Medicine in the past millennium.
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Anesthesia↗
Biomedical subjects
M Friedman
Publications and source records attributed to M Friedman.
The effect of egg albumin on the crystalline properties of carbamazepine in sustained release hydrophilic matrix tablets and in aqueous solutions.
The influence of egg albumin (EA) on the crystal habit properties of carbamazepine (CBZ) in aqueous solutions, solid-state, and in sustained release matrix tablets was investigated using differential scanning calorimetry (DSC), hot-stage microscopy (HSM), X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and contact angle goniometer (CAG). The results suggest that in solid-state mixtures, EA affected the polymorphic transitions of CBZ from the beta to the alpha form. In hydrated matrix tablets and aqueous solutions, EA influenced the conversion rate of CBZ to the dihydrate form depending on EA concentration. It was found that increasing EA concentration enhanced CBZ dihydrate aggregation, an effect that leads to the formation of crystals with high mechanical strength and decrease of CBZ solubility. Possible mechanisms, which explain crystal growth and aggregation, as well as alteration of CBZ polymorphic transitions in the solid-state, gel layer, and in aqueous solution were suggested. In the gel layer of hydrated tablets the kinetics of CBZ transformation to the dihydrate form, crystal growth and aggregation were influenced by various processes: matrix hydration, erosion mechanism and the formation of metastable conditions, which favor aggregation and growth. The release kinetics of CBZ from the matrix highly correlated with the crystalline and morphological changes occurring in the matrix.
Anticonvulsants↗
Correlation between drug release kinetics from proteineous matrix and matrix structure: EPR and NMR study.
The present study was conducted in order to probe the microstructure, microviscosity, and hydration properties of matrices containing two model drugs, naproxen sodium (NS) and naproxen (N), and egg albumin (EA) as matrix carrier. The results suggested that N release from EA matrix was controlled by a bulk erosion mechanism in combination with additional processes (crystal dissolution/crystallization rate) compared with NS matrix, which behaved as a non-erodible matrix and drug release occurred by diffusion through the gel. Using EPR technique it has been shown that incorporating NS into EA matrix strongly influences the microstructure of the protein gel, and hence the transport of the penetrant within the matrix, compared with matrices containing N. The presence of NS increased the protein chain mobility and hydration which supports our previous results showing that NS cause unfolding of EA. In contrast, N caused only marginal effect on EA chain mobility. The gel formed in EA/NS matrices was more porous compared with EA/N matrices as revealed by the lower rotational correlation time of PCA (lower microviscosity) in EA/NS matrices compared with EA/N. However, EA/N gelled matrices were more heterogeneous, i.e., containing a higher number of components having different mobility. The T(1) and T(2) relaxation studies by NMR provided an additional support for the higher chain hydration in EA/NS matrices compared with EA/N as indicated by the higher relaxation rates in the gelled matrices. Internal pH measurements by EPR revealed that the micro-pH inside 100% EA and 50/50 EA/N matrices were lower than 50/50 EA/NS matrices and in all cases lower than the penetrating buffer pH. The lower pH compartment formed in N matrices affected N solubility and crystal dissolution rate, which can explain its lower release rate compared with EA, from the same formulation. The EPR and NMR data supports our findings that NS caused unfolding of the protein, affected matrix structure, and converted it to a hydrophobic non-erodible matrix compared with EA/N matrix in which the native properties of EA were mainly retained.
Diffusion↗
Pharmacodynamic effects of bezafibrate and niacin combination: implications of the mode of administration.
The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.
Animals↗
Effect of improved nasal breathing on obstructive sleep apnea.
