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At least 127 records · Page 7Linked to original sources
PubMed1997

Effects of short-term administration of sublingual nifedipine on coronary arterial wall elastic properties: evaluation by intravascular ultrasound.

Intravascular ultrasound is suited to measure coronary cross-sectional anatomy. Therefore the regional coronary wall elasticity was evaluated by examining the response to nifedipine. In 20 patients, coronary ostial pressure (P) and intravascular ultrasound images were simultaneously recorded before and after sublingual administration of 10 mg nifedipine. We identified the perimeter of the vessel wall, with normal or atherosclerotic plaque, on ultrasound image. At the atherosclerotic site, we measured segmental perimeter (S) for each normal or plaque segment. The ratio of the individual segment length (delta S/delta P) and cyclic variation of cross-sectional area (delta A/delta P) per mm Hg increase in P were calculated. Nifedipine decreased pressure (133/79-120/73 mm Hg) and increased heart rate (79-82 beats/min). After nifedipine, delta A/delta P increased from 8.5 +/- 10.2 x 10(-3) to 16.5 +/- 14.4 x 10(-3) mm2/mm Hg at 20 normal sites (p = 0.005) but was unchanged at 17 atherosclerotic sites (6.6 +/- 7.0 x 10(-3) to 6.7 +/- 7.1 x 10(-3) mm2/mm Hg). Nifedipine increased delta S/delta P in normal segments (4.5 +/- 8.7 x 10(-3) to 9.9 +/- 10.9 x 10(-3) mm/mm Hg; p = 0.02) but produced no change in segments with calcified or soft plaque (-1.1 +/- 0.3 x 10(-3) to 1.4 +/- 1.6 x 10(-3) mm/mm Hg and 5.0 +/- 3.6 x 10(-3) to 6.1 +/- 4.8 x 10(-3) mm/mm Hg, respectively). This study demonstrated that nifedipine increases regional coronary arterial elasticity at normal segments but not at that containing mildly atherosclerotic segment, and likely that the arterial wall function indicated by the response to nifedipine was impaired at an early stage of atherosclerosis.

Administration, Sublingual↗
PubMed2002

Is epinephrine administration by sublingual tablet feasible for the first-aid treatment of anaphylaxis? A proof-of-concept study.

PURPOSE: In order to explore the feasibility of sublingual administration of epinephrine tablets as a non-invasive first-aid treatment for anaphylaxis, we studied epinephrine absorption from this dosage form in an animal model. METHODS: In a prospective, randomized, four-way crossover study, six rabbits received epinephrine 2.5 or 10 mg as a sublingual tablet, epinephrine 0.03 mg (0.3 ml) by intramuscular (IM) injection (positive control), and 0.9% NaCl (0.3 ml) IM (negative control). Pre- and post-dose blood samples were obtained for measurement of plasma epinephrine concentrations by HPLC-EC. RESULTS: After administration of epinephrine 2.5 mg as a sublingual tablet, the mean (+/-SEM) C(max) was 2369+/-392 pg/ml, and the t(max) was 20.8+/-5.7 min. After administration of epinephrine 10 mg sublingually, the C(max) was 10836+/-2234 pg/ml, and the t(max) was 21.7+/-5.4 min. After IM epinephrine, the C(max) was 6445+/-4233 pg/ml, and the t(max) was 15.8+/-4.7 min. After IM 0.9% NaCl, the C(max) (endogenous epinephrine) was 518+/-142 pg/ml. The t(max) after both of the sublingual epinephrine tablet doses did not differ significantly from the t(max) after IM epinephrine, and the C(max) after the 10 mg sublingual epinephrine tablet dose did not differ significantly from the C(max) after IM epinephrine. CONCLUSIONS: In this proof-of-concept study, administration of epinephrine as a sublingual tablet formulation resulted in rapid achievement of peak plasma epinephrine concentrations. Absorption studies in humans are needed. DEFINITIONS: HPLC-high performance liquid chromatography; EC - electrochemical detection; C(max) - maximum plasma epinephrine concentration after dosing; t(max) - time of maximum plasma epinephrine concentration.

Administration, Sublingual↗
PubMed1989

Pharmacokinetics of the newer benzodiazepines.

