for the measurement of global left ventricular volumes and ejection fraction.

Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy.

Recent evidence suggests that oxidative mechanisms may be involved in vascular smooth muscle cell (VSMC) hypertrophy. We previously showed that angiotensin II (Ang II) increases superoxide production by activating an NADH/NADPH oxidase, which contributes to hypertrophy. In this study, we determined whether Ang II stimulation of this oxidase results in H2O2 production by studying the effects of Ang II on intracellular H2O2 generation, intracellular superoxide dismutase and catalase activity, and hypertrophy. Ang II (100 nmol/L) significantly increased intracellular H2O2 levels at 4 hours. Neither superoxide dismutase activity nor catalase activity was affected by Ang II; the SOD present in VSMCs is sufficient to metabolize Ang II-stimulated superoxide to H2O2, which accumulates more rapidly than it is degraded by catalase. This increase in H2O2 was inhibited by extracellular catalase, diphenylene iodonium, an inhibitor of the NADH/NADPH oxidase, and the AT1 receptor blocker losartan. In VSMCs stably transfected with antisense p22phox, a critical component of the NADH/NADPH oxidase in which oxidase activity was markedly reduced, Ang II-induced production of H2O2 was almost completely inhibited, confirming that the source of Ang II-induced H2O2 was the NADH/NADPH oxidase. Using a novel cell line that stably overexpresses catalase, we showed that this increased H2O2 is a critical step in VSMC hypertrophy, a hallmark of many vascular diseases. Inhibition of intracellular superoxide dismutase by diethylthiocarbamate (1 mmol/L) also resulted in attenuation of Ang II-induced hypertrophy (62+/-2% inhibition). These data indicate that AT1 receptor-mediated production of superoxide generated by the NADH/NADPH oxidase is followed by an increase in intracellular H2O2, suggesting a specific role for these oxygen species and scavenging systems in modifying the intracellular redox state in vascular growth.

Arachidonic acid metabolites mediate angiotensin II-induced NADH/NADPH oxidase activity and hypertrophy in vascular smooth muscle cells.

Previously, we showed that angiotensin II stimulation of the NADH/NADPH oxidase is involved in hypertrophy of cultured vascular smooth muscle cells (VSMC). Here, we examine the pathways leading to oxidase activation, and demonstrate that arachidonic acid metabolites mediate hypertrophy by activating the p22phox-based NADH/NADPH oxidase. Angiotensin II stimulates phospholipase A2, releasing arachidonic acid, which stimulates oxidase activity in vitro. When arachidonic acid metabolism is blocked with 5,8,11,14-eicosatetraynoic acid (ETYA) or nordihydroguaiaretic acid (NDGA), oxidase activity decreases by 80 +/- 10%. In VSMC transfected with antisense p22phox to attenuate NADH/NADPH oxidase expression, arachidonic acid is unable to stimulate NADH/NADPH-dependent superoxide production. In these cells, or in cells in which NADH/NADPH oxidase activity is inhibited by diphenylene iodonium, angiotensin II-induced [3H]leucine incorporation is also inhibited. Attenuation of oxidase activation by inhibiting arachidonic acid metabolism with ETYA, NDGA, baicalein, or SKF-525A also inhibits angiotensin II-stimulated protein synthesis (74 +/- 2% and 34 +/- 1%, respectively). Thus, endogenous noncyclooxygenase arachidonic acid metabolites mediate angiotensin II-stimulated protein synthesis in cultured VSMC by activating the NADH/NADPH oxidase, providing mechanistic evidence for redox control of VSMC hypertrophy.

Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes.

We have investigated the mechanism of nitric oxide-induced damage in glial cells. Genomic DNA isolated from astrocytes and microglia, treated for 18 h with varying concentrations of a nitric oxide donor, was analysed by electrophoresis. No DNA damage was evident. Oligodendrocytes, treated with 2 mM nitric oxide for 3-48 h, showed single stranded breaks at 48 h but no laddering of nucleosomic fragments of DNA. When analysed by electron microscopy, ultrastructural changes in oligodendrocytes treated with 1 mM nitric oxide for 24 h showed intact nuclei but alterations in membranes and organelles characteristic of necrosis, including disrupted mitochondria with dissolution of their christae. Astrocytes, a glial cell type that we have previously shown to be much less sensitive to nitric oxide-induced damage, did not show ultrastructural changes. DNA analysis by flow cytometry of glial cells treated with nitric oxide supported the apparent necrotic-type death in oligodendrocytes. Double staining of oligodendrocytes, using Hoechst 33342 and propidium iodide for the simultaneous assessment of both apoptotic and necrotic cells, demonstrated that, while the proportion of dead cells increased with time and increasing concentrations of nitric oxide, the death was due to necrosis and not apoptosis. In this study, we demonstrate that direct exposure to soluble nitric oxide, produced in vitro from a nitric oxide donor chemical, ultimately kills oligodendrocytes by necrosis. Microglia and astrocytes maintain DNA and organelle integrity when exposed to exogenous nitric oxide.