OBJECTIVES: The goal was to compare the effect of an improved nasal airway on obstructive sleep apnea (OSA) by use of subjective and objective measures. METHODS: A prospective study of 50 consecutive patients with nasal airway obstruction and OSA was carried out. RESULTS: Subjectively, nasal breathing improved in 49 (98%) patients, whereas snoring decreased or disappeared in 17 (34%); the remaining 33 (66%) patients did not notice any significant change in their snoring. Daytime energy levels increased in 39 (78%) patients and remained unchanged or worsened in 11 (22%). In review of the polysomnographic data, the group overall did not have significant changes in respiratory disturbance index (RDI) or lowest oxygen saturation levels (LSaO(2)). Continuous positive airway pressure (CPAP) levels required to correct OSA decreased after nasal surgery (P < 0.01). Patients with mild OSA showed significant worsening in RDI (P < 0.05), whereas LSaO(2) levels were improved in the group with moderate OSA (P < 0.05). In patients with severe OSA neither the RDI levels nor the LSaO(2) changed, but CPAP levels required to alleviate the obstruction after surgery were reduced (P < 0.01). CONCLUSIONS: Most patients report improvement in nasal and sleep symptoms after correction of nasal airway obstruction. However, nasal surgery alone does not consistently improve OSA when measured objectively. Depending on the severity of OSA, nasal airway reconstruction may contribute to a decrease in CPAP level and improvement in oxygen saturation. Correction of the obstructed nasal airway should certainly be included in the overall treatment plan for OSA.
Adult↗
Lowering of plasma LDL cholesterol in hamsters by the tomato glycoalkaloid tomatine.
Tomatoes contain the steroidal glycoalkaloid tomatine, which has been reported to form strong, insoluble complexes with cholesterol in vitro. To determine whether tomatine can reduce dietary cholesterol absorption and plasma levels of cholesterol and triglycerides, we fed hamsters a high-fat, high-cholesterol diet with 0.05-0.2% added tomatine in the diet. The tomatine diets induced lowering of serum low-density lipoprotein (LDL) without changing high-density lipoprotein (HDL) cholesterol. Compared to the control diets, four- to fivefold more labeled dietary cholesterol and coprostanol was excreted in the feces of the tomatine-fed hamsters. The amount of cholesterol excreted in the feces corresponded to the amount of tomatine in the diet. These observations suggest that due to the formation of an insoluble tomatine-cholesterol complex and its excretion in the feces, very little dietary tomatine is absorbed from the digestive tract into the blood stream. They are also consistent with the reported low oral toxicity of tomatine compared to other glycoalkaloids.
Administration, Oral↗
The folic acid analogue methotrexate protects frog embryo cell membranes against damage by the potato glycoalkaloid alpha-chaconine.
As part of an effort to improve the safety of plant foods, a need exists to more clearly delineate the mechanisms of toxicities of glycoalkaloids, which may be present in Solanum plant species such as potatoes, tomatoes and eggplants. Alpha-chaconine is a major glycoalkaloid present in potatoes. To assess the possible influence of structure of pteridine derivatives on toxicity of potato glycoalkaloids, a previous study that demonstrated the protective effects of folic acid against the Solanum glycoalkaloid alpha-chaconine-induced toxicity on Xenopus laevis frog embryo cell membranes was extended to two folate analogues--a synthetic compound widely used as a therapeutic agent methotrexate, and naturally occurring L-monapterin. Adverse effects on embryos were evaluated by observing changes in membrane potentials with an electrochromic dye, di-4-ANEPPS, as a fluorescent probe for the integrity of the membranes. Methotrexate decreased alpha-chaconine-induced polarization, as did folic acid. This decrease may result from an alteration of membrane conformations that prevents the binding of the glycoalkaloid to the membrane receptor sites, and/or from effects on folic acid metabolism. In contrast, L-monapterin did not significantly reduce the alpha-chaconine-induced toxicity. The possible significance of these results to food safety is discussed.
Animals↗
Cinnamaldehyde content in foods determined by gas chromatography-mass spectrometry.