The assay methods used to determine the concentrations of the newer benzodiazepines include electron-capture gas-liquid chromatography, high performance liquid chromatography with ultraviolet detection, gas chromatography-mass spectrometry, radioassay and radioreceptor assay. The method used frequently is the highly sensitive and specific electron-capture gas-liquid chromatography. Other methods are associated with limitations. The triazolo- and imidazolebenzodiazepines differ structurally from the 'classical' benzodiazepines such as diazepam, and offer distinct differences in pharmacological activity and in time-course of effect. Alprazolam and triazolam, both 1,4-triazolobenzodiazepines, have high affinities for the benzodiazepine receptor as do midazolam and loprazolam, which are 1,4-imidazolebenzodiazepines. Absorption is characteristically rapid, with peak alprazolam and triazolam concentrations occurring within 1 hour after oral administration. Sublingual administration results in peak alprazolam and triazolam concentrations that are higher and occur earlier than with the oral route. The volume of distribution of alprazolam and triazolam is approximately 1L. Alprazolam is 70% bound to plasma proteins and the extent of binding is independent of concentration. Similarly, triazolam is approximately 85% bound to plasma proteins, variability in binding being explained by variations in alpha 1-acid glycoprotein concentration. The 1,4-triazolo ring prevents the oxidative metabolism of the classical benzodiazepines which results in formation of active metabolites with long elimination half-lives. Alprazolam is extensively metabolised: 29 metabolites have been identified in the urine, and its major metabolite, alpha-hydroxyalprazolam, has pharmacological activity. alpha-Hydroxyalprazolam and 4-hydroxyalprazolam are detectable in plasma in amounts which account for less than 10% of the administered dose. Mean alprazolam elimination half-life in healthy adult subjects ranges from 9.5 to 12 hours; liver disease prolongs alprazolam elimination, but renal insufficiency does not. Triazolam also undergoes oxidation and subsequent glucuronidation. alpha-Hydroxytriazolam is the major metabolite, in addition to which 4-hydroxyalprazolam and alpha-4-hydroxytriazolam have been identified in plasma and urine. The elimination half-life of triazolam ranges between 1.8 and 5.9 hours, while that of the conjugated metabolites is short, approximately 3.8 hours. Accumulation of triazolam or its metabolites after multiple doses does not occur. Liver disease prolongs triazolam elimination from the body, but renal disease does not.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration.

Eight healthy volunteers received 50 mg of dimenhydrinate, a theoclate salt of diphenhydramine, orally, sublingually, and intravenously on three separate occasions in random sequence. Plasma diphenhydramine concentrations during 12 h after each dose were measured by gas-liquid chromatography with nitrogen-phosphorous detection. Mean peak plasma concentrations after sublingual administration were slightly lower than after oral dosage (38.3 vs 47.8 ng ml-1), and the time of peak concentration was similar (2.6 vs 2.3 h after dose). These differences did not reach statistical significance. The mean total area under the plasma concentration-time curve (AUC) for sublingual administration was slightly but not significantly smaller than after oral dosage (221 vs 270 h ng ml-1). Systemic availability of diphenhydramine after sublingual dimenhydrinate, measured by the ratio of oral AUC to intravenous AUC, was slightly less than after oral dimenhydrinate (0.58 vs 0.69, NS), and both were significantly less than 1.0. Thus sublingual and oral administration of dimenhydrinate result in comparable, but incomplete, systemic availability of diphenhydramine.

Administration, Oral↗
PubMed1999

The acute effects of sublingual estradiol on left ventricular diastolic function in normotensive and hypertensive postmenopausal women.

AIM: limited information is available on estrogen influences on diastole. We aimed to investigate the acute effects of a single dose of sublingual 17beta-estradiol on left ventricular diastolic function in postmenopausal women. METHODS: the study included 28 women aged 55.6 +/- 6 (15 normotensive and 13 hypertensive), who underwent Doppler echocardiography and estradiol plasma levels determination before and 60 min after sublingual administration of 4 mg of 17beta-estradiol. RESULTS: there were no modifications in heart rate. Both systolic and diastolic blood pressure dropped significantly in the hypertensives and remained unchanged in normotensives. Estradiol levels were 1790 +/- 869 pg/ml in the normotensives and 2664 +/- 1490 in the hypertensives (P < 0.05). Peak early velocity, in the population as a whole, increased from 84 +/- 18 to 91 +/- 18 cm/s and the early-to-atrial velocity ratio from 1.1 +/- 0.4 to 1.4 +/- 0.6 (P < 0.0001 for both). Both acceleration and deceleration rates increased significantly (P < 0.0001). These changes were shared by all the patients. In addition, the hypertensive patients, who presented a baseline pattern characterized mainly by a grossly increased peak atrial velocity with reduction in the early-to-atrial velocity ratio, demonstrated a decrease in peak atrial velocity from 92 +/- 12 to 78 +/- 10 cm/s (P < 0.0001), associated with significant reductions in deceleration time (P < 0.0001) and pressure half time (P < 0.005). Therefore, the typical picture of impaired ventricular relaxation was favorably changed after estradiol administration. CONCLUSIONS: the sublingual administration of estradiol induces acute modifications in left ventricular diastolic function in postmenopausal women, with improvement in the age-related left ventricular relaxation pattern, and that these beneficial changes are more pronounced in hypertensive that in normotensive women.

