Single High Oral Dose Research Articles

Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial

Vitamin D, traditionally linked to bone metabolism, plays pleotropic roles in cellular regulation. In critically ill children, Vitamin D deficiency is associated with adverse outcomes, motivating our open-label Randomized Control Trial. Our aim is to assess short-term outcomes in Vitamin D-deficient critically ill children following a single high oral dose. Conducted at a central Indian tertiary care hospital with a sample size of 100, participants aged 1 month to 18 years will be randomized. Group A receives standard treatment with customary cholecalciferol dosing, while Group B receives standard treatment with a single high oral/nasogastric tube dose (10,000 IU/kg to 400,000 IU) of Vitamin D. Outcomes include PICU stay duration, mechanical ventilation period, occurrences of Ventilator-Associated Pneumonia and Central Line-Associated Blood Stream Infection, instances of Acute Kidney Injury, presence of Multiorgan dysfunction, maximum Vasoactive-Inotrope Score, and mortality rates. Results and interpretation will be guided by study observations. Trial registration: CTRI/2022/10/046556.

Association of Maternal Gestational Vitamin D Supplementation with Respiratory Health of Young Children.

This study aimed to evaluate the association between maternal gestational Vitamin D3 supplementation and early respiratory health in offspring. This was a population-based record-linkage study which used data from the French National Health Database System. Maternal Vitamin D3 supplementation consisted of a single high oral dose of cholecalciferol, (100,000 IU) from the seventh month of pregnancy, according to national guidelines. In total, 125,756 term-born singleton children were included, of which 37% had respiratory illness defined as hospital admission due to respiratory causes or inhalation treatment up to 24 months of age. Infants prenatally exposed to maternal Vitamin D3 supplementation (n = 54,596) were more likely to have a longer gestational age (GA) at birth (GA 36-38 weeks, 22% vs. 20%, p < 0.001 in exposed vs. non-exposed infants, respectively). After adjusting for the main risk factors (maternal age, socioeconomic level, mode of delivery, obstetrical and neonatal pathology, birth weight appropriateness, sex, and birth season), the risk of RD was found to be 3% lower than their counterparts (aOR [IC 95%], 0.97 [0.95-0.99], p = 0.01). In conclusion, this study provides evidence for the association between maternal gestational Vitamin D3 supplementation and improved early respiratory outcomes in young children.

High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial.

The role of oral vitamin D3 supplementation for hospitalized patients with COVID-19 remains to be determined. The study was aimed to evaluate whether vitamin D3 supplementation could prevent respiratory worsening among hospitalized patients with COVID-19. We designed a multicentre, randomized, double-blind, sequential, placebo-controlled clinical trial. The study was conducted in 17 second and third level hospitals, located in four provinces of Argentina, from 14 August 2020 to 22 June 2021. We enrolled 218 adult patients, hospitalized in general wards with SARS-CoV-2 confirmed infection, mild-to-moderate COVID-19 and risk factors for disease progression. Participants were randomized to a single oral dose of 500 000 IU of vitamin D3 or matching placebo. Randomization ratio was 1:1, with permuted blocks and stratified for study site, diabetes and age (≤60 vs >60 years). The primary outcome was the change in the respiratory Sepsis related Organ Failure Assessment score between baseline and the highest value recorded up to day 7. Secondary outcomes included the length of hospital stay; intensive care unit admission; and in-hospital mortality. Overall, 115 participants were assigned to vitamin D3 and 105 to placebo (mean [SD] age, 59.1 [10.7] years; 103 [47.2%] women). There were no significant differences in the primary outcome between groups (median [IQR] 0.0 [0.0-1.0] vs 0.0 [0.0-1.0], for vitamin D3 and placebo, respectively; p = 0.925). Median [IQR] length of hospital stay was not significantly different between vitamin D3 group (6.0 [4.0-9.0] days) and placebo group (6.0 [4.0-10.0] days; p = 0.632). There were no significant differences for intensive care unit admissions (7.8% vs 10.7%; RR 0.73; 95% CI 0.32 to 1.70; p = 0.622), or in-hospital mortality (4.3% vs 1.9%; RR 2.24; 95% CI 0.44 to 11.29; p = 0.451). There were no significant differences in serious adverse events (vitamin D3 = 14.8%, placebo = 11.7%). Among hospitalized patients with mild-to-moderate COVID-19 and risk factors, a single high oral dose of vitamin D3 as compared with placebo, did not prevent the respiratory worsening. ClincicalTrials.gov Identifier: NCT04411446.