Three-dimensional motion and perfusion quantification in gated single-photon emission computed tomograms.

Methods for quantification and display of left ventricular (LV) functional parameters from gated single-photon emission computed tomographs are described. Using previously documented surface detection methods, we developed techniques for calculating global variables, such as volumes and areas, as well as local variables such as segmental motion and local perfusion from gated tomographic radionuclide ventriculograms (TRVG) and gated perfusion tomograms (sestamibi). We have developed three-dimensional displays to allow realistic visualizations of the results. The motion results have been validated using correlative magnetic resonance imaging (MRI) studies; motion calculated from user-traced MR images of the heart was compared to motion calculated from automatically detected surfaces in TRVG and sestamibi. The average motion error was calculated to be 0.67 mm in TRVG and -0.21 mm in sestamibi. Errors were largest in basal LV regions; we explain this phenomenon using simulations. Finally, we present additional examples of the analysis using studies obtained from normal volunteers and from subjects whose coronary artery anatomies were known.

Quantitation of postexercise lung thallium-201 uptake during single photon emission computed tomography.

To test the hypothesis that analysis of lung thallium uptake measured during single photon emission computed tomography (SPECT) yields supplementary clinical information as reported for planar imaging, quantitative analysis of lung thallium uptake following maximal exercise was performed in 40 clinically normal subjects (Group 1) and 15 angiographically normal subjects (Group 2). Lung thallium uptake was measured from anterior projection images using a ratio of heart-to-lung activities. Seventy subjects with coronary artery disease (CAD) (Group 3) determined by angiography (greater than or equal to 70% luminal stenosis) underwent thallium perfusion SPECT. Thirty-nine percent of these subjects had multivessel and 61% had single vessel CAD. Lung thallium uptake was elevated in 47 of 70 (67%) Group 3 subjects. Group 3 subjects with elevated lung thallium uptake did not differ from Group 3 subjects with normal lung thallium uptake with respect to extent or distribution of coronary artery disease, left ventricular function, or severity of myocardial ischemia as determined by exercise and redistribution thallium SPECT. Thus, the measurement of thallium lung uptake from anterior projection images obtained during SPECT frequently identifies patients with CAD, but it may not provide supplementary information regarding the extent of myocardial ischemia or ventricular dysfunction.

Quantification of three-dimensional left ventricular segmental wall motion and volumes from gated tomographic radionuclide ventriculograms.

Tomographic radionuclide ventriculograms may be used for three-dimensional wall motion analysis. We propose that automatic quantification of these images is possible, and here we describe the implementation and validation of a method to perform this task. Automatic computer methods were developed to locate the left ventricular (LV) endocardial surfaces in all time frames of the cardiac cycle. Global, regional, and local motion and volume were computed. Results were displayed using three-dimensional graphics. The methods were validated using phantom, canine, and human studies. Actual phantom values correlated well with experimentally determined volumes, y = 1.01x + 1.29ml, r = 0.99. In the canine model, the LV endocardial surfaces were located to within an average of 1.9 mm and 3.7 mm at end-diastole and end-systole, respectively. Areas of obvious wall motion abnormalities in automatically processed patient studies corresponded well with angiographically documented coronary artery disease. End-diastolic and end-systolic volumes computed automatically from single photon emission computed tomography averaged errors of 9% and 38%, respectively, when compared with contrast ventriculographic volumes. These results indicate that it is possible to automatically identify the left ventricular endocardial surface in gated tomographic radionuclide ventriculograms. The location of these surfaces corresponds well with the location of implanted endocardial markers, and global volume computed from these surfaces corresponds well with known volumes.

Estimation of jeopardized left ventricular myocardium in symptomatic and silent ischemia as determined by iodine-123 phenylpentadecanoic acid rotational tomography.