Administration, Sublingual↗
PubMed1988

Sublingual allergen administration. I. Selective suppression of IgE production in rats by high allergen doses.

Sublingual administration of a protein allergen to immunologically naïve rats suppressed subsequent allergen-specific IgE responses. Susceptibility to this form of immunotherapy was genetically determined, with some inbred rat strains displaying immunological tolerance in the IgE antibody class alone, whilst others developed concomitant suppression of IgG. Parallel gastric intubation experiments established that the development of tolerance by sublingual allergen administration proceeded independently of events occurring in the gut resulting from swallowing the allergen. These results are consistent with clinical reports which suggest that the oral mucosa is a potentially useful site for therapeutic modulation of allergic reactivity, and indicate that appropriate animal models can be developed to probe this important question. However, further research is required to determine the relevance of these findings to current sublingual desensitization practices.

Administration, Sublingual↗
PubMed2005

Sublingual sugar administration as an alternative to intravenous dextrose administration to correct hypoglycemia among children in the tropics.

BACKGROUND: Hypoglycemia is a common determining factor of poor prognosis for children with severe malaria in sub-Saharan Africa. Intravenous dextrose administration is rarely available. Oral mucosal delivery may be an alternative to parenteral administration. A randomized, clinical trial was performed in Burkina Faso among moderately hypoglycemic children, comparing sublingual sugar administration with oral water, oral sugar, and dextrose infusion administrations. METHODS: Sixty-nine children with glucose concentrations of < 0.8 g/L were assigned randomly to 1 of 4 methods of administration, 1 with 3 different doses of sugar, as follows: oral group (OG) (n = 15): 2.5 g of sugar; sublingual group (SG) (n = 27): 2.5 g of sugar under the tongue, with 3 treatment subgroups, ie, 0.1 g/kg, 0.15 g/kg, and 0.2 g/kg; intravenous group (IG) (n = 8): 8 mL of 30% dextrose in a single bolus; water group (n = 11). Eight children received sublingual sugar twice, ie, 0.1 g/kg at baseline and 20 minutes later. Blood glucose concentrations were measured every 20 minutes for 80 minutes. Treatment failures, peak glucose concentrations, times to glucose concentration normalization, and kinetic profiles were evaluated. RESULTS: No treatment failures were observed in the SG and IG, compared with 8 (53%) and 9 (81.8%) failures in the OG and water group, respectively. SG children exhibited glucose kinetic profiles and bioavailabilities (77%, 99%, and 81% in the 3 SG groups) similar to those of IG children. Bioavailabilities were 84% and 38% in the SG and OG, respectively. Children > 7 years of age required repeated sublingual administrations to maintain normoglycemia. CONCLUSIONS: The sublingual administration of sugar proved to be effective among moderately hypoglycemic children. It is a simple and promising method to control hypoglycemia among children in both developing and developed countries. This pediatric practice should be investigated in more detail among children with severe malaria.

Administration, Oral↗
PubMed2000

A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study.

OBJECTIVES: The purpose of this study was to compare the effect of different antihypertensive agents, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and diuretic agents on endothelial function. BACKGROUND: Endothelial dysfunction is a component of essential hypertension, and various antihypertensive drugs may be able to restore normal function. METHODS: Forearm blood flow (FBF) was measured in 296 patients with essential hypertension, including 46 untreated subjects using strain-gauge plethysmography during reactive hyperemia and after sublingual administration of nitroglycerin (NTG). Forty-seven normotensive subjects were similarly evaluated as control subjects. RESULTS: The FBF during reactive hyperemia in the 296 hypertensive patients was significantly less than that in age-matched normotensive subjects. The increase in FBF after administration of sublingual NTG was similar in both groups. Systolic and diastolic blood pressures and forearm vascular resistance were greater in the untreated group than in the four treated groups and did not differ with respect to the antihypertensive agent used. The maximal FBF response from reactive hyperemia was significantly greater in the ACE inhibitor-treated group than in the group treated with calcium antagonists, beta-blockers, diuretic agents, or nothing (40.5 +/- 5.2 vs. 32.9 +/- 5.8, 34.0 +/- 5.6, 32.1 +/- 5.9, and 31.9 +/- 5.8 ml/min per 100 ml tissue, p < 0.05, respectively). Reactive hyperemia was similar in the calcium antagonist, beta-blocker, diuretic and untreated groups, and changes in FBF after sublingual NTG administration were similar in all groups. The infusion of NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the enhancement of reactive hyperemia in hypertensive patients treated with ACE inhibitors. CONCLUSIONS: These findings suggest that ACE inhibitors augment reactive hyperemia, an index of endothelium-dependent vasorelaxation, in patients with essential hypertension. This augmentation may be due to increases in NO.

