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PubMed2002

Dose-response relationships of intranasal cholecystokinin and the P300 event-related brain potential.

The gut and brain peptide cholecystokinin (CCK) has been found to improve controlled stimulus processing and attention as indicated by the late positive complex (LPC) of the event-related brain potentials (ERPs). A direct nose-brain pathway for cortical effects of intranasally administered CCK-8S has been described, although the precise transmission within this pathway is still unknown. The present study compared the effects of two doses of CCK-8S (10 and 20 microg) and placebo after intranasal administration on the LPC of the ERP in healthy male and female subjects to further elucidate mechanisms of this nose-brain pathway. ERPs were recorded in an oddball-paradigm. Results showed that both doses of CCK-8S induced a positive shift of the ERP. This effect did not differ between the 10 and 20 microg dosage of CCK-8S. The results indicate that a saturable mechanism may be responsible for the transmission of CCK-8S from the nose into the brain, since both doses of CCK-8S induced comparable increases of the ERP subcomponents.

Administration, Intranasal↗

PubMed1999

Efficacy and acceptability of intranasal 17 beta-oestradiol for menopausal symptoms: randomised dose-response study. Aerodiol Study Group.

BACKGROUND: The benefit of oestrogen therapy for menopause symptoms is well recognised. However, the means of delivery currently available have disadvantages, including variable bioavailability, intestinal and hepatic first-pass effects, and dermatological reactions. An intranasal 17beta-oestradiol spray, S21400, which bypasses such drawbacks, has been developed. We studied the efficacy and tolerability of S21400 in the treatment of postmenopausal symptoms. METHODS: In this double-blind study, 420 postmenopausal women were randomly allocated to receive intranasal placebo or S21400 in doses of 100 microg, 200 microg, 300 microg, or 400 microg, or oral oestradiol valerate in doses of 1 mg or 2 mg, daily for 12 weeks. The primary outcomes were the Kupperman Index (KI) and the incidence of hot flushes. Tolerability assessments included rhinoscopy and ciliary function tests. FINDINGS: S21400 dose-dependently decreased KI (p<0.001), with a lowest effective dose of 300 microg/day at 4 weeks (p<0.05) and 200 microg/day at 12 weeks (p<0.01). The incidence of hot flushes decreased by a maximum of 75% (S21400 lowest effective dose 200 microg/day at 4 weeks and 100 microg/day at 12 weeks). S21400 increased serum oestradiol exposure dose-dependently, to concentrations similar to those achieved with oral oestradiol 1-2 mg, with lower intra-patient and inter-patient variability. There was no significant difference in ear, nose, and throat function or adverse events between the S21400 and the placebo or oral oestradiol groups, except for a greater incidence of sneezing and application site reaction (99% mild or moderate) in the S21400 groups. S21400 was thought to be effective and convenient by the patients, and compliance was high. INTERPRETATION: Intranasally administered 17beta-oestradiol is significantly better than placebo; its effectiveness at reducing menopausal symptoms is similar to that of oral oestradiol and is also well-tolerated. Intranasal administration avoids first-pass metabolism and provides a reproducible, easily adjustable dosing mechanism that represents a new option for hormone replacement therapy.

Administration, Intranasal↗

PubMed2002

An open-label comparison of the immunogenicity and tolerability of intranasal and intramuscular formulations of virosomal influenza vaccine in healthy adults.