Whether patients with silent myocardial ischemia have a lesser mass of ischemic myocardium than patients with symptomatic ischemia is controversial. Forty-five patients with angiographic coronary artery disease (greater than or equal to 70% luminal diameter narrowing) were studied. All patients had ischemic patterns of myocardial uptake and clearance of the long-chain fatty acid perfusion/metabolic imaging agent iodine-123 phenylpentadecanoic acid after maximal exercise. Single-photon emission computed tomography was performed and 25 myocardial segments were analyzed using circumferential activity profile curves. The 21 patients with silent treadmill ischemia exercised longer than the 24 patients with painful treadmill ischemia (430 +/- 137 vs 337 +/- 96 seconds, p less than 0.01) and to a higher heart rate (138 +/- 21 vs 125 +/- 18 beats/min, p less than 0.05). Patients with treadmill silent ischemia had the same number of abnormally perfused myocardial segments as patients with painful treadmill ischemia (8.6 +/- 4.5 vs 6.5 +/- 4.1 segments, difference not significant) and the same number of reversibly ischemic myocardial segments (4.0 +/- 1.4 vs 4.2 +/- 3.0 segments, difference not significant). The angiographic severity and extent of coronary artery disease were similar in the 2 groups. Thus, in this selected group of patients, those with silent treadmill ischemia appear to have at least as great an extent of ischemic myocardium as patients with painful exertional ischemia.

Abnormal myocardial fatty acid metabolism in dilated cardiomyopathy detected by iodine-123 phenylpentadecanoic acid and tomographic imaging.

The radioidinated synthetic fatty acid iodine-123 phenylpentadecanoic acid (IPPA) has proven useful in the identification of regional abnormalities of cardiac metabolism in patients with myocardial ischemia. The present study was performed to test the hypothesis that the myocardial distribution and turnover of fatty acids, assessed noninvasively with IPPA, are altered in patients with cardiomyopathy. Nine normal volunteers and 19 patients with dilated cardiomyopathy of various etiologies underwent cardiac imaging with single-photon emission computed tomography (SPECT) after intravenous injection of IPPA. Apical short-axis and basal short-axis sections were reconstructed and quantitatively analyzed for relative IPPA activity distribution and washout. Patients with congestive cardiomyopathy demonstrated significantly greater heterogeneity of IPPA uptake than normal subjects (maximal percent variation of activity 27 +/- 11 vs 18 +/- 4, p less than 0.01). They also demonstrated a more rapid percent washout rate than control subjects (24 +/- 8 vs 17 +/- 6 for the apical short-axis section, p less than 0.05; 26 +/- 7 vs 18 +/- 5 for the basal short-axis section, p less than 0.01). These abnormalities of fatty acid distribution and turnover were independent of the etiology of the cardiomyopathy. The degree of heterogeneity of IPPA uptake was significantly related to the patients' New York Heart Association functional class (r = 0.64, p less than 0.01). Thus, compared with normal myocardium, the myocardium of patients with congestive cardiomyopathy demonstrates a more heterogeneous distribution of fatty acid uptake, which parallels the clinical severity of the disease. Furthermore, patients with congestive cardiomyopathy demonstrate a more rapid myocardial clearance of the labeled fatty acid, as assessed with SPECT imaging.

Regional cardiac adrenergic function using I-123 meta-iodobenzylguanidine tomographic imaging after acute myocardial infarction.

The effect of acute myocardial infarction (AMI) on regional cardiac adrenergic function was studied in 27 patients mean +/- standard deviation 10 +/- 4 days after AMI. Regional adrenergic function was evaluated noninvasively with I-123 meta-iodobenzylguanidine (MIBG) using a dedicated 3-detector tomograph. Four hours after its administration, there was reduced MIBG uptake in the region of infarction, 0.38 +/- 0.31 counts/pixel/mCi x 103 compared with 0.60 +/- 0.30 counts/pixel/mCi x 103 and 0.92 +/- 0.35 counts/pixel/mCi x 103 in the zones bordering and distant from the infarct area, respectively, p less than 0.001. In all patients, the area of reduced MIBG uptake after 4 hours was more extensive that the associated thallium-201 perfusion defect with defect scores of 52 +/- 22 and 23 +/- 18%, respectively, p less than 0.001. After anterior wall AMI, the 4-hour MIBG defect score was 70 +/- 13% and the degree of mismatch between myocardial perfusion and MIBG uptake was 30 +/- 9% compared with 39 +/- 17 and 21 +/- 17% after inferior AMI, p less than 0.001 and p = 0.016, respectively. The 4-hour MIBG defect score correlated inversely with the predischarge left ventricular ejection fraction, r = -0.73, p less than 0.001. Patients with ventricular arrhythmia of greater than or equal to 1 ventricular premature complexes per hour, paired ventricular premature complexes or ventricular tachycardia detected during the late hospital phase had higher 4-hour MIBG defect scores, 62.5 +/- 15.0%, than patients with no detectable complex ventricular ectopic activity and a ventricular premature complex frequency of less than 1 per hour, 44.6 +/- 23.4%, p = 0.036.(ABSTRACT TRUNCATED AT 250 WORDS)

