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Pharmaceutical formulations--suspensions and solutions.

Solutions and suspensions of drugs are used widely in the pharmaceutical industry for production of dosage forms for different routes of administration; for example, oral, parenteral and inhalation. Pharmaceutical solutions and suspensions might appear to be simple formulations but they can present many technical problems both for the manufacturing industry and for the individual pharmacist. Substances can be chemically unstable, insoluble in water, distasteful etc. Suspensions are often used as a dosage form when the drug is insoluble in water and when use of solubilizing agents is not possible. Based on method of preparation, suspensions can be divided into two categories, flocculated and deflocculated systems.

Drug Administration Routes↗

Relative bioavailability of itraconazole from an extemporaneously prepared suspension and from the marketed capsules.

The bioavailability of itraconazole from an extemporaneously prepared suspension was compared with its bioavailability from the commercially available capsules. Ten healthy volunteers were fed breakfast and were then randomly assigned to receive either 400 mg of itraconazole 40-mg/mL oral suspension or four 100-mg itraconazole capsules with 240 mL of water. They were not allowed to rest in a supine position for six hours, eat for four hours, or take any beverages for two hours post-dose. Blood samples were taken immediately after the subjects had eaten and at intervals up to 72 hours post-dose. Serum was separated and stored at -70 degrees C. Serum itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography. After 14 days, each subject was given the dosage form that he or she did not previously receive, and testing was repeated. Maximum concentration (Cmax) and time to reach maximum concentration (tmax) were determined, and the area under the serum concentration-versus-time curve from 0 to 72 hours (AUC0-72) was estimated. The suspension:capsule ratios of least-squares means for Cmax, tmax, and AUC0-72 for itraconazole were 0.15 (90% confidence interval [CI], 0.11-0.21), 0.95 (90% CI, 0.75-1.20), and 0.12 (9% CI, 0.06-0.23), respectively. The results for hydroxyitraconazole were similar: 0.19 (0.13-0.28), 0.95 (0.81-1.12), and 0.13 (0.07-0.23), respectively. The bioavailability of itraconazole from the extemporaneously prepared suspension is much lower than that from capsules.

Adult↗

Stability of terbinafine hydrochloride in an extemporaneously prepared oral suspension at 25 and 4 degrees C.

The stability of terbinafine 25 mg/mL (as the hydrochloride salt) in an extemporaneously prepared oral suspension at 25 and 4 degrees C was studied. Twenty 250-mg terbinafine tablets were crushed to a fine powder and diluted to a concentration of 25 mg/mL with sweetened vehicle. The suspension was stored in amber polyethylene prescription bottles at 25 or 4 degrees C. Samples were taken on days 0, 7, 14, 28, 42, 56, 70, and 91 for duplicate analysis of terbinafine content by high-performance liquid chromatography and to observe any changes in color and odor; pH was measured as well. Through the initial 42 days, the mean concentration of terbinafine in the samples stored at both temperatures was >93% of the initial concentration; by day 56, the mean concentration was <88%. No appreciable changes in color or odor were observed during the study period. The apparent pH of the suspension decreased slightly over the 91 days, from an initial 5.6 to 5.5. Terbinafine 25 mg/mL (as the hydrochloride salt) in an extemporaneously prepared oral suspension was stable for up to 42 days in polyethylene prescription bottles at 25 and 4 degrees C.

Administration, Oral↗

Effect of cortisporin otic suspension on cochlear function and efferent activity in the guinea pig.

To predict cochlear receptor cell insult from therapeutic aminoglycoside antibiotics, we sought to determine whether the presence of subtoxic concentrations of Cortisporin otic suspension in the cochlea can be detected by measuring changes in efferent suppression of compound action potentials recorded from the round window. Olivocochlear efferent suppression in an earlier study was reversibly inhibited by injections of gentamicin in guinea pigs. Using that same technique, we found that 2.0 microliter of Cortisporin otic suspension (neomycin, polymyxin B, hydrocortisone) placed on the round window of guinea pigs in varying concentrations causes a rapid, permanent alteration in thresholds. Solutions of Cortisporin otic suspension diluted to a concentration of 1:20 yield a reversible loss of efferent suppression without measurable changes in compound action potential. These data suggest that the presence of Cortisporin otic suspension can be detected functionally in the cochlea at very low concentrations prior to the development of a threshold shift.