Antinociceptive and anti-inflammatory activities of the aqueous leaf extract of&lt;i&gt; Erlangea tomentosa&lt;/i&gt; (Asteraceae) in rats and mice

Erlangea tomentosa (Asteraceae) is used traditionally in the preparation of herbal remedies for management of several diseases including pain and inflammation. However, its efficacy and safety have not been scientifically validated. The aim of this study was to investigate the antinociceptive and anti-inflammatory activities of the aqueous leaf extract of this plant and its acute toxicity profile in animal models. Antinociceptive activity and anti-inflammatory activity were determined using the acetic acid-induced writhing model in mice and carrageenan induced inflammation model in ratsrespectively. The oral median lethal dose (LD50) was determined using the Lorke’s Method. The extract inhibited pain due to acetic acid significantly (p&lt;0.05) at doses of 250 mg/kg and 500 mg/kg. The inflammation due to carrageenan was also significantly (p&lt;0.05) reduced at dose of 500 mg/kg body weight but not 250 mg/Kg. The LD50 value of the extract was greater than 5,000 mg/kg implying that the extract was safe in 24 hours when administered in a single high oral dose. Preliminary phytochemical screening revealed the presence of alkaloids, anthraquinones, coumarins, saponins, tannins and resins. The present study has demonstrated the antinociceptive and anti-inflammatory potential of aqueous leaf extract of Erlangea tomentosa in rats and mice; thus validates the folkloric use of the plant.&#x0D; Keywords: Erlangea tomentosa; Antinociception; Anti-inflammation; Acetic acid; Carrageenan

Oxfendazole kinetics in pigs: In vivo assessment of its pattern of accumulation in Ascaris suum

Ascaris suum is a widespread parasitic nematode that causes infection in pigs with high prevalence rates. Oxfendazole (OFZ) is effective against A. suum when used at a single high oral dose of 30 mg/kg. The aim of this study was to assess the pattern of distribution/accumulation of OFZ and its metabolites, in bloodstream (plasma), mucosal tissue and contents from small and large intestine and adult specimens of A. suum collected from infected and treated pigs. The activity of glutathione-S-transferases (GSTs) in A. suum was also investigated. Infected pigs were orally treated with OFZ (30 mg/kg) and sacrificed at 0, 3, 6 and 12 h after treatment. Samples of blood, mucosa and contents from both small and large intestine as well as adult worms were obtained and processed for quantification of OFZ/metabolites by HPLC. OFZ was the main analyte measured in all of the evaluated matrixes. The highest drug concentrations were determined in small (AUC0-t 718.7 ± 283.5 μg h/g) and large (399.6 ± 110.5 μg h/g) intestinal content. Concentrations ranging from 1.35 to 2.60 μg/g (OFZ) were measured in adult A. suum. GSTs activity was higher after exposure to OFZ both in vivo and ex vivo. The data obtained here suggest that the pattern of OFZ accumulation in A. suum would be more related to the concentration achieved in the fluid and mucosa of the small intestine than in other tissues/fluids. It is expected that increments in the amount of drug attained in the tissues/fluids of parasite location will correlate with increased drug concentration within the target parasite, and therefore with the resultant treatment efficacy. The results are particularly relevant considering the potential of OFZ to be used for soil transmitted helminths (STH) control programs and the advantages of pigs as a model to assess drug treatment to be implemented in humans.