Are stereotaxic breast biopsies adequate?

BACKGROUND: Stereotaxic core breast biopsy (SCBB) has been proposed as a cost-effective and reliable method of evaluating mammographic lesions. This study evaluates an initial experience with SCBB and assesses the adequacy of the biopsy specimens obtained. METHODS: Two hundred forty-one SCBB were performed on 221 patients during 13 months by four radiologists. Mammograms were assigned a suspicion index on a scale of 1 to 5. One pathologist performed a blinded retrospective review of all SCBB specimens and assigned an adequacy score based on the quality and amount of the tissue present. RESULTS: The majority of SCBB were ordered by general surgeons (67%). A suspicion index score of 3 was assigned to 74% of lesion specimens. Twelve percent of specimens were malignant. Overall SCBB adequacy (score > or = 2) was 77%. Adequacy was present in 74% of benign biopsy specimens as compared with 100% of malignant specimens (p < 0.005). Only 62% of specimens reported as benign without specific features were adequate. There were no differences in adequacy between individual radiologists or during the study period. CONCLUSIONS: SCBB is largely used by surgeons to assess indeterminate mammographic lesions. One of four benign specimens was inadequate. Benign SCBB specimens must be interpreted with caution.

Norepinephrine-induced down regulation of alpha 1 adrenergic receptors in cultured rabbit aorta smooth muscle cells.

Drug-induced refractoriness of alpha-adrenergic receptor-mediated vasoconstriction may be a clinically important phenomenon. We have investigated the possible molecular mechanisms underlying this phenomenon in cultured vascular smooth muscle cells derived from the rabbit aorta. alpha 1-Adrenergic receptors were identified in membranes prepared from these cells by [125I]HEAT binding. The radioligand bound to a high affinity site (Kd = 140 pM) in a saturable fashion (202 fmol/mg protein). Adrenergic agonists and antagonists competed for binding of [125I]HEAT with the expected order of potency for an alpha 1-receptor, (-)epinephrine greater than or equal to (-) norepinephrine greater than (+)epinephrine greater than isoproterenol and prazosin greater than phentolamine greater than yohimbine. Exposure of cells for 26 hours to 10 microM norepinephrine resulted in a 70% decrease in the number of alpha 1-receptors as measured by [125I]HEAT binding without any significant change in the affinity of the receptor for the ligand. When the alpha-receptors were blocked with 10 microM phentolamine the loss of receptors induced by norepinephrine was completely prevented. Similar down-regulation of the [125I]HEAT binding sites was observed when the alpha 1-agonist phenylephrine was used instead of norepinephrine. It is concluded that alpha-agonists induce down-regulation of aortic smooth muscle alpha 1-receptors. This reduction of alpha-receptors could be important in the mechanisms by which vascular smooth muscle develops refractoriness to alpha-adrenergic stimulation.

Evaluation of emulsion stability by diffuse reflectance spectroscopy.

A new method is described for evaluating the stability of emulsion bases and active components contained within such emulsions. Diffuse reflectance spectroscopy (DRS) is a technique that has the capability of detecting changes in particle size, surface properties, or drug quality of emulsions as a function of time without disturbance of the system. Such physical or chemical changes are monitored by changes in the visible and UV wavelength spectral characteristics of the emulsified systems. Four basic emulsion systems were prepared and analyzed for physical stability for 6 months by three techniques: visible coalescence, particle counting measurement, and DRS. Two drugs, aspirin and ascorbic acid, were then incorporated within stable emulsion bases, and the chemical stability of these drugs was monitored by DRS for 6 months. Results were compared with concomitant quantitative drug assay procedures. Good agreement was observed when data from DRS and analytical measurements were compared. The DRS technique may be used as a supportive method, offering simplicity and expedience, with other methods of evaluating emulsion stability and drug stability within emulsified systems.