BACKGROUND: Many intramuscular inactivated influenza vaccines achieve suboptimal results in the prevention of respiratory disease and influenza complications. This has led to the current interest in developing effective oral or intranasal preparations. OBJECTIVE: This study compared the immunogenicity and tolerability of intranasal and intramuscular formulations of virosomal subunit influenza vaccine in healthy adults. It also assessed the immunogenicity and tolerability of 3 different production lots of the intranasal vaccine containing Escherichia coli heat-labile toxin adjuvant. METHODS: This was a multicenter, Phase I, randomized, open-label pilot study in which the primary end point was immunogenicity (hemagglutination-inhibition [HI] antibody assay on days 1 and 29). The secondary end point was the frequency of adverse events (AEs). Subjects were assigned to 4 vaccination groups: groups AI, AII, and AIII received intranasal influenza vaccine from batches that differed in the hemagglutinin and neuraminidase strains used, and group B received intramuscular virosomal subunit vaccine. Assessments of health status, hematology, biochemistry, body temperature, heart rate, blood pressure, and incidence of AEs were made on days 1, 8, and 29, and serology was assessed on days 1 and 29. RESULTS: The study enrolled 88 subjects. All 3 production lots of intranasal vaccine induced an immune response to most of the viral strains administered (A/Singapore, A/Texas, A/Wuhan, B/Beijing), with no notable immunogenic differences between lots. After intranasal vaccination, geometric mean titers (GMT) increased 2.7-fold against A/Singapore (group AI); 1.8- and 3.1-fold against A/Texas (groups AII and AIII, respectively); 1.9- to 2.4-fold against A/Wuhan; and 1.5- to 1.7-fold against B/Beijing. After intramuscular vaccination. GMT increased 11.3-, 6.3-, and 2.7-fold against A/Texas, A/Wuhan, and B/Beijing, respectively. Seroprotection (HI antibody titers > or = 1:40 in > 70% of those vaccinated) was achieved against all strains in the group that received intramuscular vaccination, against A/Wuhan in all groups that received intranasal vaccination, and against A/Texas in group AII. Both vaccine formulations were well tolerated. Intranasal vaccination was associated with a low incidence ( < 20%) of nasal AEs. CONCLUSIONS: Both the intranasal and intramuscular vaccinations elicited a systemic immune response and were well tolerated. The different batches of intranasal vaccine showed a similar immunogenic profile. Intranasal administration may be preferred to intramuscular administration by some patients.

Administration, Intranasal↗

PubMedDate not supplied

Safety and tolerability of once-daily mometasone furoate aqueous nasal spray in children.

Sensitive and reproducible assessments of hypothalamic-pituitary-adrenal (HPA) axis function were used to assess the systemic exposure and tolerability of mometasone furoate aqueous nasal spray (MFNS) in 96 children aged 3 to 12 years with allergic rhinitis. In the first phase of the study, older children (aged 6 to 12 years) received MFNS at 50, 100, or 200 micrograms or placebo once daily for 7 days, and plasma cortisol concentrations were measured by radioimmunoassay before and after treatment. Plasma cortisol concentrations were not statistically significantly different from baseline values on day 7 or day 8 (1 day after treatment was stopped). Also, the mean plasma cortisol and 24-hour urinary free-cortisol concentrations of the MFNS-treated and placebo groups were not statistically significantly different. Additionally, mometasone furoate was undetectable in almost all plasma samples collected at 0.5, 1, and 2 hours after dosing on days 1 and 7. Because these findings indicated that MFNS could be safely administered to patients aged 6 to 12 years, a more rigorous assessment was conducted in younger patients (aged 3 to 5 years). The younger patients also received MFNS at 50, 100, or 200 micrograms or placebo once daily, but for a longer duration (14 days). HPA axis function was determined by the response to cosyntropin stimulation on the final day of treatment. The younger patients demonstrated a normal cortisol response to cosyntropin stimulation on day 14; that is, all the patients had an increase in plasma cortisol concentration of at least 7 micrograms/dL to at least 18 micrograms/dL. Mean plasma cortisol concentrations for the MFNS-treated groups were not statistically significantly different from the mean concentration for the placebo group, either before or after cosyntropin stimulation. MFNS was also found to be well tolerated by both the younger and older children, with headache the most frequently reported adverse event in both the placebo- and MFNS-treated groups. No clinically relevant changes in the results of physical examinations, clinical laboratory determinations, or electrocardiography were noted. These results indicate that the intranasal administration of up to 200 micrograms of MFNS once daily for up to 14 days in children aged 3 to 12 years who have allergic rhinitis is well tolerated and does not result in clinically relevant systemic exposure.

Administration, Intranasal↗

PubMed2003

Protective effects of a recombinant fragment of human surfactant protein D in a murine model of pulmonary hypersensitivity induced by dust mite allergens.