Efficacy of ponazuril in weaned feeder lambs with naturally acquired coccidiosis

Coccidiosis is a common and economically significant parasitic disease that causes diarrhea, weight loss, and death in lambs. Coccidiostats currently labeled in the US for ovine coccidiosis are challenging to administer at effective doses in sick lambs and clinically ineffectual when used late in the disease process. Newer triazinone-class coccidiocidial drugs, such as toltrazuril (Baycox®, Bayer Animal Health) are effective across a greater range of Eimeria's life cycle, resulting in improved clinical response and treatment compliance. Ponazuril (toltrazuril sulfone), an active metabolite of toltrazuril, is labeled in the United States for treatment of equine protozoal myeloencephalitis and is being used extra-label in sheep and goats for treatment of coccidiosis despite a lack of published data regarding its clinical effectiveness in sheep. The objective of this study is to determine the efficacy (fecal oocyst shedding, fecal consistency, and lamb growth performance) of a single low (2.27 mg/lb; 5 mg/kg) or high (9.1 mg/lb; 20 mg/kg) oral dose of ponazuril for treatment of naturally-acquired coccidiosis (Eimeria spp) in commercial feeder lambs.

Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection

Cadazolid is under development as an oral treatment for Clostridium difficile infection (CDI), which is the most common infectious cause of antibiotic-associated diarrhoea. Low systemic cadazolid exposures were previously reported in healthy subjects following both single and multiple oral dosing. The main objective of this study was to investigate systemic cadazolid exposure in patients with severe CDI with potential disrupted lining of the gastrointestinal tract. A single 3000mg oral dose of cadazolid was administered to six patients with microbiologically-confirmed severe CDI. Plasma and faeces were collected up to 144h post-dose for determination of cadazolid concentrations. Safety assessments were conducted over the 144-h investigational period. Cadazolid was well tolerated in patients with severe CDI, with no reported drug-related adverse events. Cadazolid systemic exposure following a single 3000mg oral dose was very low, with a peak plasma concentration (Cmax) of 2.64ng/mL and an area under the concentration–time curve (AUC0–144) of 125ng×h/mL. The median peak daily faecal cadazolid concentration was 5675 times the C. difficile MIC90 of 0.25mg/L. In subjects with severe CDI, cadazolid systemic exposure was very low following a single high oral dose. Cadazolid plasma concentrations were similar in magnitude to those previously reported for healthy subjects, whereas total systemic exposure was ca. 5–6 times higher, but was still low. Peak daily faecal cadazolid concentrations were 5675 times the 0.25mg/L C. difficile MIC90, and on Day 4 five of the six patients presented a daily faecal cadazolid concentration ≥1651 times the MIC90 [ClinicalTrial.gov ID: NCT02053181].

Oxfendazole flukicidal activity in pigs

Although oxfendazole (OFZ) is a well know broad-spectrum benzimidazole anthelmintic, the assessment of its potential trematodicidal activity remains unexplored. OFZ administration at single high doses has been recommended to control Taenia solium cysticercus in pigs. The current study investigated the flukicidal activity obtained after a single high (30mg/kg) oral dose of OFZ in pigs harbouring a natural Fasciola hepatica infection. Sixteen (16) local ecotype pigs were randomly allocated into two (2) experimental groups of 8 animals each named as follow: Untreated control and OFZ treated, in which animals received OFZ (Synanthic®, Merial Ltd., 9.06% suspension) orally at 30mg/kg. At seven (7) days post-treatment, all the animals were sacrificed and direct adult liver fluke counts were performed following the WAAVP guidelines. None of the animals involved in this experiment showed any adverse event during the study. OFZ treatment as a single 30mg/kg oral dose showed a 100% efficacy against F. hepatica. In conclusion, the trial described here demonstrated an excellent OFZ activity against F. hepatica in naturally infected pigs, after its administration at a single oral dose of 30mg/kg.

