The sequential appearance of Ia-like antigens and two different complement receptors during the maturation of human neutrophils.

Ia antigens and two different types of complement (C) receptors appeared on membrane surfaces in a distinct sequence during the maturation of human neutrophils. Taking advantage of the finding that neutrophil celll density increased with maturation, density gradient centrifugation was used to separate neutrophils into fractions that were greatly enriched in cells representing individual stages of differentiation. Myeloblasts, the earliest cells recognized in the myeloid series of both normal and myelogenous leukemic individuals, expressed Ia determinants, whereas Ia determinants were absent or diminished on the majority of promyelocytes and completely undetectable on more mature granulocytes. Double marker studies demonstrated that Ia determinants were lost from the membrane of developing myeloid cells before the appearance of any type of C receptor. In the next phase of maturation defined by surface markers, neutrophils acquired a CR2-type C receptor (C3d receptor) that was similar in specificity to CR2 of B lymphocytes. This stage of maturation approximately corresponded to the myelocyte-metamyelocyte stage defined by standard morphologic criteria, and preceded the third stage of surface marker maturation when developing neutrophils began to express CR1-type C receptors (immune adherence, C4b-C3b receptors) in addition to CR2. In the final stage of surface marker-defined maturation, CR2 was lost from high density polymorphonuclear neutrophils and CR1 was maximally expressed. Normal blood polymorphonuclear neutrophils contained only 17% of CR2-bearing cells and these were shown to be of lower density than the majority of neutrophils that expressed only CR1. There was some variation in the correlation of surface marker expression and maturation stage defined by morphologic criteria, but in all cases the sequence of marker appearance was the same: Ia leads to CR2 leads to CR1CR2 leads to CR1.

Fever, rash, and muscle tenderness. A distinctive clinical presentation of disseminated candidiasis.

Five patients had fatal, disseminated candidiasis. At the onset of candidemia, a remarkably similar and distinctive triad of high fever, papular erythematous skin lesions, and diffuse severe muscle tenderness developed in each patient. This previously unreported clinical syndrome is sufficiently unique to justify a presumptive diagnosis of disseminated candidiasis and the use of empiric antifungal therapy pending culture and biopsy results.

Leukemic infiltration of the cerebellum in acute myelomonocytic leukemia.

A 31-year-old woman with acute myelomonocytic leukemia presented with meningeal signs and a cerebellar mass attributed to leukemic infiltration. The mass disappeared with radiation therapy and intraventricular chemotherapy, but the patient subsequently suffered several spinal nerve root recurrences, disseminated herpes zoster, and progressive multifocal leukoencephalopathy. At autopsy, there was no trace of the meningeal leukemia or cerebellar infiltrate. This case illustrates several of the neurologic complications of acute nonlymphocytic leukemia, and raises the question whether patients with the myelomonocytic form of this disease might benefit from prophylactic central nervous system treatment.

Disseminated candidiasis. Newer approaches to early recognition and treatment.

The clinical triad of fever, erythematous papular rash, and diffuse muscle tenderness has recently been reported to be presumptive evidence for disseminated candidiasis in the immunocompromised host who is receiving broad-spectrum antibiotics. This case report further explores this clinical association and demonstrates that the immediate institution of antifungal therapy before laboratory test results are known may favorably alter the outcome of this frequently fatal condition. In view of the low positive yield of blood cultures, skin biopsy may represent an effective method for achieving rapid laboratory confirmation of the diagnosis.

Influence of pH on release of phenytoin sodium from slow-release dosage forms.

Physicochemical factors influencing the release of phenytoin sodium from slow-release dosage forms were studied. Some of these factors were solubility and intrinsic dissolution rate as functions of pH, type of dosage form, pH of dissolution medium used, and conversion of the sodium salt to free acid (phenytoin). The innovator's product, Extended Phenytoin Sodium Capsule (Dilantin Kapseal, 100 mg, Parke-Davis), and two experimental formulations (one nondisintegrating tablet containing polymeric materials and the other a solid dispersion in an erodible matrix) served as the slow-release dosage forms. The sodium salt converts to practically insoluble phenytoin in the gastrointestinal pH range of 1 to 8. Due to such a conversion inside or at the surface of slow-release dosage forms, the release of drug in this pH range was incomplete. The extent of drug release also varied with the type of formulation used. In contrast, complete dissolution could be obtained in water because the pH of the medium gradually rose from approximately 6 to approximately 9.2 where the drug solubility was higher. Although several phenytoin sodium products might have similar dissolution rates in water, the extents of drug release under gastrointestinal pH conditions (pH 1-8) could differ greatly, thus supporting the Food and Drug Administration recognition that the similarity in dissolution profiles in water does not assure that the products are bioequivalent. The reported lower steady-state level of phenytoin in human plasma following oral administration of a slow-release dosage form may be related to incomplete drug release.

