Plasma glucose and insulin responses to orally administered simple and complex carbohydrates

We have studied the effects of glucose, sucrose, and various starches on postprandial plasma glucose and insulin responses in 19 subjects. All carbohydrate loads were calculated to contain 50 gm. of glucose, and the response to each carbohydrate was tested twice: when given alone in a drink or when given in combination with other nutrients as a meal. The data demonstrate: (1) Glucose and sucrose elicited similar plasma glucose response curves, but sucrose elicited a somewhat greater (20 per cent) plasma insulin response. (2) Raw starch ingestion resulted in a 44 per cent lower glucose response and a 35-65 per cent lower insulin response than did either glucose or sucrose ingestion. (3) When carbohydrate was given as a meal the plasma glucose responses were 40-60 per cent lower than when the same carbohydrate was given as a drink, while the insulin responses were generally similar, and (4) when different cooked starches were compared, the plasma glucose and insulin responses to rice were significantly lower (50 per cent) than to potato. In conclusion, the size of the carbohydrate molecule appears to influence the postprandial glucose and insulin responses such that more complex carbohydrates (starches) elicit lower responses. This effect may be related to differences in digestion rather than to differences in absorption.     

Study on the developmental toxicity of orally administered isobutylidenediurea in rats

Developmental toxicity of isobutylidenediurea (IBDU) was determined by oral administration to Wistar rats. The substance was administered as an aqueous suspension to 22-24 pregnant rats per group by gavage in daily doses of 100, 400 and 1000 mg/kg body weight from day 6 post-coitum (p.c.) to day 15 p.c. The control group received the vehicle only (0.5% aqueous carboxymethyl cellulose solution). There were no substance-related effects in the dams concerning food consumption, body weight, body weight gain, uterine weights and clinical or autopsy observations even at the highest dose of 1000 mg/kg body weight/day. The reproduction data revealed no biologically relevant differences between the control and treated groups. The incidence and type of the foetal external, soft tissue and skeletal findings, which were classified as malformations, variations and/or retardations observed in the treated foetuses were similar to the concurrent and/or historical control data. Thus, under the conditions of this study, no signs of maternal toxicity or embryo/foetotoxicity were induced by IBDU and the no-observable-adverse-effect level on the maternal and developing organism was 1000 mg/kg body weight/day.     

Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two-period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model-dependent calculation of the first-order absorption rate constant, and a model-independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O-demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50-mg tablet. A standard, medium-fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation.     

Metabolism of 2-ethylhexanoic acid administered orally or dermally to the female Fischer 344 rat

1. Excretion balance studies were conducted with 2-ethylhexanoic acid (EHA) in the female Fischer 344 rat following single high (1 g/kg) or low (0.1 g/kg) oral doses of [2-14C-hexyl]EHA, following repeated oral dosing with unlabelled EHA and a final [14C]EHA oral dose at the low dose level, following dermal exposure with a high (1 g/kg) and low (0.1 g/kg) applied dose of [14C]EHA, and following a 1 mg/kg i.v. dose of [14C]EHA. 2. Oral, i.v. and dermal doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing. 3. After oral dosing of 0.1 g/kg, the mean peak blood level was 85.1 micrograms equivalents EHA/g. Maximum blood concentrations were detected at either 15 or 30 min in individual animals. After dermal application of 0.1 g/kg, the mean peak blood level of 7.9 micrograms equivalents EHA/g was attained at 8 h. 4. Occlusive dermal exposure caused damage to the epidermis in the first 24 h after application and resulted in dermal absorption of 70% relative to i.v. dosing, based on the ratio of percent dose in excreta. 5. Dermal application followed by prompt washing of the skin resulted in recovery of 101.9% from the skin surface and < 0.2% in the excreta. 6. The major urinary metabolites were the glucuronide of EHA, 2-ethyl-1,6-hexanedioic acid (namely 2-ethyladipic acid), 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-6-hydroxyhexanoic acid and ethylketohexanoic acid. Evidence for metabolism via beta-oxidation was also found, consistent with the incorporation of EHA into normal cellular intermediary metabolism.     