Single High Oral Dose Amiodarone for Cardioversion of Recent Onset Atrial Fibrillation

Selection of a pharmacological agent and mode of administration for cardioversion is a challenging task in recent onset atrial fibrillation. To report our experience using single high dose oral amiodarone for the cardioversion of recent onset atrial fibrillation to sinus rhythm in patient presenting with symptoms within 48 h. We retrospectively studied 48 patients with recent onset symptomatic atrial fibrillation presenting to the emergency department. These patients were admitted to the cardiology ward and treated with single high oral dose (30 mg/kg) amiodarone. The mean ± SD age of patients was 60.1 ± 4.4 years and 54% were male. Forty-two (90%) of them had symptoms <24h. The common risk factor for atrial fibrillation was hypertension (73%). Of 48 patients, 47 (98%) were chemically cardioverted to sinus rhythm in 6.3 ± 0.8h. The mean pre-treatment heart rate and blood pressure were 154/min and 159.3/88.0 mmHg. The lowest heart rate and blood pressure were 43/min and 122.5/80.9 mmHg respectively. High dose amiodarone was overall well tolerated except in three patients having self-limited gastrointestinal symptoms. Hospital discharge occurred in less than 24h after presentation in all but one patient. Single high dose oral amiodarone is safe and highly effective for patients with recent onset atrial fibrillation eligible for acute chemical cardioversion.

Biotransformation of ethanol to ethyl glucuronide in a rat model after a single high oral dosage

Ethyl glucuronide (EtG) is a minor ethanol metabolite that confirms the absorption and metabolism of ethanol after oral or dermal exposure. Human data suggest that maximum blood EtG (BEtG) concentrations are reached between 3.5 and 5.5h after ethanol administration. This study was undertaken to determine if the Sprague–Dawley (SD) rat biotransforms ethanol to EtG after a single high oral dose of ethanol. SD rats (male, n=6) were gavaged with a single ethanol dose (4g/kg), and urine was collected for 3h in metabolic cages, followed by euthanization and collection of heart blood. Blood and urine were analyzed for ethanol and EtG by gas chromatography and enzyme immunoassay. Blood and urine ethanol concentrations were 195±23 and 218±19mg/dL, whereas BEtG and urine EtG (UEtG) concentrations were 1,363±98ng equivalents/mL and 210±0.29mg equivalents/dL (X¯±standarderrorofthemean[S.E.M.]).Sixty-six male SD rats were gavaged ethanol (4g/kg) and placed in metabolic cages to determine the extent and duration of ethanol to EtG biotransformation and urinary excretion. Blood and urine were collected up to 24h after administration for ethanol and EtG analysis. Maximum blood ethanol, urine ethanol, and UEtG were reached within 4h, whereas maximum BEtG was reached 6h after administration. Maximum concentrations were blood ethanol, 213±20mg/dL; urine ethanol, 308±34mg/dL; BEtG, 2,683±145ng equivalents/mL; UEtG, 1.2±0.06mg equivalents/mL (X¯±S.E.M.). Areas under the concentration–time curve were blood ethanol, 1,578h∗mg/dL; urine ethanol, 3,096h∗mg/dL; BEtG, 18,284h∗ng equivalents/mL; and UEtG, 850h∗mg equivalents/dL. Blood ethanol and BEtG levels were reduced to below limits of detection (LODs) within 12 and 18h after ethanol administration. Urine ethanols were below LOD at 18h, but UEtG was still detectable at 24h after administration. Our data prove that the SD rat biotransforms ethanol to EtG and excretes both in the urine and suggest that it is similar to that of the human.

STEMI Outcomes in Patients Over 80 Years Treated with Primary PCI: Insight from a Large Multicentre Australian Registry