Lung surfactant protein D (SP-D) is a carbohydrate pattern recognition immune molecule. It can interact with a range of pathogens, stimulate immune cells and manipulate cytokine profiles during host's immune response. SP-D has also been shown to interact, via its carbohydrate recognition domains, with glycoprotein allergens of house dust mite (Dermatophagoides pteronyssinus, Derp), inhibiting specific IgE isolated from mite-sensitive asthmatic patients from binding these allergens, and blocking subsequent histamine release from sensitized basophils. In the present study, we have examined the protection offered by various doses of intranasal administration of a recombinant fragment of human SP-D (rhSP-D) in a murine model of pulmonary hypersensitivity to Derp allergens which showed characteristic high levels of specific IgE antibodies, peripheral blood eosinophilia, pulmonary infiltrates and a Th2 cytokine response. Treatment of Derp mice with rhSP-D led to significant reduction in Derp-specific IgE levels, blood eosinophilia and pulmonary cellular infiltration. The levels of IL-4 and IL-5 were decreased, while those of IL-12 and IFN-gamma were raised in the supernatant of the cultured splenocytes, indicating a Th2 to Th1 polarization. These results suggest that SP-D has a protective role in the modulation of allergic sensitization and in the development of allergic reactions to Derp allergens and highlight potential of the rhSP-D as a therapeutic for pulmonary hypersensitivity.

Administration, Intranasal↗

PubMed2001

The nasal mucosa of children with nocturnal enuresis before and after treatment with 1-deamino 8-D-arginine vasopressin spray.

Intranasal administration of 1-deamino 8-D-arginine vasopressin (DDVAP) used for treatment of nocturnal enuresis (NE), might be expected to have various effects on the nasal mucosa, e.g. altering the clearance by the mucociliary apparatus. We evaluated two samples (brushes) of epithelial surface cells from the nasal mucosa, one from each nostril, of 18 children (ten males and eight females) with a mean age of 7.7 years (range: 5-13 years) who were affected by primary NE. Samples were taken before and 1 and 6 months after administration of DDVAP spray. No qualitative changes in the epithelial surface cells from nasal mucosa were recognized and only non-statistically significant increases in percentages of goblet, ciliated, basal and unciliated cells at 1 and 6 months after therapy were observed. Thus, it appears that DDVAP spray can be used for at least 6 months in children without apparent risk of damage to the epithelial surface cells from the nasal mucosa.

Administration, Intranasal↗

PubMed2001

Preparation of desmopressin-containing liposomes for intranasal delivery.

The loading and leakage characteristics of the desmopressin-containing liposomes and the effect of liposomes on the nasal mucosa permeation and antidiuresis of desmopressin were investigated. Higher loading efficiency of desmopressin for positively charged liposomes than negatively charged liposomes was obtained, and neutral liposomes resulted in a similar loading efficiency as that of positively charged liposomes. Greater leakage of desmopressin from negatively charged liposomes than from positively charged and neutral liposomes was shown. The increase of permeability of desmopressin through the nasal mucosa indicated positively charged liposomes>negatively charged liposomes>solution. It was suggested that the enhanced contact time of positively charged liposomes with negatively charged nasal mucosa led to a high local desmopressin concentration on the penetration site to promote an effective penetration of desmopressin through the nasal mucosa. The desmopressin antidiuresis result after intranasal administration was in good agreement with the permeability result in the order of positively charged liposomes>negatively charged liposomes>solution. One of the mechanisms for the explanation of the best result on the enhancement of antidiuresis for positively charged liposomes may be the bioadhesive effect of the liposomes on the negatively charged nasal mucosa.

Administration, Intranasal↗

PubMed2001

Nasal vaccines.

The nasal route for vaccination offers some important opportunities, especially for the prophylaxis of respiratory diseases. Vaccination via the respiratory tract is reviewed and the deposition and clearance of antigens in the deep lung and nose are described and contrasted. Lymphoid structures in the respiratory tract differ according to species; the rat and mouse have a well developed nose-associated lymphoid tissue, while in man, the structure known as Waldeyer's ring (that includes the tonsils), is important as an induction site. The immune response following intranasal administration can provide protection at the administration site and at various effector sites as part of the common mucosal immune system. A number of formulation considerations are important when designing novel systems for nasal administration as are physiological factors such as mucociliary clearance.