trans-Cinnamaldehyde, the principal component of cinnamon flavor, is a potent antimicrobial compound present in essential oils such as cinnamon. In the course of studies designed to discover its maximum microbial lethality under food-processing conditions, a gas chromatographic-mass spectrophotometric procedure was developed for the extraction and analysis of essential oil components such as cinnamaldehyde from commercial cinnamon-containing foods (several brands of cinnamon breads, cereals, cookies, puddings, applesauces, and fruit juices). The cinnamaldehyde content ranged from trace amounts in orange juice to 12.2 mg/100 g (122 ppm) in apple cinnamon cereals and 31.1 mg/100 g (311 ppm) for cinnamon swirl bread (highest value). To ascertain the heat stability of cinnamaldehyde, pure cinnamaldehyde, pure eugenol, cinnamon oil, and mixtures consisting of cinnamaldehyde plus eugenol or cinnamon oil were heated at graded temperatures up to 210 degrees C and 60 min, and then possible compositional changes were examined. Eugenol was stable to heat, as were the components of cinnamon oil: carvone, eugenol, and linalool. In contrast, starting at approximately 60 degrees C, pure cinnamaldehyde undergoes a temperature-dependent transformation to benzaldehyde under the influence of heat. Eugenol, both pure and in cinnamon oil, when added to pure cinnamaldehyde protected the aldehyde against heat destruction. The protection may due to an antioxidative action of eugenol. The possible mechanism of this effect and the significance of these findings for food chemistry and microbiology are discussed.
Acrolein↗
Effect of pH on the stability of plant phenolic compounds.
It is not uncommon to treat plant-derived foods and feeds with alkali. Such exposure to high pH is being used to recover proteins from cereals and legumes, to induce the formation of fiber-forming meat analogue vegetable protein, for preparing peeled fruits and vegetables, and for destroying microorganisms. In addition to their profound effects on functional and nutritional properties in such foods, such treatments may also cause other side reactions, including the destruction of natural polyphenolic compounds. Because plants contain a large number of structurally different antioxidant, anticarcinogenic, and antimicrobial polyphenolic compounds, it is of interest to know whether such compounds are stable to heat and to high pH. In this model study, the stability of the following natural polyphenols to pH in the range 3-11 was studied with the aid of ultraviolet spectroscopy: caffeic acid, (-)-catechin, chlorogenic acid, ferulic acid, gallic acid, (-)-epigallocatechin, rutin, and the nonphenolic compound trans-cinnamic acid. This study demonstrates that caffeic, chlorogenic, and gallic acids are not stable to high pH and that the pH- and time-dependent spectral transformations are not reversible. By contrast, chlorogenic acid is stable to acid pH, to heat, and to storage when added to apple juice. (-)-Catechin, (-)-epigallocatechin, ferulic acid, rutin, and trans-cinnamic acid resisted major pH-induced degradation. The results are rationalized in terms of relative resonance stabilization of phenoxide ions and quinone oxidation intermediates. The possible significance of these findings to food chemistry and microbiology is discussed.
Drug Stability↗
Investigating the structure and properties of hydrated hydroxypropyl methylcellulose and egg albumin matrices containing carbamazepine: EPR and NMR study.
PURPOSE: The present study was conducted in order to investigate the correlation between the hydration properties of HPMC and EA matrices, gel microstructure and mobility, crystalline changes occurring in the gel and CBZ release kinetics. The influence of HPMC and EA erosion modes on CBZ release kinetics was interpreted in terms of gel microstructures. METHODS: NMR technique was used to determine the T1 and T2 relaxation rates of water in hydrated matrices. PFGSE NMR technique was employed to determine the SDC of water in the gels. EPR technique was used to determine the rotational correlation time of PCA in the hydrated matrices, gel microviscosity, mobile compartment, alpha, beta, gamma parameters and lorentzian/ gaussian ratio. These parameters are indicative of matrix microstructure. RESULTS: CBZ release mechanism from HPMC and EA matrices was markedly different. This behavior was related to the different structures of the polymer and protein. T2 relaxation studies and SDC measurements by NMR revealed higher chain hydration for HPMC compared to EA. Using the EPR technique it has been shown that the microviscosity and mobile compartment of matrices containing HPMC are lower than matrices containing EA. The microviscosity, mobile compartment and S-parameter values of hydrated matrices containing different EA/CBZ ratios were in correlation with the crystallization properties of CBZ in the gels, matrix erosion properties and CBZ release kinetics from the matrices. CONCLUSIONS: Characterization of matrix structures using EPR and NMR techniques supported our hypothesis concerning the mechanism involved in HPMC-CBZ interaction. EA/CBZ matrix microstructure features, analyzed by NMR and EPR techniques, were in correlation with the crystalline changes occurring in the gel and drug release kinetics.