Adrenergic beta-Antagonists↗
PubMed1992

Is sublingual nifedipine administration superior to oral administration in the active treatment of hypertension?

Nifedipine, a calcium-channel-blocking agent, was administered orally to 44 untreated patients (Group A) and sublingually to 51 untreated patients (Group B) who had a diastolic blood pressure more than 90 mm Hg and systolic blood pressure more than 140 mm Hg. The mean pretreatment systolic and diastolic blood pressure values were 185.3 +/- 26.0 and 115.1 +/- 13.4 mm Hg in Group A patients and 193.6 +/- 23.1 and 118.1 +/- 14.1 mm Hg in Group B patients respectively (p greater than 0.05). The hypotensive activity of nifedipine was observed at the tenth minute in both groups. Mean systolic and diastolic pressures were 168.9 +/- 23.7 and 101.9 +/- 14.2 mm Hg in Group A and 170.6 +/- 26.2 and 103.0 +/- 15.8 mm Hg in Group B, (p less than 0.001) Diastolic blood pressures dropped under 100 mm Hg at the twentieth minute in both groups. Maximal reduction of blood pressure was observed at the fortieth minute in both groups and the degree of reduction in blood pressure was also the same (mean systolic and diastolic blood pressures: 143.7 +/- 22.1 and 86.9 +/- 11.7 in Group A and 148.7 +/- 21.4 and 91.7 +/- 17.0 in Group B (p less than 0.05). The authors conclude that sublingual nifedipine administration is not superior to oral nifedipine administration (in capsular form) in the acute treatment of hypertension.

Acute Disease↗
PubMed1994

Emergency alternatives to intravenous access. Intraosseous, intratracheal, sublingual, and other-site drug administration.

Difficulties and delays in establishing intravenous access are not uncommon in emergency situations in pediatrics. Alternatives to venous cannulation exist, including intraosseous access, intratracheal drug administration, sublingual and intralingual injection, the intrapenile route, and intracardiac injection. Each of these emergency alternatives to intravenous access is discussed from the historical, technical, utilitarian, and risk-benefit aspects. It is concluded that the intraosseous effective alternative to intravenous access in emergency situations.

Administration, Sublingual↗
PubMed1983

Active and passive coronary vasodilation after intracoronary and sublingual nitroglycerin.

Nitroglycerin is known to dilate epicardial coronary arteries. It is not known, however, to what extend pressure-dependent passive vasoconstrictive effects may counteract active vasodilation. Therefore, repeated coronary angiograms were performed in 100 patients under standardized conditions before (C) and after 0.16 mg nitroglycerin intracoronarily as well as after an additional 1.6 mg nitroglycerin sublingually. Coronary diameters were determined in stenotic and nonstenotic coronary artery branches. Aortic blood pressure and heart rate were monitored continuously. Aortic blood pressure decreased slightly after intracoronary injection from 146/70 mmHg (C) to 142/77 mmHg and decreased markedly after additional sublingual administration to 129/70 mmHg. Heart rate increased from 78 beats/min (C) to 79 beats/min after intracoronary injection and to 81 beats/min after sublingual administration. Diameters in nonobstructed coronary segments increased in proximal (+7%), medial (+10%), and distal (+12%) segments after intracoronary injection; after sublingual administration a more pronounced diameter increase was observed in all segments (proximal +12%, medial +13%, distal +14%). In obstructed coronary arteries, a stenotic dilation of more than 10% was found in 73% (58/80) after intracoronary injection, but only in 50% (40/80) of the patients after sublingual administration of nitroglycerin. The average diameter increase within coronary stenoses in all patients was 24% after intracoronary injection, but only 10% after additional sublingual administration. In conclusions dilation of epicardial coronary arteries occurs in nonstenotic and stenotic segments. In nonstenotic coronary arteries, there are additive vasodilative effects after intracoronary and sublingual nitroglycerin; in coronary stenoses, however, a maximal effect is achieved after intracoronary injection which is diminished after sublingual administration.