The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute.

The objectives of this study were to (1) measure the effects of freezing rate and mannitol concentration on the physical state of freeze-dried mannitol when mannitol is present as a single component, (2) determine the relative concentration threshold above which crystalline mannitol can be observed by X-ray powder diffraction in the freeze-dried solid when a variety of noncrystallizing solutes are included in the formulation, and (3) measure the glass transition temperature of amorphous mannitol and to determine the degree to which the glass transition temperature of freeze-dried solids consisting of mannitol and a disaccharide is predicted by the Gordon-Taylor equation. Both freezing rate and mannitol concentration influence the crystal form of mannitol in the freeze-dried solid when mannitol is present as a single component. Slow freezing of 10% (w/v) mannitol produces a mixture of the alpha and beta polymorphs, whereas fast freezing of the same solution produces the delta form. Fast freezing of 5% (w/v) mannitol results primarily in the beta form. The threshold concentration above which crystalline mannitol is detected in the freeze-dried solid by X-ray diffraction is consistently about 30% (w/w) when a second, noncrystallizing solute is present, regardless of the nature of the second component. The glass transition temperature of amorphous mannitol measured from the quench-cooled melt is approximately 13 degreesC. Accordingly, mannitol is an effective plasticizer of freeze-dried solids when the mannitol remains amorphous. Glass transition temperatures of mixtures of mannitol and the disaccharides sucrose, maltose, trehalose, and lactose are well predicted by the Gordon-Taylor equation with values of k in the range of 3 to 4.

Effect of pKb on lipophilic binding of disopyramide derivatives to human plasma.

The extent of plasma binding, the partition coefficient, and the pKb of 13 disopyramide derivatives were determined. The structural variation on the diisopropylaminoethyl group of disopyramide molecules influenced these physical parameters to varying degrees. Results demonstrated that the extent of interaction between drugs and human plasma was a linear function of their lipophilicity and inversely proportional to the magnitude of the pKb value.

Preformulation method for parenteral preservative efficacy evaluation.

A method is described for rapidly and reliably evaluating parenteral preservative efficacy. Solutions containing antimicrobial preservatives were challenged with microorganisms, sampled from 0.5 to 6 h following introduction of the challenge, cultured, and counted for surviving microbial cells. Data were analyzed by computer according to two models: linear and quadratic. Decimal reduction times (D values) were calculated for each microbial challenge in each preservative solution. A D value of less than or equal to 2 h for bacteria predicts that the preservative system will pass the British Pharmacopoeia (BP) preservative efficacy test, a more rigorous test than the USP test. Fourteen preservative systems were tested in both neutral isotonic saline solutions and neutral regular insulin solutions. D values and correlation coefficients for both models were calculated. The ranking of preservative effectiveness in neutral saline solutions closely correlated with the results found using neutral regular insulin solutions. The most effective preservative systems were found to be 0.3% m-cresol and various combinations of m-cresol and phenol. The advantages and limitations of this method are discussed.

The degradation of the antitumor agent gemcitabine hydrochloride in an acidic aqueous solution at pH 3.2 and identification of degradation products.

A study of the degradation kinetics of gemcitabine hydrochloride (2'-deoxy-2',2'-difluorocytidine) in aqueous solution at pH 3.2 was conducted. The degradation of gemcitabine followed pseudo first-order kinetics, and rate constants were determined at four different temperatures. These rates were used to construct an Arrhenius plot from which degradation rates at lower temperatures were extrapolated and activation energy calculated. Four major degradation products were identified. Only one of these degradation products, the uridine analogue of gemcitabine, was a known degradation product of gemcitabine and was identified by comparison with synthesized material. The other three degradation products were isolated and characterized by spectroscopic techniques. Two of these products were determined to be the diastereomeric 6-hydroxy-5, 6-dihydro-2'-deoxy-2',2'-difluorouridines, and the other product was determined to be O(6),5'-cyclo-5,6-dihydro-2'-deoxy-2', 2'-difluorouridine. The mechanisms of formation of these degradation products are discussed.