Carbamazepine↗
Synchronized release of sulpiride and sodium decanoate from HPMC matrices: a rational approach to enhance sulpiride absorption in the rat intestine.
PURPOSE: (a) To improve the absorption of sulpiride (SP) through the intestinal wall by incorporating it together with sodium decanoate (SD) into erodible matrices, designed to synchronize the release of SP and SD over different periods of time; (b) to test, in vivo the hypothesis that this simultaneous release increases SP absorption from the intestinal lumen. METHODS: Matrix tablets, possessing different erosion rates, were prepared by changing the ratios between SD and hydroxypropyl methylcellulose (HPMC). The amounts of HPMC varied from 2.5% to 17% w/w. Double layer tablets, containing similar amounts of SP, SD, and HPMC were used as nonsynchronous controls. The erosion kinetics of the tablets was assessed gravimetrically in vitro in USP basket dissolution apparatus and in vivo in the intestine of the anesthetized rat after intra-intestinal administration. SP absorption was studied after intra-intestinal administration of the different kinds of tablets to anesthetized rats, by monitoring SP blood levels. SP and SD levels in the withdrawn samples from the dissolution systems and blood were analyzed by HPLC. RESULTS: The controlled erosion of the tablets resulted in equal release rates of SP and SD during the initial linear phase of the process. This synchronized release lasted over different time periods depending on the relative amount of HPMC in the formulations (from 1 hour to 4 hours for 2.5 and 17 % w/w of HPMC, respectively). The synchronous matrices increased SP bioavailability after intra-intestinal administration. The increase varied from 1.4 to 2.3-fold for the slow and the fast release formulations, respectively (compared with the nonsynchronous, SD containing control formulations), indicating the ability to control both erosion rate and length of intestinal segment in which absorption is taking place. CONCLUSIONS: SP bioavailability after intestinal administration can be improved only if SP is released together with SD along the entire intestinal route. This can be accomplished by the design of synchronous matrices capable of concomitant release of SP and SD despite the differences in their water solubility. The ability to manipulate and control the duration of the synchronous phase of the matrices makes it possible for SP to be absorbed at different parts of the intestine.
Animals↗
Pharmacodynamic effects of ketoprofen on crevicular fluid prostanoids in adult periodontitis.
The reported therapeutic benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) in slowing periodontal disease progression appear intimately linked to the effective inhibition of local prostaglandin synthesis. This randomized, partially double-blind, controlled trial was conducted to evaluate the pharmacodynamic effects of the NSAID, ketoprofen (KTP), on gingival crevicular fluid (GCF) prostanoids. 42 subjects, ages 35-57 years, with moderate to advanced adult periodontitis were recruited and monitored for 22 days. On day 1, subjects were randomized for 1 of 5 treatments: i) 0.5% KTP gel; ii) 1.0% KTP gel; iii) 1.0% KTP alternate gel; iv) 2.0% KTP gel; v) 25 mg KTP capsule (positive control). Subjects applied 1 ml of gel topically to their gingiva or administered one capsule p.o., b.i.d. for 14.5 days. GCF samples were collected from posterior, interproximal sites on days 1 (pre-dosing; 1, 2, 3, 6 h), 8 (pre-dosing; 2 h), 15 (pre-dosing; 2 h) and 22 (post-treatment). GCF levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were determined using RIA, and expressed in ng/ml and % reduction from baseline (%Effect). Neither a significant difference among groups nor a dose response in % effect for either prostanoid was evident, both overall and among cohorts with elevated baseline mediator levels ([PGE2]>34 ng/ml; [LTB4]>300 ng/ml). When data were combined from all groups, significant (p<0.01) % reductions in GCF PGE2 were noted at 1 and 2 h post-dosing (29% and 24% respectively). In comparing topical versus systemic formulations, all topical formulations were as equipotent as systemic dosing in altering local prostaglandin levels despite lower KTP exposures with gel treatments. These data indicate that both topical and systemic KTP therapies pharmacodynamically reduce GCF PGE2 levels in adult periodontitis subjects, allowing for potential inhibition of disease progression.