fibrillation to sinus rhythm in patients presenting with symptoms within 48 hours. Method: We retrospectively studied 48 patients with recent onset symptomatic atrial fibrillation presenting to the emergency department. These patients were admitted to the cardiology ward and treated with single high oral dose (30mg/kg) amiodarone. Results: The mean±SD age of patients was 60.1± 4.4 years and 54%weremale. 42 (90%) of themhad symptoms <24 hours. The common risk factor for atrial fibrillation was hypertension (73%). Of 48 patients, forty-seven (98%) were chemically cardioverted to sinus rhythm in 6.3± 0.8 hours. The mean pre-treatment heart rate and blood pressure were 154/min and 159.3/88.0mmHg. The lowest heart rate and blood pressure were 43/min and 122.5/80.9mmHgrespectively.Highdoseamiodaronewas overall well tolerated except in three patients having selflimited gastrointestinal symptoms. There were no serious side effects like torsade de points tachyarrhythmia or symptomatic bradycardia reported. Hospital discharge occurred in less than 24 hours after presentation in all but one patient. Conclusion: Single high dose oral amiodarone is safe and highly effective for patients with recent onset atrial fibrillation eligible for acute chemical cardioversion. doi:10.1016/j.hlc.2011.05.530 Results: In the ≥80 years group, co-morbidities including renal impairment (58.6% vs 20.2%, p< 0.001), history of previous heart failure (6.8% vs 1.4%, p< 0.001) and PVD (6.8% vs 3.5%, p= 0.005) were significantly higher. Mortality (%) Age< 80 years n= 2291 Age≥ 80 years n= 311 p 30-Day 5.9% 15.4% <0.001 12-Month 8.3% 22.0% <0.001 Procedural complications (cardiogenic shock [12.2% vs 8.7%, p= 0.043], stroke [2.9% vs 0.3%] and bleeding [7.1% vs 3.5%]) were also significantly higher. The strongest independent predictors for 30-day mortality were, cardiogenic shock (OR [95%] 10.1 [6.3–16.1]), eGFR<30 (8.1 [3.6–18.2]) and LVEF< 30% (7.4 [3.6–15.4]). Age≥ 80 years (1.6 [0.96–2.8]) was a borderline but not significant predictor. Conclusion: Patients≥80 yearswith STEMI treatedwith primary PCI are a high-risk group for in-hospital complications, short-term and longer-term mortality. However, this may be explained by higher rates of co-morbidities in the ≥80 years group rather than age itself. doi:10.1016/j.hlc.2011.05.531

Single High Oral Dose Amiodarone for Cardioversion of Recent Onset Atrial Fibrillation

Single High Oral Dose Amiodarone for Cardioversion of Recent Onset Atrial Fibrillation

Single high-dose treatment with glucosaminyl-muramyl dipeptide is ineffective in treating ankylosing spondylitis

Earlier studies have shown that high doses of TNF-alpha increase apoptosis in human autoimmune T-cell clones. Based on these studies, a treatment approach was proposed to reduce or eliminate autoimmune T cells in patients with type 1 diabetes using drugs that temporarily elevate TNF levels. Here, we report the treatment of ankylosing spondylitis patient with a single high oral dose of Likopid (glucosaminyl-muramyl dipeptide), which aimed at increasing the levels of TNF-alpha in order to induce apoptosis of autoreactive T cells. The flow cytometric analysis of blood samples collected before and after treatment demonstrated massive elimination of CD8(+) T cells. However, the treatment did not result in any notable therapeutic effect, and real-time PCR analysis demonstrated that stably expanded T-cell clones that were earlier tracked in this patient were unaffected. This report suggests that the controversial approach to eliminate autoimmune T-cell clones through overstimulation is not effective in treating ankylosing spondylitis.

Enhancement of Ovalbumin-induced Antibody Production and Mucosal Mast Cell Response by Mercury