Action Potentials↗

Comparative safety and efficacy of clarithromycin and cefadroxil suspensions in the treatment of mild to moderate skin and skin structure infections in children.

A prospective, randomized, single (investigator) blind multicenter study was performed to compare the safety and efficacy of clarithromycin and cefadroxil oral suspensions in the treatment of mild to moderate skin and skin structure infections in children. Male and female patients ages 6 months to 12 years were enrolled at 24 study centers in the United States. Patients had signs and symptoms consistent with mild to moderate skin or skin structure infections judged suitable for oral antimicrobial therapy. Clarithromycin oral suspension was given to 118 children in a dose of 7.5 mg/kg (maximum of 500 mg) twice daily; cefadroxil oral suspension was given to 113 children in a dose of 15 mg/kg (maximum of 1000 mg) twice daily. Among clinically evaluable patients clinical success rates (cure plus improvement) were 96% (71 of 74) for clarithromycin and 98% (83 of 85) for cefadroxil (P = 0.664). Bacteriologic cure rates in evaluable clarithromycin and cefadroxil patients were 96% (72 of 75) and 99% (89 of 90), respectively (P = 0.331). Pathogen eradication rates based on 204 evaluable pathogens were 97% in the clarithromycin group and 99% in the cefadroxil group (P = 0.326). Adverse events were mild or moderate and were reported in 25% of clarithromycin and 35% of cefadroxil patients (P = 0.085). In both groups adverse events involved primarily the digestive tract. No significant laboratory changes were noted. Clarithromycin oral suspension appears to be a safe and effective alternative to cefadroxil for the treatment of pediatric skin and skin structure infections.

Administration, Oral↗

Clarithromycin and cefaclor suspensions in the treatment of acute otitis media in children.

The safety and efficacy of a new oral suspension formulation of clarithromycin were evaluated in this multicenter, Phase III, single blind, comparative trial in 379 children ages 6 months to 12 years with signs or symptoms of acute otitis media. Children were randomized to receive a 10-day course of clarithromycin oral suspension (7.5 mg/kg; maximum, 500 mg) or cefaclor oral suspension (20 mg/kg; maximum, 500 mg) twice daily. Specific clinical response criteria were developed based on pretreatment signs and symptoms and results of tympanometry. Of the 379 enrolled patients 281 (74%) were evaluable (clarithromycin, 150; cefaclor, 131). There were no demographic differences between the two groups. Fifty percent of the patients had 2 to 4 episodes of otitis media (including the current episode) in the past 12 months; 63% of the patients had an infection of moderate severity. Clarithromycin and cefaclor suspensions were similarly effective for the treatment of acute otitis media. Clinical success (cure, cure with effusion or improvement) was achieved in 86% of clarithromycin-treated patients and 90% of cefaclor-treated patients. The majority of bacterial isolates for which susceptibility results were available were fully or moderately susceptible to the study drugs (96% clarithromycin, 92% cefaclor). Both drugs were well-tolerated; adverse events considered probably study drug-related were reported by 30 (15%) of clarithromycin recipients and 31 (17%) of cefaclor recipients. There were no significant differences between the groups in the numbers of patients reporting events that were thought to be related to study medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Variation in acceptance of common oral antibiotic suspensions.

Palatability of oral antibiotic suspensions is important and may be a substantial factor in determining compliance in young pediatric patients. Because no comparative systematic data are available, we undertook the present study to assess the acceptance of and compliance with oral antibiotic suspensions commonly used in Israel. During a 4-month period lists of children receiving oral antibiotic suspensions were obtained from 3 major pediatric clinics, and parents were contacted by telephone 10 to 14 days after initiation of therapy, at which time information on age, sex, main disease, prescribed drugs and duration of treatment was obtained. Information regarding acceptance, side effects and compliance was obtained from 11 questions with graded scores. In the study 546 children received one of the following drugs: amoxicillin (n = 222); cefaclor (n - 142); cefuroxime axetil (n = 107); trimethoprim/sulfamethoxazole (n = 75). No major differences in background data were noted; more than 50% of each group had acute otitis media. Seventy-three percent of the cefaclor group reported acceptance of the drug with "pleasure" or "without problems" vs. 60, 55 and 20% for amoxicillin, trimethoprim/sulfamethoxazole and cefuroxime axetil, respectively, whereas "resentment" or "refusal" was reported in 11, 16, 26 and 56%, respectively (P < 0.0001). Mothers reported to be generally "satisfied" or "extremely satisfied" with the drug in 89, 81, 74 and 67% with cefaclor, amoxicillin, trimethoprim/sulfamethoxazole and cefuroxime axetil, respectively, and 85, 77, 73 and 67% of the children, respectively, received the drug for the entire prescribed course (P < 0.001). Our data demonstrate that marked variations exist in acceptance and compliance of oral antibiotic suspensions with children.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Treatment of oropharyngeal candidiasis in immunocompetent infants: a randomized multicenter study of miconazole gel vs. nystatin suspension. The Antifungals Study Group.