Adult↗
PubMed2005

A randomised controlled trial of mifepristone in combination with misoprostol administered sublingually or vaginally for medical abortion up to 13 weeks of gestation.

OBJECTIVE: To assess women's acceptability, the efficacy and side effects of sublingual versus vaginal administration of misoprostol in combination with mifepristone for medical abortion up to 13 weeks of gestation. DESIGN: Randomised controlled trial. SETTING: Aberdeen Royal Infirmary. POPULATION: Women undergoing medical abortion under the terms of the 1967 Abortion Act. METHODS: Mifepristone (200 mg) was given orally followed 36-48 hours later by misoprostol administration (sublingual: 600 microg; vaginal: 800 microg). A second dose of misoprostol 400 microg was given 3 hours later (sublingually or vaginally). Women between 9 and 13 weeks of gestation received a further (third) dose of misoprostol 400 microg (sublingually or vaginally), 3 hours later if abortion had not occurred. MAIN OUTCOME MEASURES: Women's acceptability, efficacy of the regimen and side effects experienced. RESULTS: A total of 340 women were recruited (171 sublingual and 169 vaginal). A total of 70% of women in the sublingual group expressed satisfaction with the route of misoprostol administration; 18% answered 'Don't know' while 12% were dissatisfied, compared with 68%, 28% and 4%, respectively, in the vaginal group (P= 0.02). There was no significant difference in the need for surgical evacuation for women in the sublingual (3/158, 1.9%) and vaginal groups (4/156, 2.6%) (P= 0.70). Women receiving misoprostol sublingually were more likely to experience diarrhoea (P < 0.01), shivering (P < 0.01) and unpleasant mouth taste (P < 0.01). CONCLUSIONS: Sublingual administration of misoprostol is an effective alternative to vaginal administration for medical abortion up to 13 weeks of gestation. The prevalence of prostaglandin-related side effects, however, was higher with this route of administration.

Abortifacient Agents, Nonsteroidal↗
PubMed1990

Oxygen free radical scavenger system intermediates in essential hypertensive patients before and immediately after sublingual captopril administration.

Oxygen-free radical intermediates/scavengers were measured in 43 patients with essential hypertension who, although under antihypertensive therapy (without angiotensin-converting enzyme inhibitors), still had high blood pressure values. Measurements were taken before and 30, 60 and 120 min after sublingual administration of 25 mg captopril. Both systolic and diastolic blood pressures were reduced significantly. Twenty normotensive healthy volunteers were used as controls. The hypertensive patients had lower glutathione peroxide activity (GSHPx), higher superoxide dismutase (SOD) and serum glutathione reductase activity (GSHRx) compared with the controls. After captopril (30, 60 min) the glutathione and GSHPx increased compared with the pretreatment values. SOD and GSHRx remained high compared with the controls, while whole blood glucose-6-phosphate dehydrogenase remained low. Another group of 19 essential hypertensive patients, free of any antihypertensive medication (for at least 3 weeks), had lower GSHPx, SOD and higher GSHRx than the normal control group. Our results show significant differences in the oxygen free radical scavenger system of hypertensives compared with the normal subjects. It may be that captopril has a concomitant scavenging action together with its antihypertensive effect. Our study raises the question whether cell/organ damage will occur in hypertensive patients exposed to oxidative stress during periods of low antioxidative capacity.

Adult↗
PubMed1997

Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17 beta-estradiol.

OBJECTIVE: To investigate the pharmacokinetic profiles of different doses of micronized 17 beta-estradiol administered by oral or sublingual routes. METHODS: Single doses of micronized 17 beta-estradiol were administered orally (1 mg, 0.5 mg) or sublingually (1 mg, 0.5 mg, 0.25 mg) to six postmenopausal women in a randomized clinical trial. We calculated pharmacokinetic parameters for estradiol (E2) and estrone (E1) of maximum serum concentration, time to maximum serum concentration, terminal half-life, area under the concentration curve, and oral clearance. Serum levels of E1 sulfate also were compared at 4, 12, and 24 hours after dosing. RESULTS: Sublingual administration resulted in rapid absorption with significantly higher E2 levels than did comparable oral dosing. Estrone levels did not vary with route of administration but correlated with the dosage administered. Estrone sulfate levels correlated with the dosage administered and also tended to be higher with sublingual administration. Sublingual administration resulted in a significantly lower E1 to E2 ratio during the 24 hours than did oral administration. CONCLUSION: Sublingual administration of micronized 17 beta-estradiol results in a rapid, burst-like absorption into the systemic circulation, yielding high E2 levels that fall rapidly over the first 6 hours.