Administration, Topical↗
Middle turbinate medialization and preservation in endoscopic sinus surgery.
OBJECTIVE/HYPOTHESIS: Lateral synechia formation between the middle turbinate (MT) and the lateral nasal wall is the most common complication of endoscopic sinus surgery. In an attempt to prevent this complication, a simple technique to preserve and medialize the MT was studied. METHODS: Five hundred patients underwent endoscopic sinus surgery with MT medialization and preservation. The caudal end of the MT and the opposing septal mucosa were abraded with a microdebrider for controlled synechia formation in an attempt to avoid lateralization of the MT. Follow-up ranged from 6 to 18 months, with a mean follow-up of 10 months. RESULTS: Ninety-three percent of the patients had successful MT medialization with a well-defined synechia between the septum and the MT. CONCLUSIONS: MT medialization with a microdebrider is simple, is reliable, and should be considered an alternative to turbinate resection or to other turbinate medialization techniques.
Adult↗
Juvenile xanthogranuloma of the tongue.
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Humans↗
Intraoperative and postoperative assessment of frontal sinus patency by transillumination.
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Endoscopes↗
Endoscopic sinus surgery in patients infected with HIV.
OBJECTIVES: To be able to plan appropriate surgical treatment for patients with HIV infection who have sinusitis refractory to medical therapy. DESIGN: We retrospectively reviewed the charts of 186 patients with HIV who required surgical treatment for sinusitis between 1987 and 1998. One hundred six charts provided the necessary information and an adequate follow-up to be included in the study. Collected data included preoperative and postoperative symptoms, radiographic staging, CD4 count at the time of surgery when available, and type and extent of surgery. RESULTS: Surgical treatment evolved over the 12 years from limited surgery to standard endoscopic sinus surgery (ESS). Eighteen patients had invasive fungal disease or complications of sinusitis requiring radical surgery. Thirty-six patients were treated with minimal procedures to address involved sinuses only. These patients were treated between 1987 and 1991. Recurrent disease or further complications occurred in 80.6% of the patients in this group. Since 1992, 52 patients were treated with standard ESS following the same indications for HIV- patients. This group had an improvement of symptoms in 75% of the cases, a rate comparable to the success rate in HIV- patients. CONCLUSIONS: HIV+ patients undergoing standard ESS enjoy a satisfactory success rate. HIV+ patients with surgical indication for endoscopic sinus surgery should be treated as non-HIV+ patients. Apparently, low CD4 count (< 100) does not serve as a contraindication for definitive surgery.
Adult↗
Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease.
Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV(1) and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV(1) and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 microg delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 microg, and advantages suggested by the safety profile at doses below 36 microg in this study, a dose of 18 microg once daily was selected for use in long-term studies of the safety and efficacy of tiotropium.
Administration, Inhalation↗
Experience with percutaneous dilational tracheostomy.
Percutaneous dilational tracheostomy (PDT) has gained popularity among critical care specialists in the past 10 years. The initial studies in our specialty resulted in essentially banning the procedure as a dangerous substitute for standard operative tracheostomy. Despite this action, more than 1,100 cases of percutaneous tracheostomy have been reported with details on complications. We reviewed all published data and studied 311 patients of our own. A prospective study was performed in 3 groups of patients: 1) 50 patients scheduled for PDT performed in the operating room by a head and neck surgeon (group 1); 2) 50 patients who underwent standard operative tracheostomy performed by the same surgeon (group 2); and 3) 211 patients who underwent bedside PDT by critical care physicians (group 3). The intraoperative complication rates were 0% in group 1, 2% in group 2, and 4% in group 3; the postoperative complication rates were 13%, 4%, and 12%, respectively. There were 2 deaths in group 3, and none in groups 1 or 2. The statistically significant differences among the groups were the superiority of group I over group 3 in intraoperative complications, as well as the lower postoperative complication rate of the standard tracheostomy group. These results show that PDT can be performed with acceptable morbidity rates in relation to published complication rates of standard tracheostomy, but it has no advantage over standard tracheostomy with respect to postoperative morbidity. When they are performed by a head and neck surgeon, the morbidity associated with both standard and percutaneous tracheostomies can be reduced.
Adult↗