BACKGROUND: Miconazole gel has previously been shown to be an effective treatment for oropharyngeal candidiasis (thrush) in immunocompetent infants. This study compares miconazole gel with the standard therapeutic agent, nystatin suspension, with regard to efficacy, optimal duration of therapy and safety. DESIGN: Prospective multicenter, randomized, office-based open trial. PATIENTS: Twenty-six pediatricians enrolled 227 immunocompetent infants with signs of oropharyngeal thrush. Subjects were randomly assigned to receive 25 mg of miconazole as oral gel four times daily or 100,000 IU of nystatin as suspension four times daily after meals. All subjects were evaluated for safety. Fifteen patients whose thrush was not confirmed by culture were excluded from further analysis. The remaining 212 subjects were entered into an intention-to-treat analysis. Another 29 patients violated the study protocol; the remaining 183 subjects were evaluated for efficacy (per protocol analysis). RESULTS: Clinical cure by Day 5 of treatment was demonstrated in 84.7% of the 98 subjects in the miconazole group and 21.2% of the 85 subjects in the nystatin group (P < 0.0001). By Day 8, the cumulative clinical cure rates were 96.9% (miconazole) and 37.6% (nystatin), respectively (P < 0.0001). By Day 12.99.0% of subjects in the miconazole group and 54.1% of subjects in the nystatin group were clinically cured (P < 0.0001). Premature cessation of treatment at parents' request because of lack of clinical efficacy occurred in none of the infants treated with miconazole and in 6 infants treated with nystatin (P = 0.029). The oral yeast eradication rate on Day 5 was 54.1% with miconazole and 8.2% with nystatin (P < 0.0001). Clinical relapses of oropharyngeal thrush and side effects of the study drugs were observed with similar frequency in both study arms. CONCLUSIONS: Miconazole gel was significantly superior to nystatin suspension with regard to efficacy, rapidity of achieving cure and oropharyngeal yeast eradication. Relapses and side effects did not occur more frequently with miconazole than with nystatin. The results of this study indicate that miconazole gel is superior to nystatin suspension as the treatment for oropharyngeal candidiasis in immunocompetent infants.

Antifungal Agents↗

Comparison of the palatability of the oral suspension of cefdinir vs. amoxicillin/clavulanate potassium, cefprozil and azithromycin in pediatric patients.

BACKGROUND: Patient adherence to therapeutic regimens is extremely important to successful treatment of acute otitis media. Among pediatric patients medication palatability, particularly that of oral suspensions, is essential for patient acceptance, therapeutic compliance and successful outcome. METHODS: A series of six randomized, single blind, crossover trials were conducted, each comparing cefdinir oral suspension with one of the following antibiotic oral suspensions: amoxicillin/clavulanate potassium; cefprozil; or azithromycin. Each medication comparison was evaluated in a single center and multicenter study. Subjects 4 to 8 years of age were asked to taste and smell each medication and assign preference using a visual "smile-face" scale. Ratings were converted to a numeric score ranging from 5 ("really good") to 1 ("really bad"). RESULTS: Among the 715 subjects 85% rated the taste of cefdinir as good or really good, the highest possible ratings; 63% of subjects assigned the same ratings to amoxicillin/clavulanate potassium, cefprozil or azithromycin. Seventy-one percent rated the smell of cefdinir as good or really good; 64% assigned the same ratings to the comparators. CONCLUSIONS: Based on the findings from these trials, children 4 to 8 years of age preferred the taste and smell of cefdinir oral suspension to that of the comparator agents.