Administration, Intranasal↗

PubMed2000

Induction of antigen-specific T cell responses in human volunteers after intranasal immunization with a whole-cell pertussis vaccine.

We have studied the ability of an intranasally administered whole-cell pertussis vaccine (WCP) without adjuvant to induce antigen-specific T cell responses in humans. Six adult volunteers were given a vaccine dose (corresponding to 250 microg protein) by nasal spray four times at weekly intervals, and peripheral blood mononuclear cells were assayed for antigen-specific proliferative T cell responses. All six vaccinees had a WCP-specific response, which in four of them remained elevated throughout the 2 month study. All participants also responded to the filamentous haemagglutinin (FHA) antigen, and four of them responded to inactivated pertussis toxin (PTd). A significant correlation between T cell proliferation against WCP and WCP-specific IgA antibody levels in nasal secretions was observed. This demonstrates that intranasal administration of a non-proliferating bacterial vaccine without any additional mucosal adjuvant can induce vaccine-specific T cell responses related to mucosal IgA secretion.

Adhesins, Bacterial↗

PubMed2001

DNA vaccination against respiratory influenza virus infection.

DNA vaccination using plasmid encoding the hemagglutinin (HA) gene of influenza A/PR/8/34 virus to induce long-lasting protective immunity against respiratory infection was evaluated in this study. Using liposomes as carriers, the efficacy of DNA vaccines was determined using a lethal influenza infection model in mice. Mice immunized intranasally or intramuscularly with liposome-encapsulated pCI plasmid encoding HA (pCI-HA10) were completely protected against an intranasal 5 LD(50) influenza virus challenge. Mice immunized with liposome-encapsulated pCI-HA10, but not naked pCI-HA10, by intranasal administration were found to produce high titers of serum IgA. These results suggest DNA vaccines encapsulated in liposomes are efficacious in inducing complete protective immunity against respiratory influenza virus infection.

Administration, Intranasal↗

PubMed2002

Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy. A meta-analysis.

Since the 1940s, influenza vaccines are inactivated and purified virus or virus subunit preparations (IIV) administered by the intramuscular route. Since decades, attempts have been made to construct, as an alternative, attenuated live influenza vaccines (LIV) for intranasal administration. Presently, the most successful LIV is derived from the cold-adapted master strains A/Ann Arbor/6/60 (H2N2) and B/Ann Arbor/1/66 (AA-LIV, for Ann-Arbor-derived live influenza vaccine). It has been claimed that AA-LIV is more efficacious than IIV. In order to assess differences between the two vaccines with respect to systemic reactogenicity, antibody response, and efficacy, we performed a meta-analysis on eighteen randomised comparative clinical trials involving a total of 5000 vaccinees of all ages. Pooled odds ratios (AA-LIV versus IIV) were calculated according to the random effects model. The two vaccines were associated with similarly low frequencies of systemic vaccine reactions (pooled odds ratio: 0.96, 95% confidence interval: 0.74-1.24). AA-LIV induced significantly lower levels of serum haemagglutination inhibiting antibody and significantly greater levels of local IgA antibody (influenza virus-specific respiratory IgA assayed by ELISA in nasal wash specimens) than IIV. Yet, although they predominantly stimulate different antibody compartments, the two vaccines were similarly efficacious in preventing culture-positive influenza illness. In all trials assessing clinical efficacy, the odds ratios were not significantly different from one (point of equivalence). The pooled odds ratio for influenza A-H3N2 was 1.50 (95% CI: 0.80-2.82), and for A-H1N1, 1.03 (95% CI: 0.58-1.82). The choice between the two vaccine types should be based on weighing the advantage of the attractive non-invasive mode of administration of AA-LIV, against serious concerns about the biological risks inherent to large-scale use of infectious influenza virus, in particular the hazard of gene reassortment with non-human influenza virus strains.