Disposition, bioavailability and clinical efficacy of orally administered acepromazine in the horse

The pharmacokinetics and pharmacological efficacy of orally (p.o.) administered acepromazine were studied and compared with the intravenous (i.v.) route of administration in a cross-over study using six horses. The oral kinetics of acepromazine can be described by a two-compartment open model with first-order absorption. The drug was rapidly absorbed after p.o. administration with a half-life of 0.84 h, tmax of 0.4 h and Cmax of 59 ng/ml. The elimination was slower after p.o. administration (half-life 6.04 h) than after i.v. injection (half-life 2.6 h). The bioavailability of the orally administered drug formulation was 55.1%. After p.o. administration of 0.5 mg/kg acepromazine, the parameters of the sedative effect were similar to those obtained after i.v. injection of 0.1 mg/kg. The effect of the drug on blood cell count and haemoglobin content was similar after both p.o. administration and injection, while the effects on the parameters of penile prolapse and on the mean arterial blood pressure were less pronounced after p.o. administration than after injection. After p.o. administration, no significant effects on haematocrit-level as well as on the heart and respiratory rates were observed, while these parameters were significantly affected after injection. It is concluded that the high initial plasma level of the drug after i.v. injection may play a role in producing adverse effects of acepromazine.     

Photochemotherapy of vitiligo. Use of orally administered psoralens and a high-intensity long-wave ultraviolet light system

A new light source that provides high-intensity ultraviolet light (UVA) (300 to 400 nm) to the entire body surface makes orally administered psoralen treatment of vitilligo with an artificial light practical. In the 26 patients studied, the degree of repigmentation with either trioxsalen (TMP) or methoxsalen (8-MOP) and high intensity UVA was at least as great as that with the same oral agents and sunlight. With artificial UVA and similar treatment conditions, the two psoralen derivatives were compared in the treatment of vitiligo; TMP stimulated repigmentation as well as 8-MOP and caused fewer side effects.     

Immune suppression by lysosomotropic amines and cyclosporine on T-cell responses to minor and major histocompatibility antigens: does synergy exist?

BACKGROUND: Using murine models, we have shown that the lysosomotropic amine, chloroquine, is effective in the prevention of graft-versus-host disease (GVHD) mediated by donor T cells reactive with recipient minor histocompatibility antigens (MiHCs). Because lysosomotropic amines can suppress major histocompatibility complex (MHC) class II antigen presentation, their mechanism of action is potentially different from current immune suppressant drugs used to control GVHD such as cyclosporine. METHODS: We investigated the use of cyclosporine and the lysosomotropic amines chloroquine and hydroxychloroquine in combination for additive or synergistic immunosuppression on T-cell responses in vitro to MiHC and MHC in mice. RESULTS: We found that similar concentrations of chloroquine and hydroxychloroquine suppress the T-cell response to MiHC in mice (C57BL/6 anti-BALB.B) and that lysosomotropic amines in combination with cyclosporine result in synergistic suppression of a proliferative response to MiHC. Similar suppression and synergy appear to be present in an alloreactive response (C57BL/6 anti-BALB/c). Direct inhibition by chloroquine of T-cell proliferative responses induced by anti-CD3epsilon in the absence of antigen-presenting cells is present at higher concentrations than that required to suppress responses to MiHC or MHC. Chloroquine appears to induce decreased T-cell viability at high concentrations. This effect does not appear to be due to decreased T-cell production of interleukin-2 or interferon-gamma. At lower concentrations (<25 microg/ml), chloroquine can also decrease the ability of antigen-presenting cells to stimulate an a C57BL/6 anti-BALB/c T-cell response and can inhibit MHC class II expression after activation with lipopolysaccharide. CONCLUSIONS: Lysosomotropic amines in combination with cyclosporine appear to be synergistic in the suppression of T-cell proliferation to MiHC and MHC. Use of chloroquine in combination with cyclosporine may result in improved control of GVHD.     