Food contaminants may contribute to the recent increased incidence of food allergies. We have investigated this hypothesis experimentally. It was our objective to determine whether toxicity to the intestinal tissue by orally applied mercury (Hg) could modulate the immune response to food allergens. Effective mechanisms were studied with functional immunological and toxicological parameters. Brown Norway rats were immunized intraperitoneally by ovalbumin (OVA). Before oral challenge with OVA, immunized and non-immunized animals were exposed to HgCl 2. Immunological responses were measured by enzyme-linked immunosorbent assays [anti-OVA-IgE and-IgG, rat mast cell protease II (RMCPII), interferon- γ, interleukin-4, lymphocyte proliferation] and by flow cytometry (lymphocyte subpopulations). Toxicity of Hg to the intestinal barrier was determined by measuring viability, DNA damage and induction of glutathione S-transferase in isolated intestinal epithelial cells and lymph node cells, and by measuring permeability, short-circuit current and tissue conductance of the intact intestinal epithelium. A single high oral dose of HgCl 2 enhanced the serum concentrations of anti-OVA-IgE and IgG ( P<0.05) and of RMCPII ( P<0.05) in immunized rats. The treatment resulted in a higher number of CD4/CD25+ T cells in the lymph nodes ( P<0.05). The multiple application of low HgCl 2 doses (5×0.2 mg/kg body weight) only resulted in an elevated RMCPII serum concentration ( P<0.05). Neither treatment schedules impaired proliferation and cytokine production of lymphocytes. In non-immunized rats only minor immunological changes were observed. Oral HgCl 2 induced genotoxic damage in lymph node cells and in jejunal epithelial cells ( P<0.05). Moreover, HgCl 2 increased the permeability of intestinal epithelial tissue and of Caco-2 monolayers and was genotoxic and cytotoxic to isolated intestinal epithelial cells in vitro. In conclusion, these studies indicate that the food contaminant Hg can stimulate the immune response to OVA in immunized rats. One possible mechanism could be the toxicity of Hg to the intestinal epithelial and the lymph node cells. Whether humans with allergies respond to high oral doses of Hg in a similar way needs to be investigated in further studies.

Evaluation of DNA-Damaging, Clastogenic, and Promoting Activities of Metoclopramide and Procainamide in Rats

The DNA-damaging and clastogenic activities of metoclopramide (MCA) and procainamide (PCA), two substituted benzamides not systematically tested for genotoxicity before clinical use, were investigated in rats given a single high oral dose (500 mg/kg) of these drugs. Neither MCA nor PCA induced DNA fragmentation in liver, kidney, gastric mucosa, spleen, and bone marrow, as detected by the alkaline elution technique. Moreover, neither drug increased the frequency of micronucleated hepatocytes and the frequency of micronucleated polychromatic erythrocytes in the bone marrow of partially hepatectomized rats. However, in rats initiated with N-nitrosodiethylamine and given water containing 0.125% MCA for 14 successive days a clear-cut and statistically significant increase in the number and size of liver gamma-glutamyltranspeptidase-positive foci and basophilic foci, which are consistent with potential promoting activity, was observed. Under the same experimental conditions the effect of PCA was markedly lower, only limited to a modest increase of the number and area of gamma-glutamyltranspeptidase-positive foci.

Serum levels of gastrin, insulin and glucagon as possible factors of anorexia in pigs infected once with Ascaris suum

In order to determine possible mediators for development of anorexia in pigs infected with Ascaris suum, serum levels of gastrin, insulin and glucagon were measured. After a single high oral dose of 100 000–200 000 embryonated eggs the serum levels of gastrin and insulin in the infected pigs did not significantly differ from those in controls. Serum glucagon levels in the infected groups, however, were lower than those in controls and the difference was more evident 24 days post-inoculation and later.

Quantitative thallium-201 single photon emission computed tomography after oral dipyridamole for assessing the presence, anatomic location and severity of coronary artery disease

The objective of this investigation was to determine whether analysis of thalliura-201 images as detected by quantitative single photon emission computed tomography after a single high oral dose of dipyridamole (300 mg) would accurately detect the presence of coronary artery disease and the anatomic location of the individual stenosis. Analyses were performed on 100 patients who concomitantly underwent diagnostic coronary arteriography and myocardial imaging. Tomographic myocardial perfusion defects were quantified using computer-generated polar maps.Eighty-four patients had significant coronary artery disease defined as >50% luminal diameter stenosis. The sensitivity for detecting patients with coronary disease was 92% overall, 89% in patients without previous myocardial infarction and 97% in those with prior infarction. The technique had a sensitivity of 80, 87 and 51% for localizing coronary artery stenosis of the left anterior descending, the right coronary and the left circumflex artery, respectively. The corresponding specificity was 84, 92 and 92%. Furthermore, the presence of severe (≥70%) multivessel disease was identified with a sensitivity of 79% and a specificity of 87%.In conclusion, quantitative thallium-201 single photon emission computed tomography after oral dipyridamole has high sensitivity and specificity for diagnosing the presence of coronary disease, ascertaining the location of stenosed vessels and Identifying the presence of multivessel disease.