Adaptation, Physiological↗

PubMed2002

Intranasal inoculation of a recombinant influenza virus containing exogenous nucleotides in the NS segment induces mucosal immune response against the exogenous gene product in mice.

To establish a mucosal vaccine system, we evaluated the immunogenicity of a recombinant influenza virus, designated NS2Acat, in which the chloramphenicol acetyltransferase (CAT) reporter gene is fused in frame to the NS1 gene in the NS gene segment. The NS2Acat replicated slightly within the lungs in BALB/c mice after intranasal administration, accompanying expression of the CAT and the viral HA mRNA. NS2Acat induced delayed-type hypersensitivity (DTH) and sensitized the CAT-specific T lymphocytes in the regional lymph nodes, which proliferated and synthesized several cytokines in vitro upon antigenic challenge. These results suggest that NS2Acat is capable of eliciting a respiratory immune response against the fused gene product.

Administration, Intranasal↗

PubMed2002

Characterization of protective immune responses induced by nasal influenza vaccine containing mutant cholera toxin as a safe adjuvant (CT112K).

Immune responses induced by a nasal influenza vaccine with a mutant cholera toxin (CT112K), known to be a safe adjuvant, were characterized in BALB/c mice to confirm the most suitable regimen of this vaccine for humans. Mice received a primary intranasal administration of the adjuvant (0.1 micro g)-combined PR8 vaccine (0.1 micro g) and a secondary administration of the PR8 vaccine alone (0.1 micro g) 4 weeks later. Two weeks after the secondary immunization, the mice were infected with a nonlethal or a lethal dose of PR8 viruses. Nasal and lung wash virus titers 1 or 3 days after infection indicated that complete protection could be provided by secondary immune responses, which had an immediate effect of preventing infection 2 weeks after the secondary immunization. In this two-dose regimen, high levels of secondary IgA, IgG and IgM antibody-forming cell (AFC) responses were induced in the nasal-associated lymphoid tissue and the spleen. In parallel with the AFC responses, high levels of nasal wash anti-PR8 HA IgA, and lung and serum IgG antibody (Ab) responses were induced 2 weeks after the secondary immunization. The two-dose regimen also induced accelerated delayed-type hypersensitivity responses, which exhibited almost the same peak height as that in the case of the primary response. In addition, the two-dose regimen induced a low memory cell activity of cytotoxic T lymphocytes, detected by in vitro culture of spleen cells. Thus, the immediate effect of preventing infection was mainly provided by the secondary Ab responses. Moreover, the levels of nasal wash IgA Abs correlated well with cross-protection against infection with variant viruses in the upper respiratory tract (RT). These results suggest that the major protective factors among Ab and T cell-mediated immune responses, which are induced by the two-dose regimen using CT112K-combined vaccines, are the cross-reactive IgA Abs in the upper RT and the less cross-reactive IgG Abs in the lower RT, and that the two-dose regimen is a suitable vaccination condition for humans.

Adjuvants, Immunologic↗

PubMed1999

Immunity to airborne challenge with Venezuelan equine encephalitis virus develops rapidly after immunization with the attenuated vaccine strain TC-83.

Mice vaccinated subcutaneously with the attenuated vaccine strain of Venezuelan equine encephalitis virus (VEEV) rapidly develop immunity to subcutaneous or airborne challenge with virulent VEEV. The specificity of this immune response was demonstrated by challenge with a heterologous virus (St. Louis encephalitis virus). Examination of the levels of VEEV-specific antibody classes in serum and respiratory secretions suggested that the rapid development of immunity was coincident with the appearance of specific IgM and IgG (but not IgA) in the respiratory tract. In order to confirm the role of respiratory tract antibody, mice were passively immunised either intraperitoneally or intranasally with polyclonal VEEV-specific IgG. Intranasal administration of specific IgG significantly enhanced protection against airborne challenge. These results confirm the need to emphasise local antibody production in the development of improved VEEV vaccines.