Administration, Oral↗

Effect of charcoal and sorbitol-charcoal suspension on the elimination of intravenous phenobarbital.

The effects of two different oral charcoal suspensions on the elimination of a 200 mg/70 kg, 1 h intravenous (i.v.) infusion of phenobarbital and the tolerances of the two regimens were determined in a randomized crossover study in six healthy male volunteers. Phenobarbital was given i.v. alone or together with 105 g of oral activated charcoal suspension or with 105 g of a commercially available sorbitol-charcoal suspension over a 36-h period. A 13-34% decrease in the area under the serum concentration time curve (AUC) for 0-60 h occurred with the administration of the activated charcoal, and a 19-52% decrease occurred with the commercial sorbitol-charcoal regimen. The mean apparent systemic clearance of total phenobarbital increased from 0.089 +/- 0.019 ml/min/kg to 0.141 +/- 0.029 and 0.146 +/- 0.036 ml/min/kg with the charcoal and sorbitol-charcoal treatments, respectively. No significant change in the fraction of phenobarbital bound to protein was detected. The charcoal regimen caused constipation in one subject. All subjects taking the sorbitol-charcoal preparation experienced diarrhea; there were no changes in electrolytes with either charcoal suspension. All subjects preferred the sorbitol-charcoal preparation.

Adult↗

Continuous muscle stretch prevents disuse muscle atrophy and deterioration of its oxidative capacity in rat tail-suspension models.

OBJECTIVE: The purpose of this study was to evaluate the effect of continuous muscle stretch on disuse-atrophied muscles. DESIGN: Sprague-Dawley rats were used and divided into five groups: control group, hind limb suspended for 3 and 7 days, and hind-limb suspension plus strenuous continuous muscle stretch for 3 and 7 days. In the hind-limb suspension plus strenuous continuous muscle stretch groups, the gastrocnemius-plantaris-soleus muscles were stretched using a plastic plate that immobilized the ankle joint at the maximum dorsal flexed position during the hind-limb suspension period. The intracellular energy metabolism of the working muscle during electric stimulation was evaluated by phosphorus-31 magnetic resonance spectroscopy in vivo. Changes in phosphocreatine, inorganic phosphate, and the intracellular pH were monitored to evaluate intramuscular oxidative capacity. Maximum tension and muscle wet mass were also measured. RESULTS: The oxidative capacity, muscle wet weight, and maximum tension decreased after hind-limb suspension. The muscle oxidative capacity at control levels was maintained during the first 3 days in muscles subjected to continuous strenuous stretch. It was also effective to prevent the decrease in muscle mass and maximum twitch tension during the initial 3 days. However, the effects did not persist. CONCLUSION: Continuous strenuous stretch was effective to prevent disuse muscle atrophy and its functional deterioration; however, its effects did not last long.

Animals↗

Solid-solid contacts due to surface roughness and their effects on suspension behaviour.

Solid-solid contacts due to microscopic surface roughness in viscous fluids were examined by observing the translational and rotational behaviours of a suspended sphere falling past a lighter sphere or down an inclined surface. In both cases, a roll-slip behaviour was observed, with the gravitational forces balanced by not only hydrodynamic forces but also normal and tangential solid-solid contact forces. Moreover, the nominal separation between the surfaces due to microscopic surface roughness elements is not constant but instead varies due to multiple roughness scales. By inverting the system, so that the heavy sphere fell away from the lighter sphere or the plane, it was found that the average nominal separation increases with increasing angle of inclination of the plane or the surface of the lighter sphere from horizontal; the larger asperities lift the sphere up from the opposing surface and then gravity at large angles of inclination is too weak to pull the sphere back down to the opposing surface before another large asperity is encountered. The existence of microscopic surface roughness and solid-solid contacts is shown to modify the rheological properties of suspensions. For example, the presence of compressive, but not tensile, contact forces removes the reversibility of sphere-sphere interactions and breaks the symmetry of the particle trajectories. As a result, suspensions of rough spheres exhibit normal stress differences that are absent for smooth spheres. For the conditions studied, surface roughness reduces the effective viscosity of a suspension by limiting the lubrication resistance during near-contact motion, and it also modifies the suspension microstructure and hydrodynamic diffusivity.