Administration, Oral↗
PubMed2003

Safety of sublingual immunotherapy in children with asthma.

INTRODUCTION: Two previously published studies on sublingual immunotherapy (SLIT) did not report any serious adverse event associated with the local therapy; however, adverse events were observed in greatly variable percentages. The aim of the study was to evaluate the tolerability profile of sublingual swallow and spit immunotherapy in a large number of children treated for allergic asthma. METHODS: Adverse effects related to sublingual administration of allergen vaccines were evaluated in 354 children with allergic asthma. Each patient was followed for at least 37 months and received a monthly dose of major allergens (extract) in the range of 1.5-14.8mug, equivalent to 3-20 times the amount contained in the usual monthly maintenance injections via the subcutaneous routes. RESULTS: No adverse event was observed in 90.4% of the children. We observed 0.155 mild to moderate reactions per 1000 administrations. Dosage adjustment was required in 15 patients. In five children, immunotherapy was stopped as a precaution - one patient developed rhino-conjunctivitis, two patients developed urticaria, and two children developed wheezing. None of the reactions were due to dosage errors. No anaphylactic reaction or multiple-organ life-threatening events occurred. CONCLUSIONS: The results of our study showed an incidence of mild to moderate unwanted effects of 9.6%, lower than that previously reported, and no life-threatening adverse effects. Nevertheless, asthma, urticaria, and rhinoconjunctivitis can occur. SLIT is quite a safe therapy for the treatment of allergic children with asthma; however, careful evaluation of the single patient is necessary since SLIT is self-administered and a cumulative monthly dose higher than that normally administered as an injection is usually attainable.

Administration, Sublingual↗
PubMed1996

Alternate drug delivery routes for A-71623, a potent cholecystokinin-A receptor agonist tetrapeptide.

A-71623 (BOC-Trp-Lys(epsilon-N-2-methylphenylaminocarbonyl)- Asp-(N-methyl)-Phe-NH2) is a tetrapeptide which has high affinity and selectivity for cholecystokinin receptors; it is a potent appetite suppresser in animal studies. Because of its low (< 1%) oral bioavailability, studies were performed to assess the feasibility of delivery of A-71623 by pulmonary, sublingual, and transdermal routes of administration. The pKa was determined to be 4.2 by spectrophotometric titration; aqueous solubility is increased by increasing pH and by increasing ethanol content. The solubility of A-71623 in ethanol/propellant mixtures was investigated; solubility ranged from 1.0 to 2.5 mg/mL in mixtures of ethanol, propellant 11 (trichlorofluoromethane), and propellant 12 (dichlorodifluoromethane). The log apparent octanol/water partition coefficient was 2.8 at pH 5 and 1.0 at pH 8. Maximum stability at 70 degrees C was seen in the range of pH values of 5.5-7.5; hydrolysis of the N-terminal BOC group appears to be the primary route of degradation. Increasing ethanol content increases the stability; Arrhenius analysis indicated a t90 of 150 days under ambient conditions in 25% ethanol. Intratracheal delivery of 3 mumol/kg A-71623 in 50% ethanol to rats showed rapid and efficient absorption of drug from the lungs, with a Cmax of 2.7 microM and an AUC of 85 microM*min. Similar studies in dogs showed bioavailabilities of 59% and 46% for 2 and 3 mumol/kg intratracheal doses, respectively, relative to intravenous administration. Sublingual administration of 1 mumol/kg A-71623 in a vehicle of 80% ethanol/2% Klucel/2.5% peppermint oil gave high prolonged plasma levels of A-71623, with a Cmax of 0.37 microM, indicating high bioavailability and favorable partitioning and distribution effects from the sublingual cavity for this formulation. Transdermal delivery was examined by in vitro diffusion through human skin; the permeability coefficient of A-71623 in 40% ethanol was 2.6 x 10(-5) cm/hr, suggesting that transdermal delivery of up to 2 mg/day may be feasible. In conclusion, the results provide preliminary indications that delivery of efficacious doses of A-71623, and perhaps other CCK analogs, by alternate routes of delivery is probably feasible.

Administration, Cutaneous↗