Effect of orally administered hydrocortisone on the ocular tension in primary open-angle glaucoma subjects. Preliminary report

We studied the possible influence on the pattern of diurnal ocular tension curve by peroral hydrocortisone in 16 eyes of 16 subjects with primary open-angle glaucoma. The baseline diurnal curve was determined by Schiotz tonometry six times daily starting at 10 a.m. and repeated every four hours. The baseline curve showed a significant rise in the daytime with a fall during the night. On another day, 20 mg hydrocortisone was given perorally at 5 p.m., for a repeat 24-h measurement period. A significant rise in ocular tension over the baseline resulted in the following night-time tonometric readings, i.e. at 10 p.m. (P less than 0.01) and 2 a.m. (P less than 0.001). The results seem to strongly indicate that plasma cortico-steroid levels dictate the pattern of diurnal variation of ocular tension.     

Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration

The pharmacokinetics of methylprednisolone and prednisolone were evaluated in 24 healthy men after oral administration of single and multiple doses for 3 days. For each drug, 6 different administration regimens with doses ranging from 1 to 80-mg of methylprednisolone and 1.25 to 100-mg of prednisolone, and administration intervals ranging from 3 to 24 hours for both were investigated. Plasma was assayed using a normal phase high-performance liquid chromatography (HPLC) method. Methylprednisolone showed linear pharmacokinetics with no apparent dose or time dependency. Prednisolone showed marked dose dependency with higher clearance and volume of distribution for higher doses. This can be explained by its saturable protein binding of plasma, because unbound clearance and unbound volume of distribution were not dose-dependent. After multiple administration, prednisolone showed significant time-dependent pharmacokinetics with increased unbound clearance and increased unbound volume of distribution. Due to the complicated pharmacokinetic properties of prednisolone, it is extremely difficult to determine the dose needed to obtain a desired target concentration. The pharmacokinetics of methylprednisolone are more predictable because methylprednisolone concentrations are proportional to dose, and no determination of plasma protein binding is needed.     

Lack of volatilization and escape of orally administered trichloroethylene from the gastrointestinal tract of rats

The sugar residues in glycoconjugates present in the parotid and mandibular glands of the adult fallow-deer were detected and characterized by using a battery of eight different lectin-horseradish peroxidase conjugates. In some cases a treatment with sialidase preceded the lectin staining. Parotid secretory cells produced glycoconjugates with N-acetylgalactosamine, N-acetylglucosamine and mannose residues. Mucous acinar cells were the most reactive sites of the mandibular gland and contained conspicuous quantities of oligosaccharides with terminal sialic acid radicals. Galactosil-(beta 1-->3)N-acetylgalactosamine was the most abundant penultimate sugar linked to N-acetylneuraminic acid. Mandibular mucous cells also presented N-acetylglucosamine and sialylated components with the terminal dimer sialic acid-N-acetylgalactosamine. Demilunar cells contained glycoconjugates with fucose and mannose residues. The apical surface of duct cells was stained by all the lectins.     

Effects of 25-hydroxycholesterol and 7-ketocholesterol, inhibitors of sterol synthesis, administered orally to mice

When 25-hydroxycholesterol or 7-ketocholesterol was fed to mice with the diet, growth was suppressed and mature mice lost weight. The effect of the 7-ketone upon body weight was effectively counteracted by cholesterol whereas cholestanol and beta-sitosterol were ineffective. Growth repression due to 25-hydroxycholesterol was only partially relieved by cholesterol. The effects of 25-hydroxycholesterol and 7-ketocholesterol upon body weight were related to an apparent effect upon appetite. However the sterols were not unpalatable since diets containing them were not rejected in favor of control diet. Intestinal sterol synthesis was inhibited soon after the administration of dietary 7-ketocholesterol or 25-hydroxycholesterol but inhibition decreased with prolonged feeding. When fed by gavage, the sterols suppressed intestinal sterol synthesis as soon as 2 h after administration. In contrast, cholesterol administered by gavage did not affect intestinal sterol synthesis during a 24 h test period. When fed with the diet 25-hydroxycholesterol and 7-ketocholesterol did not depress hepatic cholesterol synthesis beyond the low levels found in pair-fed controls. Inhibition of intestinal sterol synthesis was accompanied by a decrease in the concentration of cholesterol in the intestinal mucosa and, usually, by a drop in the molar ratio of cholesterol to phospholipids.     