Computer Simulation↗

Viscoelasticity of single wall carbon nanotube suspensions.

We investigate the viscoelastic properties of an associating rigid rod network: aqueous suspensions of surfactant stabilized single wall carbon nanotubes (SWNTs). The SWNT suspensions exhibit a rigidity percolation transition with an onset of solidlike elasticity at a volume fraction of 0.0026; the percolation exponent is 2.3+/-0.1. At large strain, the solidlike samples show volume fraction dependent yielding. We develop a simple model to understand these rheological responses and show that the shear dependent stresses can be scaled onto a single master curve to obtain an internanotube interaction energy per bond approximately 40k(B)T. Our experimental observations suggest SWNTs in suspension form interconnected networks with bonds that freely rotate and resist stretching. Suspension elasticity originates from bonds between SWNTs rather than from the stiffness or stretching of individual SWNTs.

Elasticity↗

The influence of erythrocyte shape on suspension viscosities.

Erythrocyte shape changes are known to occur in vivo and can readily be induced in vitro. We have analysed the influence of increasing stomatocytosis produced by 0-0.64 mmol l-1 chlorpromazine and increasing echinocytosis induced with 0-120 mmol l-1 salicylate or 0-8 mmol l-1 2,4-dinitrophenol on suspension viscosities. The morphological index of each sample was determined and related to the suspension viscosity. It was found that the viscosity was increased by echinocytosis in dextran-free solutions, where no aggregation occurred. The viscosity could be normalized by retransforming echinocytes into discocytes. Under conditions with erythrocyte aggregation (suspension with 4 g dl-1 dextran 70, low shear rate: 0.1 s-1) a small degree of echinocytosis produced the highest viscosity, whereas at higher degrees of echinocytosis the ability to aggregate was reduced and the viscosity was similar to that of discocytes or stomatocytes. Erythrocytes incubated in hypotonic medium (constant cell number/volume) had a higher viscosity than cells in iso- or hypertonic medium. Severely hypotonic medium led to sphering of erythrocytes which reduced the ability of these cells to aggregate and hence decreased the viscosity of suspensions with dextran at low shear rate. The results indicate that discocytes have the lowest viscosity and thus the best oxygen transport efficiency and that iso- to hypertonicity provides a lower viscosity and better oxygen transport efficiency than hypotonicity. These results may contribute to the understanding of blood flow in health and disease.

Blood Viscosity↗

Reduced oral itraconazole bioavailability by antacid suspension.

AIMS: To investigate the effects of antacid suspension on oral absorption of itraconazole. METHODS: A randomized, open-labelled, two-period, crossover study with a 1-week washout period was conducted in 12 healthy Thai male volunteers. The participants were allocated in either treatment A or B in the first period. In treatment A, the volunteers were orally administered with 200 mg of itraconazole alone. In treatment B, the volunteers were administered orally with 200 mg of itraconazole co-administered with antacid suspension. Serial serum samples were collected over the period of 24 h and subsequently analysed by using a validated high-pressure liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: Time to reach maximal concentration (Tmax), maximal concentration (Cmax) and area under the curve (AUC0-infinity) were markedly decreased in antacid-treated group. Tmax for treatment A was 3.0 +/- 0.4 and 5.1 +/- 2.7 h for treatment B. Cmax and AUC0-infinity of treatments A and B were 146.3 +/- 70.5 vs. 43.6 +/- 16.9 (ng/mL) and 1928.5 +/- 1114.6 vs. 654.8 +/- 452.2 (ng x h/mL) respectively. 90% Confidence interval (90% CI) of Cmax and AUC0--infinity were 24.1-42.1 and 16.2-65.9 respectively. CONCLUSIONS: Rate and extent of itraconazole oral absorption were markedly decreased by concurrent use of antacid suspension. Hence, co-administration of itraconazole and antacid suspension should be avoided.

Adolescent↗

Routine tail suspension husbandry facilitates onset of seizure susceptibility in EL mice.