Pharmacokinetics of sulphanilamide and its three acetyl metabolites in dairy cows and calves.

An intravenous low dosage of sulphanilamide (SAA) (14.0 mg/kg) to 6 pre-ruminant calves revealed a biphasic SAA plasma disposition with a mean elimination half-life of 4.1 h. The main metabolite in plasma was N4-acetylsulphanilamide (N4), which 4 hours after injection exceeded the parent SAA plasma concentration. Urinary recovery of SAA was 10 to 16% of the dose; of N4, it was at least 69%. Traces of the N1-acetyl (N1) metabolite and the doubly acetylated derivative (N1N4) were present in urine. The renal clearances of the N1 and N4 metabolites showed a tubular secretion pattern, which was at least 2 to 6 times higher than that of SAA. A single high oral SAA dose of 200 mg/kg to 3 dairy cows resulted in extensive metabolism of SAA into N4, N1, and N1N4 metabolites; their mean maximum plasma concentrations were 64, 48, 0.72 and 24 micrograms/ml, respectively. The mean disposition half-life of SAA in plasma and milk was 10 h. In milk the metabolite concentrations exceeded those in plasma; the N4 and N1N4 metabolite concentrations in milk exceeded that of SAA. The mean maximum concentrations of SAA, N4, N1, and N1N4 in milk were 52, 89, 2.3, and 98 micrograms/ml, respectively. For SAA and its metabolites, the binding to plasma and milk proteins was determined. No glucuronide or sulphate conjugates of SAA and its acetyl metabolites could be found in plasma, milk, or urine. Based on the sensitivity of the bioassay (0.2 micrograms SAA/ml), a withholding time of 5 days was suggested for milk following single oral SAA dosage of 200 mg/kg.

Simultaneous determination of tropatepine and its major metabolites by high-performance liquid chromatographic—mass spectrometric identification : Application to metabolic and kinetic studies

Tropatepine is used to combat against extrapyramidal syndrome induced by neuroleptic drugs. A high-performance liquid chromatographic method was proposed for the simultaneous determination of tropatepine and its potential metabolites in biological fluids. After double extraction of compounds in hexane and back-extraction in hydrochloric acid, the chromatographic separation was performed on a reversed-phase column with an acetonitrile—perchlorate buffer mixture as mobile phase. Compounds were detected at 229 nm and the detection limit was about 15 ng/ml. The method was applied to bile and urine samples collected in rats, after a single high oral dose of 100 mg/kg of tropatepine hydrochloride. Gas chromatography—mass spectrometry was used for identification of the potential metabolites. Nortropatepine and tropatepine S-oxide were identified in this way, and it seemed that tropatepine was subjected to a large and intense metabolic process. The analytical procedure and the results of the metabolic investigation were applied to a preliminary pharmacokinetic study in patients undergoing long-term oral therapy with tropatepine.

Effects of a single high oral dose of thyroxine on the pituitary-thyroid-axis.

Ten euthyroid and 9 hypothyroid volunteers were orally administered 2 mg L-thyroxine (T4) to study the interaction between substitutive and suppressive effects of a single high T4 dose. After a significant rise the serum T4 concentration for 5 days in euthyroid and for 11 days in hypothyroid patients an inhibition of basal and of TRH stimulated TSH release was observed. Maximal inhibition of the TSH response in hypothyroid patients occurred 1 to 7 days after the individual T4 peak. This interval was significantly correlated to the extent of the respective T4 rise. In euthyroid subjects TSH response was significantly inhibited for 8, in hypothyroid patients for 22 days. In all but 3 of the euthyroid patients there was a significant inhibition of the thyroidal 132I uptake on day 8. Normalization of thyroidal 132I uptake and of pituitary TSH secretion generally coincided.