Solid dispersions of testosterone with reduced presystemic inactivation.

Dissolution rates of solid dispersions of testosterone in various lipids or polyethylene glycol 6000 with and without surfactants were determined. In a limited study, selected dispersions were evaluated for oral absorption efficiency in a 32-year-old male. Significant reductions in urinary testosterone metabolites to testosterone ratios were observed with a 1:4 weight ratio of testosterone-polyethylene glycol 6000 and a 1:4:0.25 weight ratio of testosterone-cholesteryl stearate-sorbitan monolaurate.

Solid dispersion of morphine-tristearin with reduced presystemic inactivation in rats.

Solid dispersions of morphine in tristearin, beta-sitosterol, and cholesterol were prepared by evaporation of their ethanol solutions. Weight ratios of morphine-lipid of 1:1, 1:3, and 1:4.5 were prepared. Dissolution studies of the solid dispersions and morphine were conducted in a simulated GI medium at 37 degrees. The release rates of morphine from the tristearin dispersions were the slowest. The 1:1 morphine-tristearin dispersion was administered orally to rats. Free and total morphine levels in rat urine were determined by spectrofluorometric and enzymatic immunoassay procedures, respectively. The morphine-tristearin dispersion yielded a higher percentage of free morphine after 24 and 48 hr as compared with morphine and its sulfate.

Oral absorption efficiency of acid-labile antibiotics from lipid-drug delivery systems.

The utility of cholesterol, cholesteryl acetate, and beta-sitosterol in protecting and improving the oral absorption efficiency of acid-labile antibiotics is discussed. The potassium salts of penicillin G and penicillin V and erythromycin lactobionate were studied. The stability of the two penicillins in simulated gastric fluid was determined iodometrically. The rank order of acid protective activity was: cholesteryl acetate greater than beta-sitosterol greater than cholesterol. Oral administration of erythromycin lactobionate coated with cholesteryl acetate produced a twofold increase in human urinary excretion of erythromycin when compared with the uncoated material. Potassium salts of penicillin G and penicillin V coated with cholesteryl acetate yielded 1.6- and 2-fold higher urine levels, respectively, as compared with the uncoated candidates.

Dissolution rates of corticoid solutions dispersed on silicas.

Two nonporous and three porous amorphous silicas were used as dispersion media to convert corticoid solutions into free-flowing powders. The corticoids (prednisone, prednisolone, and hydrocortisone) were dissolved in N,N-dimethylacetamide-polyethylene glycol 400 (7:3 v/v) and their 10% (w/v) solutions were mixed with the silicas (1:3 v/w). Dissolution rates of the corticoids from such powdered solutions were more rapid than their micronized powders in various aqueous media.

Modified colorimetric method of plasma prednisolone.

A simple, precise, rapid, and sensitive colorimetric method was adapted for the quantitative analysis of prednisolone in dog plasma. A paper chromatographic procedure was modified by the use of thin-layer plates coated with microcrystalline cellulose. Heparinized blood samples were separated from the cellular elements and extracted with methylene chloride. After washing with acid and alkali, the extract was evaporated to dryness. The residue was dissolved in methanol and streaked on the TLC plate. After development, the band that was detected by UV light was scraped off and extracted with methanol. The methanol extract was treated with the Porter-Silber reagent (phenylhydrazine). Absorbance was measured at 410 nm. Replicate assays indicated a mean recovery of 97.5% and a coefficient of variation of 5.13%.

Utility of fasting essential amino acid plasma levels in formulation of nutritionally adequate diets III: lowering of rat serum cholesterol levels by lysine supplementation.

A lysine-supplemented ration lowered the serum cholesterol levels of rats. The level of lysine supplementation was derived from the fasting plasma essential amino acid profile.

Utility of fasting essential amino acid plasma levels in formulation of nutritionally adequate diets IV: lowering of human plasma cholesterol and triglyceride levels by lysine and tryptophan supplementation.

The administration of capsules containing L-lysine monohydrochloride (0.205 g) and L-tryptophan (0.069 g) three times daily after meals resulted in a significant drop in plasma cholesterol and triglyceride levels. The proportion of amino acids in the blend was derived from the average fasting plasma essential amino acid profile.

Surface tension lowering and dissolution rate of hydrocortisone from solid solutions of selected n-acyl esters of cholesterol.

The dissolution of hydrocortisone into simulated intestinal fluid from lipid delivery systems followed second-order kinetics. As the ratio of hydrocortisone to lipid was increased from 1:1 to 1:6, the dissolution rate decreased. Solvent deposition of solid solutions of hydrocortisone and lipid on lactose resulted in the enhancement of the dissolution rate. For the 1:1 hydrocortisone-lipid solid solutions, the rank order of the dissolution rate was hydrocortisone-cholesteryl stearate, hydrocortisone, hydrocortisone-cholesterol, hydrocortisone-cholesteryl acetate, hydrocortisone-cholesteryl palmitate, hydrocortisone-cholesteryl n-butyrate, hydrocortisone-cholesteryl laurate, and hydrocortisone-cholesteryl n-decylate. A direct correlation was found between the dissolution rate of hydrocortisone and the surface tension lowering of simulated intestinal fluid by the corticoid and various lipids.

Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical bases and their hydrochloride salts. I: Phenazopyridine.

The pH-solubility profile of phenazopyridine as determined by the addition of HCl or NaOH solutions to its aqueous suspension was identical to that of its hydrochloride salt except during phase transition from base to salt. With the addition of HCl to a suspension of the base, the pH dropped to a certain point and then remained constant until a supersaturated solution was formed. Only after a high supersaturation did precipitation of the hydrochloride salt occur. The solubility of the salt decreased at low pH due to a common ion effect. Unlike solubility profiles, the pH-intrinsic dissolution rate profiles of the base and its salt differed greatly. At low pH, the dissolution rate of the hydrochloride salt decreased with an increase in HCl concentration, whereas the dissolution rate of the base increased. The self-buffering action of the base and the increase in solubility, leading to a supersaturation of the diffusion layer was responsible for the increase in its dissolution rate with a lowering of the pH of the medium. Good conformity with the Noyes-Whitney equation was demonstrated when the solubility values under pH conditions such that the diffusion layer thickness approaches zero (Cs,h = 0) were used rather than solubilities under pH conditions of the bulk media (Cs). Supersaturation of the dissolution medium was observed during dissolution of the hydrochloride salt at pH 7.

Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical acids and their sodium salts. II: Salicylic acid, theophylline, and benzoic acid.

The pH-solubility profiles of salicylic acid and theophylline, as determined by the addition of HCl or NaOH to their aqueous suspensions, were identical with those of their sodium salts except during phase transitions from acid to salt or vice versa. Supersaturated solutions were formed during phase transitions. Unlike the solubility profiles, the pH-intrinsic dissolution rate profiles of an acid and its salt differed greatly. Good conformity with the Noyes-Whitney equation was demonstrated when the solubility values under pH conditions as the diffusion layer thickness, h, approaches zero (Cs,h = 0) were used rather than solubilities under pH conditions of the bulk media (Cs). The pH when h approaches zero (pHh = 0) was estimated by equilibration of a dissolution medium with an excess of material. Good correlation was shown between the pHh = 0 values of benzoic acid estimated according to this method and the pHh = 0 values reported in the literature. The intrinsic dissolution rate constant, the ratio of the diffusion coefficient to the diffusion layer thickness (D/h), may be assumed constant when comparing the dissolution rates of salicylic acid, theophylline and sodium theophylline. On the other hand, D/h decreased significantly during dissolution of sodium salicylate due to a large increase in Cs,h = 0 and the consequent increase in viscosity in the diffusion layer. A simple method of predicting the dissolution rate of an acid or a salt at different pH values has been developed.

Effects of amorphous silicon dioxides on drug dissolution.

The dissolution profiles of prednisone, digoxin, and griseofulvin in simulated GI fluids were determined after solvent deposition or ball milling with three commercially available grades of amorphous silicon dioxide. The former procedure resulted in adsorbates showing evidence of drug entrapment by the two grades with larger average pore diameters. Ball milling the drugs with the grade possessing the largest average particle diameter produced triturations with the slowest dissolution rates. A relationship between drug dissolution and extent of dilution with the amorphous silicon dioxides was shown. Particle-size measurements revealed that the ball milling procedure was more apt to broaden the size distribution as compared with the solvent-deposition method of drug incorporation.

Stabilizing effect of fructose on aqueous solutions of hydrocortisone.

Accelerated stability studies (37 degrees, 47 degrees, and 57 degrees) were conducted on buffered aqueous solutions (pH 7.4, 8.4, and 9.4) of hydrocortisone in the presence of various molar ratios of D-fructose. First-order degradation was observed. Significant improvement in hydrocortisone stability was seen in those solutions containing a 25 M excess of D-fructose. Hydrocortisone solutions containing dextrose, lactose, sucrose, sorbitol, propylene glycol, or glycerin in the same molar ratio were not stabilized.

Instability of digoxin in digoxin-amorphous silicon dioxide triturates prepared by solvent deposition and ball milling.

Digoxin underwent hydrolytic degradation to its molecular components when solvent deposited on or ball milled with various commercial grades of amorphous silicon dioxide. The degradation was greater during ball milling than after solvent deposition, and increased with a longer ball milling. By itself digoxin was also degraded by ball milling, but not as much as when a silicon dioxide was present. The extent of the degradation appeared to depend on the acidity, surface area and pore size of the silicon dioxide used. A similar degradative behavior was observed for the related glycoside digitoxin.