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects

OBJECTIVES: To understand the pharmacokinetic and pharmacodynamic properties of recombinant human erythropoietin (epoetin alfa) and to continue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated administration. METHODS: Epoetin alfa was administered as single subcutaneous doses of 300, 450, 600, 900, 1200, 1350, 1800, and 2400 IU/kg and in multiple subcutaneous dose regimens: 150 IU/kg 3 times a week for 4 weeks and 600 IU/kg once per week for 4 weeks in 2 open-label, randomized placebo-controlled studies in healthy volunteers. RESULTS: The absorption rate of epoetin alfa after subcutaneous administration was independent of dose, whereas clearance was dose-dependent in that it decreased with increasing dose. There was a linear relationship between response measured as percentage of reticulocytes area under the curve (AUC) and erythropoietin AUC for single doses up to 1800 IU/kg. Beyond the 1800 IU/kg dose, there was a saturation of response. The mean percentage of reticulocytes after single-dose regimens began to increase by days 3 to 4, reached their maximum at days 8 to 11, and returned to baseline values by day 22. In contrast, the mean percentage of reticulocytes after both multiple-dose regimens were maintained above baseline values through day 22 as both regimens stimulated modest but sustained increases in percentage of reticulocytes (1% to 2%). The mean percentage of reticulocytes AUC for 600 IU/kg epoetin alfa given once a week for 4 weeks was apparently greater than the mean percentage of reticulocytes AUC for 150 IU/kg 3 times a week for 4 weeks. Although daily oral iron supplementation was given, mean serum ferritin levels declined by approximately 75% through day 22 in subjects treated with multiple doses of epoetin alfa. CONCLUSIONS: These findings show that the pharmacologic response to epoetin alfa is a function of dose and dosing regimen. Repeated administration of epoetin alfa was more effective in stimulating a reticulocyte response than single-dose administration of the same total amount of epoetin alfa.     

Nonresponse to hepatitis B vaccines and the kinetics of anti-HBs production

The present paper demonstrates the immunohistochemical distribution of proteoglycan (PG) molecules carrying chondroitin sulfate (CS) chains with 6-sulfated hexosamine residues, or CS and/or dermatan sulfate (DS) chains with 4-sulfated residues in the developing bovine ruminal papillae (RP) using monoclonal antibodies (mAbs) 3B3, 2B6, and MO225. These PGs carrying chondroitin 6-sulfate that were detected by mAb 3B3, and the glucuronic acid 2-sulfate-N-acetyl-galactosamine 6-sulfate unit that was detected by the mAb MO225 were distributed in the mesenchyme and epithelial basement membrane in the rumen, and were thus correlated to the outgrowth of the RP. The PG carrying DS was detected by the mAb 2B6 and was distributed in the lower region of the mesenchyme and intermuscular connective tissue during the development of the RP. These findings suggest that PGs carrying CS chains with 6-sulfation are involved in the outgrowth of the RP, and that PGs carrying DS are involved in organization in the mesenchyme.     

The ontogeny of feeding in rats: I. Ingestive and behavioral responses to oral infusions.

Reports on 3 experiments with Charles River rat pups. When milk infusions were made through oral cannulas in the front of their mouths, 1–20 day old Ss actively ingested the diet, and their intake was related to the length of deprivation. Ss decreased their ingestive responding after they had consumed large volumes of milk. In addition, 1-, 3-, and 6-day-old Ss, when 24-hr deprived, exhibited an intense behavioral activation in response to milk infusion. The behavioral activation appeared to be stimulated primarily by taste and the opportunity to swallow. Milk infusions did not produce activation in older Ss; their behavior was more exclusively ingestive and food directed. Results demonstrate that (a) from birth, rat pups are capable of an active form of ingestion, independent of normal suckling from the mother; (b) such ingestion is controlled by physiological factors; (c) food has arousing properties in young animals; and (d) as pups grow older, their ingestive responding is refined from a generalized and nondirected activation to specific and directed feeding responses. (57 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parameters for the measurement of long-term effects of an orally administered drug in organic and functional circulatory disorders. Preliminary communication