Administration, Intranasal↗

PubMed2002

Cellular activation and neuronal transport of intranasally instilled benzo(a)pyrene in the olfactory system of rats.

Nasal tissues can be exposed to benzo(a)pyrene (BaP), e.g. present in diesel exhaust particles and some workplace atmospheres. In this study rats were given 3H-BaP intranasally. Autoradiography and beta-spectrometry were then used to trace cells in the nasal olfactory mucosa having capacity to activate the compound to tissue-bound metabolites. We also examined if deposition of 3H-BaP on the olfactory mucosa results in translocation of labelled material to the brain along olfactory neurons. The results showed that intranasal administration of 3H-BaP results in formation of tissue-bound metabolites in sustentacular cells and in the cells of Bowman's glands. Initially the bound material was localised to a higher extent to the sustentacular cells than to the cells of Bowman's glands, whereas at longer survival intervals the uptake in the cells of Bowman's glands dominated. In the latter the covalently bound material was accumulated to a higher extent in the nuclei than in the cytoplasms. We speculate that BaP may interact with the aryl hydrocarbon receptor (AhR) in these cells and that AhR may target activated BaP to the nucleus. Our results further indicated that application of 3H-BaP on the nasal mucosa results in transport of BaP and/or BaP-metabolites along the axons of the olfactory neurons to the olfactory bulb.

Administration, Intranasal↗

PubMed2003

Uptake of cobalt from the nasal mucosa into the brain via olfactory pathways in rats.

In the olfactory epithelium the primary olfactory neurons are in contact with the environment in the nasal cavity and they are also connected to the olfactory bulbs of the brain. These neurons may therefore provide a pathway by which foreign materials may reach the brain. Inhalation of cobalt-containing dust or fumes occurs in several workplaces, which may result in high exposure of the nasal tissues. In the present study, we used autoradiography and gamma-spectrometry to examine the transport of cobalt in the olfactory system after intranasal administration of 57Co2+ in rats. The results showed an uptake of the metal in the olfactory mucosa and a transport to the olfactory bulbs of the brain. The metal accumulated in the olfactory nerve layer and the terminals of the primary olfactory neurons in the glomerular layer of the bulb. In addition, low levels of cobalt were seen to migrate into the interior of the bulbs and the anterior parts of the olfactory cortex, indicating that the metal is able to leave the terminals of the primary olfactory neurons. Occupational exposure to cobalt, which is a neurotoxic metal, occurs in several workplaces, e.g. the hard metal industry. Memory deficits have been observed among workers exposed to hard metal via inhalation, and it was considered that cobalt may be the neurotoxic component of the hard metal. We propose that inhaled hard metal (as a dust powder or in a mist form) is deposited in the nasal passages and that released cobalt, after uptake into the brain via the olfactory pathway, may cause neurotoxicity. We consider that the olfactory route of entry of cobalt into the brain may be important and should be taken into account when risk assessments are performed concerning occupational inhalation of this metal.

Administration, Intranasal↗

PubMed2001

Improved nasal bioavailability of elcatonin by insoluble powder formulation.

The bioavailability of elcatonin (ECT) via the nasal route was investigated with a powder dosage form utilizing water-insoluble calcium carbonate (CaCO(3)) in comparison with the liquid dosage form. Total radioactivity and the radioactivity of intact [3H]ECT were measured to evaluate the nasal absorption in vivo and the nasal mucosal transport in vitro. The systemic bioavailability of both total radioactivity and intact [3H]ECT following intranasal administration of the powder formulation in rats was significantly greater than in the case of the liquid formulation. In contrast, similar permeability of ECT across excised rabbit nasal mucosa was seen for both formulations, and was close to that of [14C]inulin, suggesting that the ECT transport is predominantly paracellular in each case. However, the powder formulation significantly prolonged the residence time of [3H]ECT in the rat nasal cavity, compared with the liquid formulation. We conclude that the powder formulation utilizing CaCO(3) improves the nasal bioavailability by increasing the residence time of ECT in the nasal cavity and is likely to be effective in increasing systemic drug delivery.

Administration, Intranasal↗

PubMed1999

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).

Absorption↗