PURPOSE: Tail suspension can elicit seizures in susceptible EL mice, a model of idiopathic, multifactorial epilepsy. Further, repeated tail suspension hastens the lifetime onset of seizure susceptibility in these mice. The present study tested the hypothesis that curtailing human handling during development would delay the onset of seizure susceptibility relative to EL mice handled regularly by using tail suspension for standard laboratory husbandry. METHODS: Control mice were handled by the tail for bedding changes, whereas unhandled mice bedding was changed by using specially designed connector cages that allowed mice to transfer without handling to a cage containing clean bedding. Seizure susceptibility was tested beginning at 70, 80, 90, 100, or 140 days of age by using a handling-induced seizure-susceptibility paradigm. RESULTS: Among handled mice, more than half of the sample exhibited seizures by age 80 days relative to fewer than one fourth of unhandled mice. In addition, each group was tested a second time 10 days after the initial seizure-susceptibility test to detect potential experience-induced increases in seizure susceptibility. Once again, a higher frequency of handled mice expressed seizures at significantly younger ages relative to unhandled mice. CONCLUSIONS: Although it was already known that repeated tail suspension could speed the onset of seizure susceptibility in EL mice, the present results are the first to demonstrate the converse finding that decreasing routine human handling can delay significantly the onset of seizure susceptibility. This suggests that removal of nonconsensual aspects of human-animal contact may delay or prevent the onset of seizure susceptibility.

Age Factors↗

Evaluation of a new method for the preparation of homogeneous mycelial suspensions.

Guidry, D. J. (Louisiana State University, New Orleans) and G. H. Trelles. Evaluation of a new method for the preparation of homogeneous mycelial suspensions. J. Bacteriol. 83:53-60. 1962.-An all-glass tissue homogenizer (providing both conical and cylindrical grinding surfaces) was employed in the preparation of homogeneous mycelial suspensions. Pellets of mycelium from constant shake liquid culture were submitted to grinding for various periods of time. The effect of grinding time on optical density of the homogenate, hyphal fragment size, and viability of the fungus was determined. A grinding time of 4 min was found to yield suspensions of mycelium in which 89% of the hyphal fragments contained four or less than four cells. Optical density was used as the basis for both preparation of standard samples of inoculum and measurement of growth. Preparation of a light transmittance curve facilitates the preparation of suspensions of any desired concentration. Although plate colony counts on samples from the same flask showed satisfactory agreement, there was appreciable variation in counts on samples from different flasks. The variation in growth from flasks receiving equal samples of inoculum was also determined. Results indicate that, at concentrations of mycelium equal to an optical density of 0.301, a difference of 15% or more in the optical density of two samples (10 flasks per sample) can be accepted as significant. Some of the factors influencing variation in viability of inoculum as well as variation in flask growth have been determined. Ways in which experimental errors can be kept to a minimum are discussed.

Fungi↗

Interaction of hyperthyroidism and hindlimb suspension on skeletal myosin heavy chain expression.

We examined the novel interaction of hyperthyroidism and hindlimb suspension on the pattern of myosin heavy chain (MHC) expression (mRNA and protein) in skeletal muscles. Female Sprague-Dawley rats were assigned to four groups: 1) normal control (Con); 2) thyroid hormone treated [150 micrograms 3,5,3'-triiodothyronine (T3). kg-1. day-1] (T3); 3) hindlimb suspension (HS); or 4) T3-treated and HS (T3 + HS). Results show for the first time the novel observation that the combination T3 + HS induces a rapid and sustained, marked (80-90%) downregulation of type I MHC gene expression that is mirrored temporally by concomitant marked upregulation of type IIb MHC gene expression, as evidenced by the de novo synthesis of type IIb MHC protein in the soleus. The fast type IIx MHC isoform showed a differential response among the experimental groups, generally increasing with the separate and combined treatments in both the soleus and vastus intermedius muscles while decreasing in the plantaris muscles. The fast type IIa MHC was the least responsive to suspension of the MHCs and reflected its greatest responsiveness to T3 treatment while also undergoing differential adaptations in slow vs. fast muscle (increases vs. decreases, respectively). These results confirm previous findings that all four adult MHC genes are sensitive to T3 and suspension in a muscle-specific manner. In addition, we show that T3 + HS can interact synergistically to create novel adaptations in MHC expression that could not be observed when each factor was imposed separately.

Animals↗