In many cases of drug-induced allergic hepatitis, peripheral lymphocytes were transformed by the stimulation with a given drug in the presence of autologous serum. However, when rat liver microsome fraction of soluble liver specific antigen fraction was added to the culture instead of autologous serum, the drug-induced lymphocyte transformation was more efficiently seen than autologus serum, while rat liver mitochondria fraction was less effective. On the other hand, in the cases of allergic drug eruption which did not show any liver injury, the addition of liver subcellular fractions were much less effective to induce the lymphocyte transformation than autologous serum. These results may suggest that liver subcellular component is involved in pathogenesis of drug-induced allergic hepatitis.     

Value of orally administered retard morphine for therapy of severe pulmonary emphysema of the pink-puffer type. A pilot study

BACKGROUND AND OBJECTIVE: In severe "pink puffer" emphysema the patients' physical capacity is limited by dyspnoea despite maximal application of established treatment. This pilot study investigated the effect of retarded morphine, taken orally for 10 days, on ventilation, dyspnoea, walking capacity and wakefulness. PATIENTS AND METHODS: Twenty clinically stable patients (11 men, 9 women, mean age 68.5 [50-81] years) with "pink puffer" emphysema were studied over a period of 10 days in a prospective, non-controlled trial of cross-over design. Criteria for inclusion in the study were: 1-second forced expiratory volume (FEV1) < 1 I, vital capacity < 50% and normocapnia. In addition to their existing therapy patients received either no further therapy or retarded morphine. Morphine dosage was increased to maximally 3 x 30 mg daily, depending on effectiveness and side effects, dyspnoea at rest and immediately after a 6-min walk (assessed with Borg's visual analog scale), maximal walking capacity were determined, as well as blood gases, respiratory minute volume and the respiratory drive (airway occlusion pressure [P0.1]), responsiveness of the respiratory pathways to CO2 and wakefulness (concentration, fatigue, interest in surroundings). RESULTS: Twelve patients completed the study (group A). In the remaining patients (group B) the test had to be stopped prematurely because of undesirable side effects or an exacerbation of the underlying infection. In group A, morphine (mean dosage: 49.2 +/- 28.4 mg/d) caused a reduction of PaO2, dyspnoea on activity, the resting minute respiratory volume, respiratory drive and CO2 response, and an increase in PaCO2, HCO3- and the 6-min walking distance. Morphine did not produce a change in subjectively evaluated vigilance and the blood pH. CONCLUSION: After strict patient selection oral morphine produced a reduction of exercise dyspnoea and an increase in walking capacity in half of the patients with severe pulmonary emphysema. There also occurred a slight rise in PaCO2 without any relevant respiratory acidosis or significant decrease in wakefulness.     

The effect of orally administered histamine on the weight gain and development of gizzard lesions in chicks

The results of a large scale trial confirmed preliminary findings that the feeding to chicks of a diet containing 4 mg/g of histamine can result in the production of localised lesions in the gizzard and depressed growth rate. This finding supports an earlier suggestion that when dietary fish meal is associated with gizzard erosion the condition is mediated, in part, by the histamine produced by certain types of bacterial spoilage of fish protein.     

Effect of orally administered betel leaf (Piper betle Linn.) on digestive enzymes of pancreas and intestinal mucosa and on bile production in rats

The influence of two varieties of betel leaf (Piper betle Linn.) namely, the pungent Mysore and non-pungent Ambadi, was examined on digestive enzymes of pancreas and intestinal mucosa and on bile secretion in experimental rats. The betel leaves were administered orally at two doses which were either comparable to human consumption level or 5 times this. The results indicated that while these betel leaves do not influence bile secretion and composition, they have a significant stimulatory influence on pancreatic lipase activity. Besides, the Ambadi variety of betel leaf has a positive stimulatory influence on intestinal digestive enzymes, especially lipase, amylase and disaccharidases. A slight lowering in the activity of these intestinal enzymes was seen when Mysore variety of betel leaf was administered, and this variety also had a negative effect on pancreatic amylase. Further, both the betel leaf varieties have shown decreasing influence on pancreatic trypsin and chymotrypsin activities.